Ethics of a therapeutic trial: addressing limitations of an active intervention in optic nerve lymphoma

We report a unique case of optic nerve lymphoma after completion of chemotherapy for non-Hodgkin's lymphoma. The uncommon nature of presentation, our therapeutic dilemma and the further course of treatment are reported. In cases with extremely poor prognosis, unnecessary treatment puts additional strain both financially and psychologically on the patients and their family. Therapeutic focus should be on hospice care and family counselling. The decision to not treat is a crucial component of cancer management; however, the ethics of this decision are yet to be suitably addressed by the literature.

https://ift.tt/2GjlUrZ

Secondary mania following cancer chemotherapy with capecitabine

Mania-like states occurring due to neurological, metabolic or toxic conditions, without a primary mood disorder have been reported in scientific literature as secondary mania. A major clinical problem in such situations often stems from the difficulty to understand if the mood disturbance is indeed secondary to an organic cause or a coincidental primary mood disorder. Chemotherapy regimens have been associated with multiple psychiatric complications, including psychosis, mania and anxiety. Capecitabine is implicated to be associated with encephalopathy whose clinical presentation often mimics that of psychosis. However, presentations with mania have not been reported until with the capecitabine and oxaliplatin combination chemotherapy regimen. In this report, we describe a case of secondary mania in a patient suffering from carcinoma colon on treatment with chemotherapy regimen of capecitabine and oxaliplatin.

https://ift.tt/2GzYhil

Large intra-abdominal seminoma in a left undescended testicle complicated by torsion

A 39-year-old man presented with a 2-day history of worsening constant, dull diffuse lower abdominal pain with associated constipation and known history of left undescended testicle. He was evaluated at an outside hospital where a non-contrasted CT scan revealed a 20 cm well-circumscribed soft tissue mass within the pelvis.

He was referred and further imaging revealed a 12 cm heterogeneous mass with foci of air that appeared to be contiguous with the left spermatic cord. This constellation of findings could represent torsion of undescended left testicle with infarction or underlying malignancy. Tumour markers were only significant for elevated lactate dehydrogenase of 1445. A subsequent ultrasound-guided biopsy of the mass demonstrated seminoma.

Surgical resection revealed a large intra-abdominal mass emanating from the left spermatic cord with 270° of torsion. There appeared to be a left atrophic remnant testicle at the base of the mass with final pathology confirming the diagnosis of classic seminoma.

https://ift.tt/2E3pS6b

Pneumatosis intestinalis in a preterm infant: should we treat all intestinal pneumatosis as necrotising enterocolitis?

Gastric pneumatosisis a very rare site of pneumatosis intestinalis (PI), and we report this finding in a preterm female infant with cyanotic congenital heart disease. The infant was stable initially on nasal intermittent mandatory ventilation; however, torrential pulmonary flow through a large patent ductus arteriosus prompted closure using oral ibuprofen. After an episode of haematochezia, she developed PI, affecting mainly the gastric wall and small intestine with portal venous gas. Her bowel movements were regular, with no abdominal distension or significant gastric aspirates. She was haemodynamically stable with negative infective markers. Management consisted of endotracheal intubation and ventilation, gastric decompression and broad-spectrum antibiotics. Both the gastric and intestinal pneumatosis resolved within 24 hours and she made an uneventful recovery. If PI is not due to necrotising enterocolitis, enteral nutrition can be initiated early and prolonged course of broad-spectrum antibiotics could have been avoided.

https://ift.tt/2GES6tl

Basilic vein haemangioma: an unusual differential diagnosis for cubital fossa mass

Subcutaneous masses along the cubital fossa can be a diagnostic dilemma. Most patients are asymptomatic and usually present for a cosmetic reason. Diagnosis can be confirmed by radiological findings and histopathology. We present a case report of a similar mass that turned out to be a haemangioma arising from the basilic vein with brief review of literature.

https://ift.tt/2Gh7lVN

Salvage therapy post pomalidomide-based regimen in relapsed/refractory myeloma

Abstract

The combination of pomalidomide and low-dose dexamethasone (Pom-Dex) has proved effective and safe in patients with end-stage relapsed/refractory multiple myeloma (RRMM), otherwise characterized by a very poor outcome. MM remains an incurable disease with unavoidable relapses, and the outcome after pomalidomide is still dismal. However, some patients demonstrate prolonged survival even beyond pomalidomide therapy.

We sought to analyze the treatment of RRMM patients following Pom-Dex therapy and the response and survival after this next treatment line.

We studied 134 patients treated with Pom-Dex until progression across two IFM studies. Seventy percent of these patients received further therapy after Pom-Dex. Among the treated patients, one third responded and one third maintained stable disease. The median OS for treated patients was 12 months (6.5;17), with 22 and 12.5% of patients surviving beyond 2 and 3 years, respectively. The factors associated with a better outcome were exposure to a triplet-based regimen containing a novel agent, response to therapy, absence of adverse cytogenetic, and a longer time from diagnosis to post pomalidomide therapy.

This study suggests that patients relapsing after Pom-Dex therapy can still benefit from a further line of treatment. A subset of these treated patients even displayed a prolonged OS, while the prognosis remained very poor without treatment. An active approach could therefore be recommended even in this adverse situation, however guided by the patients' prognosis factors.

https://ift.tt/2pPN6sb

Atypical chronic lymphocytic leukemia presenting with massive IgM paraprotein

https://ift.tt/2GluPt9

Leukemia-propagating cells demonstrate distinctive gene expression profiles compared with other cell fractions from patients with de novo Philadelphia chromosome-positive ALL

Abstract

Relapse remains one of the major obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ALL) even after allogeneic hematopoietic stem cell transplantation. The persistence of leukemia-propagating cells (LPCs) may lead to the recurrence of Ph⁺ALL. Using a xenograft assay, LPCs enrichment in the CD34⁺CD38⁻CD58⁻ fraction in Ph⁺ALL was recently identified. A further cohort study indicated that the LPCs phenotype at diagnosis was an independent risk factor for relapse of Ph⁺ALL. However, little is known about the potential molecular mechanism of LPCs-mediated relapse. Therefore, the gene expression profiles of the sorted LPCs and other cell fractions from patients with de novo Ph⁺ALL were investigated using RNA sequencing (RNA-Seq). Most of the differentially expressed genes between the LPCs and other cell fractions were related to the regulation of the cell cycle and metabolism, as identified by the gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Consistent with the RNA-Seq results, the mRNA levels of cell cycle-related genes, such as cyclin-dependent kinase 4, were significantly lower in the LPCs fraction than in other cell fractions. Moreover, the proportion of quiescent cells in LPCs was significantly higher than in other cell fractions. In summary, distinctive gene expression profiles and clusters, which were mostly related to the regulation of the cell cycle and metabolism, were demonstrated between LPCs and other cell fractions from patients with de novo Ph⁺ALL. Therefore, it would be beneficial to develop novel LPCs-based therapeutic strategies for Ph⁺ALL patients.

https://ift.tt/2IbIXFD

Hydroxyurea responses in clinically varied beta, HbE-beta thalassaemia and sickle cell anaemia patients of Eastern India

Abstract

The haematological and clinical response to hydroxyurea was estimated in HbE-beta, beta thalassaemia and sickle cell anaemia patients of Eastern India, with variable clinical severity and transfusion requirement to determine whether hydroxyurea can help these patients to maintain their steady haemoglobin level without blood transfusions. Three hundred patients (189 HbE-beta thalassaemia, 95 beta thalassaemia and 16 other haemoglobinopathies including sickle cell anaemia) were selected for hydroxyurea therapy and were followed up for 48–60 months. Results suggest significant response to hydroxyurea therapy in 19 beta and 99 HbE-beta patients in the transfusion-dependent group (GR-I). All of them became transfusion-independent while on hydroxyurea therapy. The majority of responding patients were IVS1-5(G-C) in one of their alleles in HbE-beta cases (83 out of 119). Though IVS1-5(G-C) was found to be the commonest mutation in our selected patients, the mutational background of the patients does not found to have any significant correlation with the response category towards hydroxyurea as per the results observed in our study. But, the drug works pretty well in most of the transfusion-dependent patients, as these patients were withdrawn from regular blood transfusion. At the same time, partial or no response to the drug hydroxyurea was also recorded in our study.

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Combined PD-1 and JAK1/2 inhibition in refractory primary mediastinal B-cell lymphoma

https://ift.tt/2pPo5wB

Mesenchymal stem cells transplantation in hematological patients with acute graft-versus-host disease: characteristics and risk factors for infectious complications

Abstract

The role of MSCs in infection prevention and treatment is still discussed in transplant and hematological patients. The spectrum and risk factors for infections after MSCs transplantation in patients with acute GVHD have not been studied before. To determine the risk factors and spectrum of infectious complications in patients received mesenchymal stem cell transplantation as a treatment for acute GVHD. A prospective observational study was performed to evaluate the risk factors and characteristics of infectious complications after MSCs transplantation in adult patients having acute GVHD. Thirty-four episodes of MSCs transplantation in patients with acute GVHD after allogeneic HSCT were enrolled in the study. MSCs were given at a median dose of 1.32 (interquartile range 0.87–2.16) mln cells/kg per infusion at 91 days (interquartile range 31–131 days) after HSCT. Data relating to age, gender, date, and type of transplantation, characteristics of MSCs, infectious agents, and antimicrobial therapy and prevention regimens were prospectively collected in all of the enrolled patients. The episode of proven infectious complication was set as a primary outcome. There were totally 68 patients with acute GVHD in the study; among them there were 34 cases of MSCs transplantation performed. Among the registered infectious episodes were viral infections (CMV-associated disease, EBV-associated disease), invasive pulmonary aspergillosis, bacterial bloodstream infections, and pneumonia. MSCs transplantation has shown no statistically significant association with risk of infectious complications in patients with acute GVHD in a performed multivariate analysis. Among the most frequent infections in acute GVHD, we have described CMV, invasive aspergillosis, and bacterial infections (bloodstream infections or pneumonia). Among risk factors for infectious complications in patients with acute GVHD with/without MSCs transplantation are progression of main disease and neutropenia below 500 cells/mm³ (for aspergillosis) and unrelated HSCT in the past history and progression of main disease (for bacterial bloodstream infections and pneumonia).

https://ift.tt/2pPnZVL

Correction to: A phase I–II study of plerixafor in combination with fludarabine, idarubicin, cytarabine, and G-CSF (PLERIFLAG regimen) for the treatment of patients with the first early-relapsed or refractory acute myeloid leukemia

Abstract

The name of Pau Montesinos was inadvertently presented as Pau Montesinos Fernández in the original article.

The original version of this article was revised: The name of Pau Montesinos was inadvertently presented as Pau Montesinos Fernández.

https://ift.tt/2J4hVBi

Serious concerns on the inability of FDG-PET in excluding residual viable lymphoma

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Internal tandem duplication mutations in the tyrosine kinase domain of FLT3 display a higher oncogenic potential than the activation loop D835Y mutation

Abstract

Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for a large number of leukemia-related deaths. Mutations in FMS-like tyrosine kinase 3 (FLT3) is one of the most prevalent findings in this heterogeneous disease. The major types of mutations in FLT3 can be categorized as internal tandem duplications (ITD) and point mutations. Recent studies suggest that ITDs not only occur in the juxtamembrane region as originally described, but also in the kinase domain. Although the juxtamembrane ITDs have been well characterized, the tyrosine kinase domain ITDs have not yet been thoroughly studied due to their recent discovery. For this reason, we compared ITD mutations in the juxtamembrane domain with those in the tyrosine kinase domain, as well as with the most common activating point mutation in the tyrosine kinase domain, D835Y. The purpose of this study was to understand whether it is the nature of the mutation or the location of the mutation that plays the main role in leukemogenesis. The various FLT3 mutants were expressed in the murine pro-B cell line Ba/F3 and examined for their capacity to form colonies in semisolid medium. The size and number of colonies formed by Ba/F3 cells expressing either the internal tandem duplication within juxtamembrane domain of the receptor (JMD-ITD) or the tyrosine kinase domain (TKD)-ITD were indistinguishable, while Ba/F3 cells expressing D835Y/FLT3 failed to form colonies. Cell proliferation and cell survival was also significantly higher in TKD-ITD expressing cells, compared to cells expressing D835Y/FLT3. Furthermore, TKD-ITD is capable of inducing phosphorylation of STAT5, while D835Y/FLT3 fails to induce tyrosine phosphorylation of STAT5. Other signal transduction pathways such as the RAS/ERK and the PI3K/AKT pathways were activated to the same level in TKD-ITD cells as compared to D835Y/FLT3 expressing cells. Taken together, our data suggest that TKD-ITD displays similar oncogenic potential to the JMD-ITD but a higher oncogenic potential than the D835Y point mutation.

https://ift.tt/2J5zcdp

Polyneuropathy and myopathy in beta-thalassemia major patients

Abstract

The thalassemias are the most common single gene disorder in the world. Nowadays, the average life expectancy of patients in developed countries has increased significantly, while, there was an increase of complications. We aimed to investigate peripheral neuropathy and myopathy in this patient group using a neurophysiological study. We performed nerve conduction studies and electromyography of upper and lower extremities on 36 beta-thalassemia major (β-thal) patients. The electrophysiological findings were correlated with demographic data and laboratory parameters of the disease. Patients with β-thal present polyneuropathy or myopathy at (50%). Polyneuropathy was detected in (38.9%) and myopathy in (27.8%), while polyneuropathy and myopathy were present at (16.7%) with an overlap of the diseases in 1/3 of the patients. There was not a statistically significant correlation of polyneuropathy and myopathy with age, sex, splenectomy, nor with respect to laboratory parameters, hemoglobin, and ferritin. However, there was a statistically significant correlation of polyneuropathy and myopathy with iron overload, as recorded by the magnetic resonance imaging (MRI) of the heart and the liver. Our findings suggest that iron overload plays a key role in the pathogenesis of polyneuropathy and myopathy in β-thal patients, and performing heart and liver MRI for the prediction of such lesions in an annual basis is warranted.

https://ift.tt/2pLdpyS

Sequential development of monoclonal B cell lymphocytosis-derived small lymphocytic lymphoma and plasma cell leukemia

https://ift.tt/2IZIS9k

PI3K/Akt inhibitor LY294002 potentiates homoharringtonine antimyeloma activity in myeloma cells adhered to stromal cells and in SCID mouse xenograft

Abstract

Homoharringtonine (HHT) is a known anti-leukemia drug that inhibits multiple myeloma (MM) cells both in vitro and in vivo. Our prior study demonstrated that the potency of HHT in MM cells was compromised significantly when myeloma cells were co-cultured with BM stromal cells. This study aimed to investigate whether PI3K/Akt inhibitor LY294002 could potentiate the antimyeloma activity of HHT against MM cells adhered to BM stromal cells and in vivo xenograft models. A co-culture system composed of MM cells and human stromal cells was employed to mimic MM cells in bone marrow niche. The inhibitory and pro-apoptotic effect of HHT and LY294002 was determined by CCK-8 assay or flow cytometry. Expression of PI3K/Akt signaling molecules and anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) was assessed by western blot analysis and/or reverse transcription real-time quantitative PCR (RT-qPCR). MM xenografts were used to evaluate antitumor effect of combined therapy with HHT and LY294002. Adhesion to BM stromal cells rendered MM cells resistant to HHT whereas silencing Mcl-1 partly reversed the resistance. LY294002 induced apoptosis in MM cells and potentiated the antimyeloma effects of HHT by inhibiting the PI3K/Akt signal pathway which was abnormally activated during adhesion. LY294002 also enhanced the antimyeloma effect of HHT in in vivo xenograft models. These findings suggest that activation of PI3K/Akt signal pathway was responsible for the resistance to HHT in MM cells adhered to stromal cells. LY294002 can potentiate the antimyeloma activity of HHT both in vitro and in vivo, which may represent a new clinical treatment in MM.

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Relapse of acute promyelocytic leukemia in the external auditory canal confirmed by PML / RARA dual-fusion and RARA break-apart fluorescence in situ hybridization

https://ift.tt/2pPnH17

CD19 targeted CAR-T therapy versus chemotherapy in re-induction treatment of refractory/relapsed acute lymphoblastic leukemia: results of a case-controlled study

Abstract

Chimeric antigen receptor modified T cells against CD19 (CART19s) have potent anti-leukemia activities in patients with refractory/relapsed acute lymphoblastic leukemia (R/R ALL). This study was designed to investigate the correlation between safety/efficacy and therapeutic modalities including chemotherapy and CART19 therapy. Total 23 and 69 patients were enrolled in the CART19 group and in the chemotherapy group, respectively. The safety and efficacy profiles of 66 and 22 patients in the 2 groups were evaluated. The complete remission (CR) rate was higher in the CART19 group than that in the chemotherapy group (90.9 vs 37.9%, P = 0.000). For patients relapsed after allo-HSCT and chemotherapy, CR rates were 100% (8/8) vs 48.0% (12/25) (P = 0.009) and 85.7% (12/14) vs 31.7% (13/41) (P = 0.000), respectively. Moreover, a higher percentage in the CART19 group had results below the threshold for minimal residual disease (100 vs 7.58%, P = 0.000). In survival analysis, the overall survival rate at 12 months was higher in the CART19 group than that in the chemotherapy group (60.9 vs 10.1%, P = 0.000). For post-transplant patients achieving CR, 25.0% (2/8) and 75.0% (9/12) complicated with GVHD (P = 0.04) in the CART19 group and chemotherapy group, respectively. For all CR patients, the median duration of absolute neutrophil count less than 500/μL and platelet count less than 20,000/μL were longer in the CART19 group than in the chemotherapy group (p = 0.0047 and 0.0003, respectively). Our data demonstrated that patients with CART19s therapy acquired higher rates of remission and longer survival, confirming the encouraging application of CART19 therapy in R/R ALL.

https://ift.tt/2J08AdI

Infections associated with ruxolitinib: study in the French Pharmacovigilance database

https://ift.tt/2pSRqpY

The orally available multikinase inhibitor regorafenib (BAY 73-4506) in multiple myeloma

Abstract

A promising approach to the treatment of multiple myeloma (MM) involves agents that target not only the myeloma cells directly, but also the tumor microenvironment which promotes tumor cell growth, angiogenesis, and MM bone disease. Here we investigate the orally available multikinase inhibitor, regorafenib (BAY 73-4506), for its therapeutic efficacy in MM. Regorafenib is a potent inhibitor of angiogenic (VEGFR 1-3, PDGFR-b) as well as oncogenic (c-KIT, RET, FGFR, Raf) kinases. We show that regorafenib induces apoptosis in all MM cell lines at below clinically achievable concentrations. Regorafenib overcomes the growth advantage conferred by a stroma cell MM and an endothelial cell MM, co-culture systems, and abrogates growth factor-stimulated MEK, ERK, and AKT phosphorylation at nanomolar to micromolar concentrations. Moreover, it inhibits endothelial cell growth and tubule formation, abrogates both VEGF secretion and VEGF-induced MM cell migration, inhibits osteoclastogenesis, and shows synergistic cytotoxicity with dexamethasone, the immunomodulatory drug pomalidomide, and the p110δ inhibitor idelalisib. Most importantly, regorafenib significantly delays tumor growth in a xenograft mouse model of human MM. These results provide the rationale for further clinical evaluation of regorafenib, alone and in combination, in the treatment of MM.

https://ift.tt/2J2uSf3

De-escalating treatment in the adjuvant setting in HER2-positive breast cancer

Future Oncology, Ahead of Print.


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The merit of tyrosine kinase inhibitors in the adjuvant setting of high-risk renal cell carcinoma: a meta-analysis

Future Oncology, Ahead of Print.


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De-escalating treatment in the adjuvant setting in HER2-positive breast cancer

Future Oncology, Ahead of Print.


https://ift.tt/2GTLox4

The merit of tyrosine kinase inhibitors in the adjuvant setting of high-risk renal cell carcinoma: a meta-analysis

Future Oncology, Ahead of Print.


https://ift.tt/2IeAvFL

De-escalating treatment in the adjuvant setting in HER2-positive breast cancer

Future Oncology, Ahead of Print.


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The merit of tyrosine kinase inhibitors in the adjuvant setting of high-risk renal cell carcinoma: a meta-analysis

Future Oncology, Ahead of Print.


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Mechanistic Modeling of Antibody-Drug Conjugate Internalization at the Cellular Level Reveals Inefficient Processing Steps

Antibody-drug conjugates (ADC) offer an avenue for specific drug delivery to target cells. Here, parameters with important roles in the cellular processing of ADCs were quantitatively measured for Ab033, an antibody against epidermal growth factor receptor (EGFR). In EGFR-overexpressing cancer cell lines, Ab033 internalized at rates of 0.047 min-1 and 0.15 min-1 for A431 and H441 cells, respectively. Once internalized, Ab033 either trafficked to the lysosome or was recycled; up to 45% of internalized Ab033 returned to the cell surface. Despite such recycling, intracellular accumulation of Ab033 continually increased over 24 hr. Ab033 was conjugated to form a dual toxin ADC containing both cleavable and non-cleavable linker-drug payloads for release rate comparisons. Intracellular concentrations of freed drug from cleavable linker were greater than from non-cleavable linker and exceeded 5x106 drug molecules per A431 cell after 24 hr. Compared to intracellular antibody accumulation, formation of released drug was delayed, likely due to the time needed for endo-lysosomal trafficking and subsequent linker/antibody proteolysis. Informed by the quantitative data, a cellular ADC model was constructed and used to summarize processing inefficiencies. Modeling simulations were conducted to determine parameter sensitivity on intracellular drug concentrations, with rates of EGFR internalization and recycling as well as ADC trafficking found to be the most sensitive towards final intracellular drug concentrations. Overall, this study shows Ab033 ADCs to be a viable strategy for delivery of cytotoxic drugs into tumor cells with subsequent modeling efforts able to highlight key processing steps to be improved for increased drug delivery.

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Gallium Maltolate Disrupts Tumor Iron Metabolism and Retards the Growth of Glioblastoma by Inhibiting Mitochondrial Function and Ribonucleotide Reductase

Gallium, a metal with antineoplastic activity, binds transferrin (Tf) and enters tumor cells via Tf receptor1 (TfR1); it disrupts iron homeostasis leading to cell death. We hypothesized that TfR1 on brain microvascular endothelial cells (BMECs) would facilitate Tf-Ga transport into the brain enabling it to target TfR-bearing glioblastoma. We show that U-87 MG and D54 glioblastoma cell lines and multiple glioblastoma stem cell (GSCs) lines express TfRs and that their growth is inhibited by gallium maltolate (GaM) in vitro. After 24-h of incubation with GaM, cells displayed a loss of mitochondrial reserve capacity followed by a dose-dependent decrease in oxygen consumption and a decrease in the activity of the iron-dependent M2 subunit of ribonucleotide reductase (RRM2). Immunohistochemical staining of rat and human tumor-bearing brains showed that glioblastoma, but not normal glial cells, expressed TfR1 and RRM2 and that glioblastoma expressed greater levels of H- and L-ferritin than normal brain. In an orthotopic U-87 MG glioblastoma xenograft rat model, GaM retarded the growth of brain tumors relative to untreated control (p=0.0159) and reduced tumor mitotic figures (p=0.045). Tumors in GaM-treated animals displayed an upregulation of TfR1 expression relative to control animals thus indicating that gallium produced tumor iron deprivation. GaM also inhibited iron uptake and upregulated TfR1 expression in U-87 MG and D54 cells in vitro. We conclude that GaM enters the brain via TfR1 on BMECs and targets iron metabolism in glioblastoma in vivo, thus inhibiting tumor growth. Further development of novel gallium compounds for brain tumor treatment is warranted.

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Itraconazole-induced inhibition on human esophageal cancer cell growth requires AMPK activation

We here evaluated the anti-esophageal cancer cell activity by the antifungal drug itraconazole. Our results show that μg/mL concentrations of itraconazole potently inhibited survival and proliferation of established (TE-1 and Eca-109) and primary human esophageal cancer cells. Itraconazole activated AMP-activated protein kinase (AMPK) signaling, which was required for subsequent esophageal cancer cell death. Pharmacological AMPK inhibition, AMPKα1 shRNA or dominant negative mutation (T172A) almost completely abolished itraconazole-induced cytotoxicity against esophageal cancer cells. Significantly, itraconazole induced AMPK-dependent autophagic cell death (but not apoptosis) in esophageal cancer cells. Further, AMPK activation by itraconazole induced multiple receptor tyrosine kinases (RTKs: EGFR, PDGFRα and PDGFRβ) lysosomal translocation and degradation to inhibit downstream Akt activation. In vivo, itraconazole oral gavage potently inhibited Eca-109 tumor growth in severe combined immunodeficient (SCID) mice. It was yet ineffective against AMPKα1 shRNA-expressing Eca-109 tumors. The in vivo growth of the primary human esophageal cancer cells was also significantly inhibited by itraconazole administration. AMPK activation, RTKs degradation and Akt inhibition were observed in itraconazole-treated tumors. Together, itraconazole inhibits esophageal cancer cell growth via activating AMPK signaling.

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Analysis of HSP27 and the autophagy marker LC3B+ puncta following preoperative chemotherapy identifies high-risk osteosarcoma patients

Chemotherapy-induced autophagy is a proposed mechanism of chemoresistance and potential therapeutic target in osteosarcoma. We evaluated heat shock protein 27 (HSP27) and autophagy-related proteins as predictors of pathologic treatment response and prognostic markers among osteosarcoma patients who received standard chemotherapy. We analyzed 394 tumor specimens (pre-treatment, post-treatment, and metastases) from 260 osteosarcoma patients by immunohistochemistry for cytoplasmic light chain 3B (LC3B)-positive puncta, sequestosome 1 (SQSTM1), high mobility group box 1 (HMGB1), and HSP27 expression. The staining percentage and intensity for each marker were scored and the extent to which marker expression was correlated with pathologic response, relapse-free survival (RFS), and overall survival (OS) was assessed. LCB3+ puncta in post-treatment primary tumors (50%) and metastases (67%) was significantly higher than in pre-treatment biopsy specimens (30%; p=0.023 and <0.001). Among 215 patients with localized osteosarcoma, both pre-treatment (multivariate hazard ratio [HR]=26.7 [95% confidence interval=1.47-484], p=0.026) and post-treatment HSP27 expression (multivariate HR=1.85 [1.03-3.33], p=0.039) were associated with worse OS. Lack of LC3B+ puncta at resection was an independent poor prognostic marker in both univariate (HR=1.78 [1.05-3.03], p=0.034) and multivariate models (HR=1.75 [1.01-3.04], p=0.045). Patients with LC3B+/HSP27- tumors at resection had the best 10-year OS (75%) whereas patients with LC3B-/HSP27+ tumors had the worst 10-year survival (25%). Neither HSP27 expression nor the presence of LCB3+ puncta was correlated with pathologic treatment response. Our findings establish HSP27 expression and LC3B+ puncta as independent prognostic markers in osteosarcoma patients receiving standard chemotherapy and support further investigation into strategies targeting HSP27 or modulating autophagy in osteosarcoma treatment.

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Nano-engineered mesenchymal stem cells increase therapeutic efficacy of anticancer drug through true active tumor targeting

Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor targeting strategy that relies on engineering mesenchymal stem cells (MSCs) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Further, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano-engineered MSCs resulted in greater than 9-fold higher AUClung of PTX (1.5 µg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 µg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano-engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor specific drug delivery and significantly improved anti-cancer efficacy of conventional chemotherapeutic drugs.

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ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models

Anti-angiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved anti-angiogenic drugs primarily inhibit the vascular endothelial growth factor (VEGF) pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared to either parental antibody treatment alone, due in part to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater anti-tumor response and outperformed anti-VEGF treatment. ABT-165 displayed non-linear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life > 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment-related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel anti-angiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic and safety profiles in pre-clinical models. Given these preclinical attributes, ABT-165 has progressed to a Phase 1 study.

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Trastuzumab resistant HER2+ breast cancer cells retain sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition.

HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2+ breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2+ breast cancer cells to poly (ADP-Ribose) polymerase inhibitors (PARPi), agents that target homologous recombination (HR) deficient tumors, independent of a DNA repair deficiency. In this study, we investigated whether HER2+ trastuzumab resistant (TR) breast cancer cells were susceptible to PARPi and the mechanism behind PARPi induced cytotoxicity. We demonstrate that the PARPi ABT-888 (veliparib) decreased cell survival in-vitro and tumor growth in vivo of HER2+ trastuzumab resistant breast cancer cells. PARP-1 siRNA confirmed that cytotoxicity was due, in part, to PARP-1 inhibition. Furthermore, PARP-1 silencing had variable effects on the expression of several NF-B-regulated genes. In particular, silencing PARP-1 inhibited NF-B activity and reduced p65 binding at the IL-8 promoter, which resulted in a decrease in IL-8 mRNA and protein expression. Our results provide insight in the potential mechanism by which PARPi induces cytotoxicity in HER2+ breast cancer cells and support the testing of PARPi in patients with HER2+ breast cancer resistant to trastuzumab.

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Mechanistic Modeling of Antibody-Drug Conjugate Internalization at the Cellular Level Reveals Inefficient Processing Steps

Antibody-drug conjugates (ADC) offer an avenue for specific drug delivery to target cells. Here, parameters with important roles in the cellular processing of ADCs were quantitatively measured for Ab033, an antibody against epidermal growth factor receptor (EGFR). In EGFR-overexpressing cancer cell lines, Ab033 internalized at rates of 0.047 min-1 and 0.15 min-1 for A431 and H441 cells, respectively. Once internalized, Ab033 either trafficked to the lysosome or was recycled; up to 45% of internalized Ab033 returned to the cell surface. Despite such recycling, intracellular accumulation of Ab033 continually increased over 24 hr. Ab033 was conjugated to form a dual toxin ADC containing both cleavable and non-cleavable linker-drug payloads for release rate comparisons. Intracellular concentrations of freed drug from cleavable linker were greater than from non-cleavable linker and exceeded 5x106 drug molecules per A431 cell after 24 hr. Compared to intracellular antibody accumulation, formation of released drug was delayed, likely due to the time needed for endo-lysosomal trafficking and subsequent linker/antibody proteolysis. Informed by the quantitative data, a cellular ADC model was constructed and used to summarize processing inefficiencies. Modeling simulations were conducted to determine parameter sensitivity on intracellular drug concentrations, with rates of EGFR internalization and recycling as well as ADC trafficking found to be the most sensitive towards final intracellular drug concentrations. Overall, this study shows Ab033 ADCs to be a viable strategy for delivery of cytotoxic drugs into tumor cells with subsequent modeling efforts able to highlight key processing steps to be improved for increased drug delivery.

https://ift.tt/2IcudXe

Nuclear Factor-{kappa}B Promotes Urothelial Tumorigenesis and Cancer Progression via Cooperation with Androgen Receptor Signaling

We investigated the role of NF-B in the development and progression of urothelial cancer as well as cross-talk between NF-B and androgen receptor (AR) signals in urothelial cells. Immunohistochemistry in surgical specimens showed that the expression levels of NF-B/p65 (P=0.015)/phospho-NF-B/p65 (P<0.001) were significantly elevated in bladder tumors, compared with those in non-neoplastic urothelial tissues. The rates of phospho-NF-B/p65 positivity were also significantly higher in high-grade (P=0.015)/muscle-invasive (P=0.033) tumors than in lower grade/non-muscle-invasive tumors. Additionally, patients with phospho-NF-B/p65-positive muscle-invasive bladder cancer had significantly higher risks of disease progression (P<0.001) and cancer-specific mortality (P=0.002). In immortalized human normal urothelial SVHUC cells stably expressing AR, NF-B activators and inhibitors accelerated and prevented, respectively, their neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene. Bladder tumors were identified in 56% (mock), 89% (betulinic acid), and 22% (parthenolide) of N-butyl-N-(4-hydroxybutyl)nitrosamine-treated male C57BL/6 mice at 22 weeks of age. NF-B activators and inhibitors also significantly induced and reduced, respectively, cell proliferation/migration/invasion of AR-positive bladder cancer lines, but not AR-knockdown or AR-negative lines, and their growth in xenograft-bearing mice. In both non-neoplastic and neoplastic urothelial cells, NF-B activators/inhibitors up/down-regulated, respectively, AR expression, whereas AR overexpression was associated with increases in the expression levels of NF-B/p65 and phospho-NF-B/p65. Thus, NF-B appeared to be activated in bladder cancer, which was associated with tumor progression. NF-B activators/inhibitors were also found to modulate tumorigenesis and tumor outgrowth in AR-activated urothelial cells. Accordingly, NF-B inhibition, together with AR inactivation, has the potential of being an effective chemopreventive and/or therapeutic approach for urothelial carcinoma.

https://ift.tt/2pNf9Z8

Gallium Maltolate Disrupts Tumor Iron Metabolism and Retards the Growth of Glioblastoma by Inhibiting Mitochondrial Function and Ribonucleotide Reductase

Gallium, a metal with antineoplastic activity, binds transferrin (Tf) and enters tumor cells via Tf receptor1 (TfR1); it disrupts iron homeostasis leading to cell death. We hypothesized that TfR1 on brain microvascular endothelial cells (BMECs) would facilitate Tf-Ga transport into the brain enabling it to target TfR-bearing glioblastoma. We show that U-87 MG and D54 glioblastoma cell lines and multiple glioblastoma stem cell (GSCs) lines express TfRs and that their growth is inhibited by gallium maltolate (GaM) in vitro. After 24-h of incubation with GaM, cells displayed a loss of mitochondrial reserve capacity followed by a dose-dependent decrease in oxygen consumption and a decrease in the activity of the iron-dependent M2 subunit of ribonucleotide reductase (RRM2). Immunohistochemical staining of rat and human tumor-bearing brains showed that glioblastoma, but not normal glial cells, expressed TfR1 and RRM2 and that glioblastoma expressed greater levels of H- and L-ferritin than normal brain. In an orthotopic U-87 MG glioblastoma xenograft rat model, GaM retarded the growth of brain tumors relative to untreated control (p=0.0159) and reduced tumor mitotic figures (p=0.045). Tumors in GaM-treated animals displayed an upregulation of TfR1 expression relative to control animals thus indicating that gallium produced tumor iron deprivation. GaM also inhibited iron uptake and upregulated TfR1 expression in U-87 MG and D54 cells in vitro. We conclude that GaM enters the brain via TfR1 on BMECs and targets iron metabolism in glioblastoma in vivo, thus inhibiting tumor growth. Further development of novel gallium compounds for brain tumor treatment is warranted.

https://ift.tt/2Glg9dx

Itraconazole-induced inhibition on human esophageal cancer cell growth requires AMPK activation

We here evaluated the anti-esophageal cancer cell activity by the antifungal drug itraconazole. Our results show that μg/mL concentrations of itraconazole potently inhibited survival and proliferation of established (TE-1 and Eca-109) and primary human esophageal cancer cells. Itraconazole activated AMP-activated protein kinase (AMPK) signaling, which was required for subsequent esophageal cancer cell death. Pharmacological AMPK inhibition, AMPKα1 shRNA or dominant negative mutation (T172A) almost completely abolished itraconazole-induced cytotoxicity against esophageal cancer cells. Significantly, itraconazole induced AMPK-dependent autophagic cell death (but not apoptosis) in esophageal cancer cells. Further, AMPK activation by itraconazole induced multiple receptor tyrosine kinases (RTKs: EGFR, PDGFRα and PDGFRβ) lysosomal translocation and degradation to inhibit downstream Akt activation. In vivo, itraconazole oral gavage potently inhibited Eca-109 tumor growth in severe combined immunodeficient (SCID) mice. It was yet ineffective against AMPKα1 shRNA-expressing Eca-109 tumors. The in vivo growth of the primary human esophageal cancer cells was also significantly inhibited by itraconazole administration. AMPK activation, RTKs degradation and Akt inhibition were observed in itraconazole-treated tumors. Together, itraconazole inhibits esophageal cancer cell growth via activating AMPK signaling.

https://ift.tt/2pPvtsk

Analysis of HSP27 and the autophagy marker LC3B+ puncta following preoperative chemotherapy identifies high-risk osteosarcoma patients

Chemotherapy-induced autophagy is a proposed mechanism of chemoresistance and potential therapeutic target in osteosarcoma. We evaluated heat shock protein 27 (HSP27) and autophagy-related proteins as predictors of pathologic treatment response and prognostic markers among osteosarcoma patients who received standard chemotherapy. We analyzed 394 tumor specimens (pre-treatment, post-treatment, and metastases) from 260 osteosarcoma patients by immunohistochemistry for cytoplasmic light chain 3B (LC3B)-positive puncta, sequestosome 1 (SQSTM1), high mobility group box 1 (HMGB1), and HSP27 expression. The staining percentage and intensity for each marker were scored and the extent to which marker expression was correlated with pathologic response, relapse-free survival (RFS), and overall survival (OS) was assessed. LCB3+ puncta in post-treatment primary tumors (50%) and metastases (67%) was significantly higher than in pre-treatment biopsy specimens (30%; p=0.023 and <0.001). Among 215 patients with localized osteosarcoma, both pre-treatment (multivariate hazard ratio [HR]=26.7 [95% confidence interval=1.47-484], p=0.026) and post-treatment HSP27 expression (multivariate HR=1.85 [1.03-3.33], p=0.039) were associated with worse OS. Lack of LC3B+ puncta at resection was an independent poor prognostic marker in both univariate (HR=1.78 [1.05-3.03], p=0.034) and multivariate models (HR=1.75 [1.01-3.04], p=0.045). Patients with LC3B+/HSP27- tumors at resection had the best 10-year OS (75%) whereas patients with LC3B-/HSP27+ tumors had the worst 10-year survival (25%). Neither HSP27 expression nor the presence of LCB3+ puncta was correlated with pathologic treatment response. Our findings establish HSP27 expression and LC3B+ puncta as independent prognostic markers in osteosarcoma patients receiving standard chemotherapy and support further investigation into strategies targeting HSP27 or modulating autophagy in osteosarcoma treatment.

https://ift.tt/2Gmi6X3

Nano-engineered mesenchymal stem cells increase therapeutic efficacy of anticancer drug through true active tumor targeting

Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor targeting strategy that relies on engineering mesenchymal stem cells (MSCs) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Further, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano-engineered MSCs resulted in greater than 9-fold higher AUClung of PTX (1.5 µg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 µg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano-engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor specific drug delivery and significantly improved anti-cancer efficacy of conventional chemotherapeutic drugs.

https://ift.tt/2pNgWgS

ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models

Anti-angiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved anti-angiogenic drugs primarily inhibit the vascular endothelial growth factor (VEGF) pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared to either parental antibody treatment alone, due in part to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater anti-tumor response and outperformed anti-VEGF treatment. ABT-165 displayed non-linear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life > 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment-related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel anti-angiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic and safety profiles in pre-clinical models. Given these preclinical attributes, ABT-165 has progressed to a Phase 1 study.

https://ift.tt/2Gkriey

Trastuzumab resistant HER2+ breast cancer cells retain sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition.

HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2+ breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2+ breast cancer cells to poly (ADP-Ribose) polymerase inhibitors (PARPi), agents that target homologous recombination (HR) deficient tumors, independent of a DNA repair deficiency. In this study, we investigated whether HER2+ trastuzumab resistant (TR) breast cancer cells were susceptible to PARPi and the mechanism behind PARPi induced cytotoxicity. We demonstrate that the PARPi ABT-888 (veliparib) decreased cell survival in-vitro and tumor growth in vivo of HER2+ trastuzumab resistant breast cancer cells. PARP-1 siRNA confirmed that cytotoxicity was due, in part, to PARP-1 inhibition. Furthermore, PARP-1 silencing had variable effects on the expression of several NF-B-regulated genes. In particular, silencing PARP-1 inhibited NF-B activity and reduced p65 binding at the IL-8 promoter, which resulted in a decrease in IL-8 mRNA and protein expression. Our results provide insight in the potential mechanism by which PARPi induces cytotoxicity in HER2+ breast cancer cells and support the testing of PARPi in patients with HER2+ breast cancer resistant to trastuzumab.

https://ift.tt/2pMF2Z1

T-Cell Dysfunction in Glioblastoma: Applying a New Framework

A functional, replete T cell repertoire is an integral component to adequate immune surveillance and to the initiation and maintenance of productive anti-tumor immune responses. Glioblastoma (GBM), however, is particularly adept at sabotaging anti-tumor immunity, eliciting severe T cell dysfunction that is both qualitative and quantitative. Understanding and countering such dysfunction are among the keys to harnessing the otherwise stark potential of anti-cancer immune-based therapies. While T cell dysfunction in GBM is long described, newer immunologic frameworks now exist for re-classifying T cell deficits in a manner that better permits their study and reversal. Herein, we divide and discuss the various T cell deficits elicited by GBM within the context of the five relevant categories - Senescence, Tolerance, Anergy, Exhaustion, and Ignorance. Categorization is appropriately made according to the molecular bases of dysfunction. Likewise, we review the mechanisms by which GBM elicits each mode of T cell dysfunction and discuss the emerging immunotherapeutic strategies designed to overcome them.

https://ift.tt/2Gj5HmA

5-Fluorouracil enhances Protoporphyrin IX accumulation and lesion clearance during photodynamic therapy of actinic keratoses: A mechanism-based clinical trial

PURPOSE: Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used for AK. Empirical reports suggest that combining them can improve the therapeutic response. However, the optimal combined regimen was not clear in terms of proper sequence, timing, and mechanism. This clinical study explored mechanisms of action for neoadjuvantal 5FU and PDT for treatment of AK. EXPERIMENTAL DESIGN: A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days; the other side served as no-pretreatment control. Methylaminolevulinate cream was applied to both sides for 3 h, and PpIX levels measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months post-PDT. RESULTS: PpIX levels were increased 2- to 3-fold in 5FU-pretreated lesions versus controls. Altered expression of heme-synthetic enzymes (CPO and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates (CR) after PDT with or without 5FU pretreatment were 75% vs. 45% at 3 months, and 67% vs. 39% at 6 months, respectively; these differences were statistically significant. CONCLUSIONS: Serial 5FU and PDT improves AK clearance by at least two mechanisms, enhanced photosensitizer accumulation and p53 induction. Because 5FU and PDT are FDA-approved modalities, the combined regimen can be readily employed in clinical practice to reduce AK burden and reduce SCC risk. ClinicalTrials.gov NCT01525329.

https://ift.tt/2GFp78C

T-Cell Dysfunction in Glioblastoma: Applying a New Framework

A functional, replete T cell repertoire is an integral component to adequate immune surveillance and to the initiation and maintenance of productive anti-tumor immune responses. Glioblastoma (GBM), however, is particularly adept at sabotaging anti-tumor immunity, eliciting severe T cell dysfunction that is both qualitative and quantitative. Understanding and countering such dysfunction are among the keys to harnessing the otherwise stark potential of anti-cancer immune-based therapies. While T cell dysfunction in GBM is long described, newer immunologic frameworks now exist for re-classifying T cell deficits in a manner that better permits their study and reversal. Herein, we divide and discuss the various T cell deficits elicited by GBM within the context of the five relevant categories - Senescence, Tolerance, Anergy, Exhaustion, and Ignorance. Categorization is appropriately made according to the molecular bases of dysfunction. Likewise, we review the mechanisms by which GBM elicits each mode of T cell dysfunction and discuss the emerging immunotherapeutic strategies designed to overcome them.

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5-Fluorouracil enhances Protoporphyrin IX accumulation and lesion clearance during photodynamic therapy of actinic keratoses: A mechanism-based clinical trial

PURPOSE: Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used for AK. Empirical reports suggest that combining them can improve the therapeutic response. However, the optimal combined regimen was not clear in terms of proper sequence, timing, and mechanism. This clinical study explored mechanisms of action for neoadjuvantal 5FU and PDT for treatment of AK. EXPERIMENTAL DESIGN: A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days; the other side served as no-pretreatment control. Methylaminolevulinate cream was applied to both sides for 3 h, and PpIX levels measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months post-PDT. RESULTS: PpIX levels were increased 2- to 3-fold in 5FU-pretreated lesions versus controls. Altered expression of heme-synthetic enzymes (CPO and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates (CR) after PDT with or without 5FU pretreatment were 75% vs. 45% at 3 months, and 67% vs. 39% at 6 months, respectively; these differences were statistically significant. CONCLUSIONS: Serial 5FU and PDT improves AK clearance by at least two mechanisms, enhanced photosensitizer accumulation and p53 induction. Because 5FU and PDT are FDA-approved modalities, the combined regimen can be readily employed in clinical practice to reduce AK burden and reduce SCC risk. ClinicalTrials.gov NCT01525329.

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Clinical safety of 3-T brain magnetic resonance imaging in newborns

Abstract

Background

The effects and potential hazards of brain magnetic resonance imaging (MRI) at 3 T in newborns are debated.

Objective

Assess the impact of 3-T MRI in newborns on body temperature and physiological parameters.

Material and methods

Forty-nine newborns, born preterm and at term, underwent 3-T brain MRI at term-corrected age. Rectal and skin temperature, oxygen saturation and heart rate were recorded before, during and after the scan.

Results

A statistically significant increase in skin temperature of 0.6 °C was observed at the end of the MRI scan (P<0.01). There was no significant changes in rectal temperature, heart rate or oxygen saturation.

Conclusion

Core temperature, heart rate and oxygen saturation in newborns were not affected by 3-T brain MR scanning.

https://ift.tt/2IblZOT

Clinical safety of 3-T brain magnetic resonance imaging in newborns

Abstract

Background

The effects and potential hazards of brain magnetic resonance imaging (MRI) at 3 T in newborns are debated.

Objective

Assess the impact of 3-T MRI in newborns on body temperature and physiological parameters.

Material and methods

Forty-nine newborns, born preterm and at term, underwent 3-T brain MRI at term-corrected age. Rectal and skin temperature, oxygen saturation and heart rate were recorded before, during and after the scan.

Results

A statistically significant increase in skin temperature of 0.6 °C was observed at the end of the MRI scan (P<0.01). There was no significant changes in rectal temperature, heart rate or oxygen saturation.

Conclusion

Core temperature, heart rate and oxygen saturation in newborns were not affected by 3-T brain MR scanning.

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Making Breast Tumors Tamoxifen-Sensitive [News in Brief]

Blocking PDGF transforms basal-like tumors into easier-to-treat luminal ones.

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Germline mutations as potential causes of childhood solid tumours: comments on the Norwegian childhood cancer cohort study

Germline mutations as potential causes of childhood solid tumours: comments on the Norwegian childhood cancer cohort study

Germline mutations as potential causes of childhood solid tumours: comments on the Norwegian childhood cancer cohort study, Published online: 29 March 2018; doi:10.1038/s41416-018-0059-0

Germline mutations as potential causes of childhood solid tumours: comments on the Norwegian childhood cancer cohort study

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End-of-life decision-making across cancer types: results from a nationwide retrospective survey among treating physicians

End-of-life decision-making across cancer types: results from a nationwide retrospective survey among treating physicians

End-of-life decision-making across cancer types: results from a nationwide retrospective survey among treating physicians, Published online: 29 March 2018; doi:10.1038/s41416-018-0070-5

End-of-life decision-making across cancer types: results from a nationwide retrospective survey among treating physicians

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Quantitative proteomic profiling of primary cancer-associated fibroblasts in oesophageal adenocarcinoma

Quantitative proteomic profiling of primary cancer-associated fibroblasts in oesophageal adenocarcinoma

Quantitative proteomic profiling of primary cancer-associated fibroblasts in oesophageal adenocarcinoma, Published online: 29 March 2018; doi:10.1038/s41416-018-0042-9

Quantitative proteomic profiling of primary cancer-associated fibroblasts in oesophageal adenocarcinoma

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Germline mutations as potential causes of childhood solid tumours: comments on the Norwegian childhood cancer cohort study

Germline mutations as potential causes of childhood solid tumours: comments on the Norwegian childhood cancer cohort study

Germline mutations as potential causes of childhood solid tumours: comments on the Norwegian childhood cancer cohort study, Published online: 29 March 2018; doi:10.1038/s41416-018-0059-0

Germline mutations as potential causes of childhood solid tumours: comments on the Norwegian childhood cancer cohort study

https://ift.tt/2GTbh0c

End-of-life decision-making across cancer types: results from a nationwide retrospective survey among treating physicians

End-of-life decision-making across cancer types: results from a nationwide retrospective survey among treating physicians

End-of-life decision-making across cancer types: results from a nationwide retrospective survey among treating physicians, Published online: 29 March 2018; doi:10.1038/s41416-018-0070-5

End-of-life decision-making across cancer types: results from a nationwide retrospective survey among treating physicians

https://ift.tt/2E319yW

Quantitative proteomic profiling of primary cancer-associated fibroblasts in oesophageal adenocarcinoma

Quantitative proteomic profiling of primary cancer-associated fibroblasts in oesophageal adenocarcinoma

Quantitative proteomic profiling of primary cancer-associated fibroblasts in oesophageal adenocarcinoma, Published online: 29 March 2018; doi:10.1038/s41416-018-0042-9

Quantitative proteomic profiling of primary cancer-associated fibroblasts in oesophageal adenocarcinoma

https://ift.tt/2GSg0PN

The effect of selection and referral biases for the treatment of localised prostate cancer with surgery or radiation

The effect of selection and referral biases for the treatment of localised prostate cancer with surgery or radiation

The effect of selection and referral biases for the treatment of localised prostate cancer with surgery or radiation, Published online: 29 March 2018; doi:10.1038/s41416-018-0071-4

The effect of selection and referral biases for the treatment of localised prostate cancer with surgery or radiation

https://ift.tt/2GREJnh

Barriers to the recognition of medullary thyroid carcinoma on FNA: Implications relevant to the new American Thyroid Association guidelines

Cancer Cytopathology, EarlyView.


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Northern Italy in the American South: Assessing interobserver reliability within the Milan System for Reporting Salivary Gland Cytopathology

Cancer Cytopathology, EarlyView.


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Northern Italy in the American South: Assessing interobserver reliability within the Milan System for Reporting Salivary Gland Cytopathology

Cancer Cytopathology, EarlyView.


https://ift.tt/2Ibh14H

Minimally invasive versus open pancreatic enucleation. Systematic review and meta‐analysis of surgical outcomes

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2E3soZZ

Hospital volume and short‐term outcomes after cytoreductive nephrectomy

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2GS6k7U

Surgical site infection in immediate breast reconstruction: Does chemotherapy timing make a difference?

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2E3y7iu

Impact of histological subtype on the prognosis of patients undergoing surgery for colon cancer

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2GS6k7K

Should surgery be part of the multimodality treatment for stage IIIB non‐small cell lung cancer?

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2IbrUDz

Duct‐to‐mucosa versus dunking techniques of pancreaticojejunostomy after pancreaticoduodenectomy: Do we need more trials? A systematic review and meta‐analysis with trial sequential analysis

Journal of Surgical Oncology, EarlyView.


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Minimally invasive versus open pancreatic enucleation. Systematic review and meta‐analysis of surgical outcomes

Journal of Surgical Oncology, EarlyView.


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Surgical site infection in immediate breast reconstruction: Does chemotherapy timing make a difference?

Journal of Surgical Oncology, EarlyView.


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Impact of histological subtype on the prognosis of patients undergoing surgery for colon cancer

Journal of Surgical Oncology, EarlyView.


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Should surgery be part of the multimodality treatment for stage IIIB non‐small cell lung cancer?

Journal of Surgical Oncology, EarlyView.


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The prognostic impact of differentiation at the invasive front of biliary tract cancer

Journal of Surgical Oncology, EarlyView.


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Issue Information

International Journal of Cancer, Volume 142, Issue 10, Page 1961-1967, 15 May 2018.


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Issue Information

International Journal of Cancer, Volume 142, Issue 10, Page 2188-2189, 15 May 2018.


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Issue Information

International Journal of Cancer, Volume 142, Issue 10, Page 2188-2189, 15 May 2018.


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Dysplastic megalencephaly phenotype presenting with prenatal high-output cardiac failure

Abstract

Dysplastic megalencephaly, also known as bilateral hemimegalencephaly, is a rare cerebral malformation characterized by bilateral cerebral hemisphere overgrowth and extensive malformation of cortical development. Affected patients present clinically with intractable seizures, severe neurological impairment and global developmental delay. There is a small body of literature reporting megalencephaly's association with neonatal high-output cardiac failure and a lack of literature describing prenatal findings. We report a case of dysplastic megalencephaly presenting with progressive high-output cardiac failure during fetal life. Prenatal and postnatal imaging findings as well as neonatal course are described. A companion case with similar imaging findings will help illustrate the prenatal imaging characteristics of this association. Knowledge of this potential complication related to dysplastic megalencephaly may help guide parental counseling and obstetric management.

https://ift.tt/2GfgMJj

Dysplastic megalencephaly phenotype presenting with prenatal high-output cardiac failure

Abstract

Dysplastic megalencephaly, also known as bilateral hemimegalencephaly, is a rare cerebral malformation characterized by bilateral cerebral hemisphere overgrowth and extensive malformation of cortical development. Affected patients present clinically with intractable seizures, severe neurological impairment and global developmental delay. There is a small body of literature reporting megalencephaly's association with neonatal high-output cardiac failure and a lack of literature describing prenatal findings. We report a case of dysplastic megalencephaly presenting with progressive high-output cardiac failure during fetal life. Prenatal and postnatal imaging findings as well as neonatal course are described. A companion case with similar imaging findings will help illustrate the prenatal imaging characteristics of this association. Knowledge of this potential complication related to dysplastic megalencephaly may help guide parental counseling and obstetric management.

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Prostate‐specific antigen nadir within 12 months as an early surrogate marker of biochemical failure and distant metastasis after low‐dose‐rate brachytherapy or external beam radiotherapy for localized prostate cancer

Cancer Medicine, EarlyView.


https://ift.tt/2E3QAvs

Inhibition of breast cancer cell growth by methyl pyropheophenylchlorin photodynamic therapy is mediated though endoplasmic reticulum stress‐induced autophagy in vitro and vivo

Cancer Medicine, EarlyView.


https://ift.tt/2Gfez0t

A novel rapid quantitative method reveals stathmin‐1 as a promising marker for esophageal squamous cell carcinoma

Cancer Medicine, EarlyView.


https://ift.tt/2E3Qy6O

Attitudes toward early palliative care in cancer patients and caregivers: a Korean nationwide survey

Cancer Medicine, EarlyView.


https://ift.tt/2GfBqsQ

Cancer risk in patients with alopecia areata: a nationwide population‐based matched cohort study

Cancer Medicine, EarlyView.


https://ift.tt/2Ie4rBP

Determination of a radotinib dosage regimen based on dose–response relationships for the treatment of newly diagnosed patients with chronic myeloid leukemia

Cancer Medicine, EarlyView.


https://ift.tt/2Ggq5J1

Prognostic significance of NFIA and NFIB in esophageal squamous carcinoma and esophagogastric junction adenocarcinoma

Cancer Medicine, EarlyView.


https://ift.tt/2IczHBk

The influence of insurance type on stage at presentation, treatment, and survival between Asian American and non‐Hispanic White lung cancer patients

Cancer Medicine, EarlyView.


https://ift.tt/2E3DePI

Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome

Cancer Medicine, EarlyView.


https://ift.tt/2GgCYD5

Functional transcriptomic annotation and protein–protein interaction analysis identify EZH2 and UBE2C as key upregulated proteins in ovarian cancer

Cancer Medicine, EarlyView.


https://ift.tt/2E00PRv

Prognostic significance of the infiltration of CD163+ macrophages combined with CD66b+ neutrophils in gastric cancer

Cancer Medicine, EarlyView.


https://ift.tt/2Ggq5bZ

Epidemiology of multiple myeloma in 17 Latin American countries: an update

Cancer Medicine, EarlyView.


https://ift.tt/2E3D3E2

Cancer risk in patients with alopecia areata: a nationwide population‐based matched cohort study

Cancer Medicine, EarlyView.


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Association of family history and survival in patients with colorectal cancer: a pooled analysis of eight epidemiologic studies

Cancer Medicine, EarlyView.


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Five‐year results of a phase II trial of preoperative 5‐fluorouracil, epirubicin, cyclophosphamide followed by docetaxel with capecitabine (wTX) (with trastuzumab in HER2‐positive patients) for patients with stage II or III breast cancer

Cancer Medicine, EarlyView.


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Prostate‐specific antigen nadir within 12 months as an early surrogate marker of biochemical failure and distant metastasis after low‐dose‐rate brachytherapy or external beam radiotherapy for localized prostate cancer

Cancer Medicine, EarlyView.


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Inhibition of breast cancer cell growth by methyl pyropheophenylchlorin photodynamic therapy is mediated though endoplasmic reticulum stress‐induced autophagy in vitro and vivo

Cancer Medicine, EarlyView.


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A novel rapid quantitative method reveals stathmin‐1 as a promising marker for esophageal squamous cell carcinoma

Cancer Medicine, EarlyView.


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A phase 4 study of nilotinib in Korean patients with Philadelphia chromosome‐positive chronic myeloid leukemia in chronic phase: ENESTKorea

Cancer Medicine, EarlyView.


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Impact of pediatric cancer on family relationships

Cancer Medicine, EarlyView.


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Performance of the UroVysion® FISH assay for the diagnosis of malignant effusions using two cutoff strategies

Cancer Medicine, EarlyView.


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Risk of thyroid cancer in relation to height, weight, and body mass index in Japanese individuals: a population‐based cohort study

Cancer Medicine, EarlyView.


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Functional transcriptomic annotation and protein–protein interaction analysis identify EZH2 and UBE2C as key upregulated proteins in ovarian cancer

Cancer Medicine, EarlyView.


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Prognostic significance of the infiltration of CD163+ macrophages combined with CD66b+ neutrophils in gastric cancer

Cancer Medicine, EarlyView.


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Epidemiology of multiple myeloma in 17 Latin American countries: an update

Cancer Medicine, EarlyView.


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Vulvar field resection

Michael Hoeckel joins The Lancet Oncology to discuss his latest trial on the surgical treatment of vulvar carcinoma based on the theory of ontogenetic cancer fields.

https://ift.tt/2pL6zdw

[Corrections] Correction to Lancet Oncol 2018; 19: 434–36

Curigliano G. Addition of platinum salts to neoadjuvant chemotherapy in triple-negative breast cancer: a new standard of care? Lancet Oncol 2018; 19: 434–36—In this Comment, the bracketed text in the third sentence of the first paragraph should have read, "(168 [53%] of 316 patients vs 49 [31%] of 158 patients, p<0·0001)", and the bracketed text in the fourth sentence of the second paragraph should have read, "(26 [57%] of 46 patients in the paclitaxel plus carboplatin plus veliparib group vs 12 [50%] of 24 in the paclitaxel plus carboplatin group vs nine [41%] of 22 in the paclitaxel alone group)".

https://ift.tt/2E1NPuH

[Correspondence] Genetic testing for young women with breast cancer

Ellen Copson and colleagues1 reported on the effect of carrying a BRCA1 or BRCA2 mutation on survival in a cohort of young women with breast cancer. They did genetic testing on 2733 patients with breast cancer in the Prospective Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort in the UK and found 12% carried a BRCA1 or BRCA2 mutation. At 10 years, survival of BRCA carriers and non-carriers was not significantly different. Copson and colleagues did not find a significant protective effect of bilateral mastectomy on breast cancer death after a mean follow-up of 8·2 years; however, only 21 (6·2%) women with a mutation had a bilateral mastectomy, even though, among carriers, the 10-year cumulative risk of contralateral breast cancer is 30% at 5 years2 and 54 participants were reported to have contralateral breast cancer (which might have been prevented).

https://ift.tt/2pMaIxH

[Corrections] Correction to Lancet Oncol 2017; 18: 1221–37

Lacas B, Bourhis J, Overgaard J, et al. Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis. Lancet Oncol 2017; 18: 1221–37—In this Article, a change has been made to the authorship. Adam S Garden has been replaced by Beth Beadle in the authorship list. Beth Beadle has also been added to the investigator list in the supplementary appendix. These corrections have been made to the online version as of March 28, 2018.

https://ift.tt/2E0UchO

[Corrections] Correction to Lancet Oncol 2018; 19: 510–20

Maio M, Lewis K, Demidov L, et al. Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 2018; 19: 510–20—In the Summary, Findings, in the second sentence, the p value should have read p=0·26. The appendix file has also been updated. These corrections have been made to the online version as of March 28, 2018, and the printed version is correct.

https://ift.tt/2pMPqA5

[Clinical Picture] Periosteal aneurysmal bone cyst

A 29-year-old woman with known type 2 diabetes presented to the musculoskeletal oncology clinic at the McGill University Health Centre (Montreal, QC, Canada) in February, 2015, with complaints of pain and swelling of her left leg for a few months. According to the patient, her swelling had increased in size over a few months before presentation. The pain was confined to the medial aspect of the proximal leg. On examination, she did not have any skin changes, but had a tender palpable mass measuring approximately 8·0 cm.

https://ift.tt/2Glb5Wo

[Correspondence] Genetic testing for young women with breast cancer – Authors' reply

It is clear both from our data and that of Kelly Metcalfe and colleagues that long-term survivors of breast cancer with BRCA mutations will probably benefit from bilateral mastectomy.1,2 However, patients will only benefit from avoiding a future primary breast cancer if they survive their first diagnosis.

https://ift.tt/2pN1Tny

[Series] Chemotherapy medication errors

Although chemotherapy is a well established treatment modality, chemotherapy errors represent a potentially serious risk of patient harm. We reviewed published research from 1980 to 2017 to understand the extent and nature of medication errors in cancer chemotherapy, and to identify effective interventions to help prevent mistakes. Chemotherapy errors occur at a rate of about one to four per 1000 orders, affect at least 1–3% of adult and paediatric oncology patients, and occur at all stages of the medication use process.

https://ift.tt/2E3CiLc

[Editorial] New interventions offer prostate cancer hope

Prostate cancer is one of the most common cancers worldwide, with about 1·1 million cases diagnosed annually. Depending on the stage of disease at diagnosis, prostate cancer can be managed with combinations of active surveillance, surgery, radiotherapy, and androgen-deprivation therapy (ADT). However, some men have aggressive disease, in which rising concentrations of prostate-specific antigen (PSA) herald biochemical relapse and metastatic disease, even after treatment. Currently, no standard treatment is available for these men; however, promising new data from two trials presented at the 2018 ASCO Genitourinary Cancers Symposium (Feb 8–10, 2018, San Francisco, CA, USA) suggest that this situation might be about to change.

https://ift.tt/2pPcZZ9

[Series] Oncology drugs in the crosshairs of pharmaceutical crime

Oncology drugs clearly have become a target for pharmaceutical crime. In 2016, falsified oncology drugs ranked fifth in the most commonly falsified drug category among the reports received by the Pharmaceutical Security Institute. Although the prevalence of illicit oncology drugs in the legal supply chains appears to be small, these drugs are difficult to detect, particularly in clinical practice. Forthcoming countermeasures to detect illicit drugs in high-income countries include compulsory antitampering devices and product verification technology for a risk-based selection of medicines.

https://ift.tt/2E1WSf2

[Comment] The NHS and migrant patients with cancer

In 2017, the National Health Service (NHS) England's National Cancer Programme announced that substantial strides had been made towards the full delivery of the NHS 5-year national cancer strategy, which promises "world-class cancer outcomes" by 2020–21.1 Despite a commitment to improving care, treatment, and support for everyone diagnosed with cancer, access is steadily being restricted for migrant patients with cancer.2,3

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[Perspectives] Slogans and donor pages of cancer centres: do they convey discordant messages?

Slogans are essential to the identity of a brand and help the brand communicate with its audience. Although associated with commercial products, slogans are often used by hospitals and cancer centres as part of a marketing strategy. Cancer centre expenditure on advertising has increased in recent years. Within the small body of scientific literature examining cancer centre advertising, data are scarce on the use of cancer centre slogans.

https://ift.tt/2GiPPAw

[Perspectives] The rise and fall of the wellness warriors

In 2009, Belle Gibson was diagnosed with terminal brain cancer. She only had 4 months left to live. But rather than follow her doctor's advice, Belle bravely rejected the medical establishment and beat her cancer through a rigorous wellness regime of superfoods, natural medicine, and Gerson therapy (coffee enemas, hourly raw juice, and an organic, vegetarian diet). After a few years, she remained healthy and beautiful and had amassed over 200 000 followers on Instagram. She learnt to code and created a wellness app to promote the diet that saved her life, which became one of the flagship apps for Apple's new smart-watch and was awarded the Best New Aussie App for 2013.

https://ift.tt/2pMM400

[Perspectives] Opportunities for improving oncology care

Do you want to see my Fitbit dashboard with my heart rate and number of steps the past week? Can I talk to you on Skype or FaceTime so you can see my rash? Is there a mobile app I can use for exercise or meditation? When Charlotte, aged 56 years, came back for her long-term follow-up visit 2 years after her haematopoietic stem cell transplant for acute myeloid leukaemia, she was delighted that she had passed this major hurdle without a recurrence. She had prepared for her appointment by looking at transplant websites for different problems survivors can have, reading papers on graft versus host disease rash, and making a list of her concerns and questions.

https://ift.tt/2E1WEVe

[Corrections] Correction to Lancet Oncol 2013; 14: 1067–76

Sgroi DC, Sestak I, Cuzick J, et al. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol 2013; 14: 1067–76—In this Article, the 95% CI curves in figure 3, and the graphs on appendix p 7 and p 10, were found to have been calculated using an incorrect statistical method, and as such the width of the CI lines (not the risk curves) needed to be corrected.

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[Series] Medication overuse in oncology: current trends and future implications for patients and society

The high cost of cancer care worldwide is largely attributable to rising drugs prices. Despite their high costs and potential toxic effects, anticancer treatments could be subject to overuse, which is defined as the provision of medical services that are more likely to harm than to benefit a patient. We found 30 studies documenting medication overuse in cancer, which included 16 examples of supportive medication overuse and 17 examples of antineoplastic medication overuse in oncology. Few specific agents have been assessed, and no studies investigated overuse of the most toxic or expensive medications currently used in cancer treatment.

https://ift.tt/2GgA5hp

[Corrections] Correction to Lancet Oncol 2018; 19: 295–309

de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2018; 19: 295–309—In this Article, the Open Access licence has been changed from CC-BY-NC-ND to CC BY. This correction has been made to the online version as of March 28,2018.

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[Comment] Adjuvant therapy in colon cancer: less is more

The results of the SCOT trial reported by Timothy Iveson and colleagues1 in The Lancet Oncology establish a new standard of care in the adjuvant treatment of stage III colon cancer. The investigators showed the non-inferiority of treatment with 3 months of adjuvant chemotherapy versus 6 months of the same treatment in terms of 3 year disease-free survival. These results endorse the adoption of a shorter duration of adjuvant chemotherapy. Patients treated with the shorter duration of therapy had significant reductions in adverse events, including a more than halving in the number of grade 2 or worse sensory neuropathy events.

https://ift.tt/2GltYIG

Peptide Receptor Radionuclide Therapy and the Treatment of Gastroentero-pancreatic Neuroendocrine Tumors: Current Findings and Future Perspectives

Abstract

Purpose and Methods

Patients with inoperable and metastasized neuroendocrine tumors (NETs), particularly those with grades 1 and 2, usually receive treatment with somatostatin analogues (SSAs). Peptide receptor radionuclide therapy (PRRT) has gained momentum over the past two decades in patients who progress on SSAs. 177Lu-DOTATATE is currently the most widely used radiopeptide for PRRT. We reviewed the recent evidence on PRRT and the treatment of gastroentero-pancreatic neuroendocrine tumors (GEP-NETs).

Results

¹⁷⁷Lu-DOTATATE can be used as neoadjuvant treatment in patients with inoperable GEP-NETs, who might be candidate for surgery after treatment and as adjuvant therapy after surgical intervention. Combination treatments of PRRT with chemotherapy or targeted agents as well as combinations of radionuclides in patients with NETs have been explored over the last few years. The majority of patients with NETs experience partial response or have disease stabilization, a small percentage has complete response, while some 30% of patients, however, will have disease progression. The safety and efficacy of retreatment with extra cycles of PRRT as salvage therapy have been evaluated in small retrospective series.

Conclusion

Overall, there is evidence that disease control and quality of life improve significantly after 117Lu PRRT therapy. Clinical trials on this therapy are scarce, and there is a need for further studies to establish proper management guidelines.

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Peptide Receptor Radionuclide Therapy and the Treatment of Gastroentero-pancreatic Neuroendocrine Tumors: Current Findings and Future Perspectives

Abstract

Purpose and Methods

Patients with inoperable and metastasized neuroendocrine tumors (NETs), particularly those with grades 1 and 2, usually receive treatment with somatostatin analogues (SSAs). Peptide receptor radionuclide therapy (PRRT) has gained momentum over the past two decades in patients who progress on SSAs. 177Lu-DOTATATE is currently the most widely used radiopeptide for PRRT. We reviewed the recent evidence on PRRT and the treatment of gastroentero-pancreatic neuroendocrine tumors (GEP-NETs).

Results

¹⁷⁷Lu-DOTATATE can be used as neoadjuvant treatment in patients with inoperable GEP-NETs, who might be candidate for surgery after treatment and as adjuvant therapy after surgical intervention. Combination treatments of PRRT with chemotherapy or targeted agents as well as combinations of radionuclides in patients with NETs have been explored over the last few years. The majority of patients with NETs experience partial response or have disease stabilization, a small percentage has complete response, while some 30% of patients, however, will have disease progression. The safety and efficacy of retreatment with extra cycles of PRRT as salvage therapy have been evaluated in small retrospective series.

Conclusion

Overall, there is evidence that disease control and quality of life improve significantly after 117Lu PRRT therapy. Clinical trials on this therapy are scarce, and there is a need for further studies to establish proper management guidelines.

https://ift.tt/2pSiDJo

Germline mutations as potential causes of childhood solid tumours: comments on the Norwegian childhood cancer cohort study

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Quantitative proteomic profiling of primary cancer-associated fibroblasts in oesophageal adenocarcinoma

https://ift.tt/2GU6tHR

Germline mutations as potential causes of childhood solid tumours: comments on the Norwegian childhood cancer cohort study

https://ift.tt/2Ie6PIV

The effect of selection and referral biases for the treatment of localised prostate cancer with surgery or radiation

https://ift.tt/2Ie6Jkx

Hepatocellular carcinoma is diagnosed at a later stage in alcoholic patients: Results of a prospective, nationwide study

Cancer, EarlyView.


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High frequency of the PNPLA3 rs738409 [G] single‐nucleotide polymorphism in Hmong individuals as a potential basis for a predisposition to chronic liver disease

Cancer, Volume 124, Issue S7, Page 1583-1589, April 1, 2018.


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Time, trust, and transparency: Lessons learned from collecting blood biospecimens for cancer research from the Asian American community

Cancer, Volume 124, Issue S7, Page 1614-1621, April 1, 2018.


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Issue Information

Cancer, Volume 124, Issue S7, Page 1519-1526, April 1, 2018.


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Association of externalizing religious and spiritual beliefs on stage of colon cancer diagnosis among black and white multicenter urban patient populations

Cancer, EarlyView.


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Cancer survival among Alaska Native people

Cancer, EarlyView.


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Duct‐to‐mucosa versus dunking techniques of pancreaticojejunostomy after pancreaticoduodenectomy: Do we need more trials? A systematic review and meta‐analysis with trial sequential analysis

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2GS6koq

Hospital volume and short‐term outcomes after cytoreductive nephrectomy

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2GS6k7U

Surgical site infection in immediate breast reconstruction: Does chemotherapy timing make a difference?

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2E3y7iu

Should surgery be part of the multimodality treatment for stage IIIB non‐small cell lung cancer?

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2IbrUDz

Hepatocellular carcinoma is diagnosed at a later stage in alcoholic patients: Results of a prospective, nationwide study

Cancer, EarlyView.


https://ift.tt/2GiXqTW

Moving toward a true depiction of tobacco behavior among Asian Indians in California: Prevalence and factors associated with cultural smokeless tobacco product use

Cancer, Volume 124, Issue S7, Page 1607-1613, April 1, 2018.


https://ift.tt/2GfvJes

Salvage treatment using carbon ion radiation in patients with locoregionally recurrent nasopharyngeal carcinoma: Initial results

Cancer, EarlyView.


https://ift.tt/2pNWNGJ

Results of a lay health education intervention to increase colorectal cancer screening among Filipino Americans: A cluster randomized controlled trial

Cancer, Volume 124, Issue S7, Page 1535-1542, April 1, 2018.


https://ift.tt/2pPopLz

High frequency of the PNPLA3 rs738409 [G] single‐nucleotide polymorphism in Hmong individuals as a potential basis for a predisposition to chronic liver disease

Cancer, Volume 124, Issue S7, Page 1583-1589, April 1, 2018.


https://ift.tt/2GgtJCT

Increased resource use in men with metastatic prostate cancer does not result in improved survival or quality of care at the end of life

Cancer, EarlyView.


https://ift.tt/2pNIfqI

Colorectal cancer beliefs, knowledge, and screening among Filipino, Hmong, and Korean Americans

Cancer, Volume 124, Issue S7, Page 1552-1559, April 1, 2018.


https://ift.tt/2Gg5rca

Time, trust, and transparency: Lessons learned from collecting blood biospecimens for cancer research from the Asian American community

Cancer, Volume 124, Issue S7, Page 1614-1621, April 1, 2018.


https://ift.tt/2pPom2l

Social–cultural, traditional beliefs, and health system barriers of hepatitis B screening among Hmong Americans: A case study

Cancer, Volume 124, Issue S7, Page 1576-1582, April 1, 2018.


https://ift.tt/2GiXnre

Impact of a smoke‐free–living educational intervention for smokers and household nonsmokers: A randomized trial of Chinese American pairs

Cancer, Volume 124, Issue S7, Page 1590-1598, April 1, 2018.


https://ift.tt/2pPogaZ

Knowledge of colorectal cancer screening guidelines and intention to obtain screening among nonadherent Filipino, Hmong, and Korean Americans

Cancer, Volume 124, Issue S7, Page 1560-1567, April 1, 2018.


https://ift.tt/2GfIPIM

Practice patterns of image guided particle therapy in Europe: A 2016 survey of the European Particle Therapy Network (EPTN)

Image guidance is critical in achieving accurate and precise radiation delivery in particle therapy, even more than in photon therapy. However, equipment, quality assurance procedures and clinical workflows for image-guided particle therapy (IGPT) may vary substantially between centres due to a lack of standardization. A survey was conducted to evaluate the current practice of IGPT in European particle therapy centres.

https://ift.tt/2Id7iev

Is accurate contouring of salivary and swallowing structures necessary to spare them in head and neck VMAT plans?

Current standards for organ-at-risk (OAR) contouring encourage anatomical accuracy which can be resource intensive. Certain OARs may be suitable for alternative delineation strategies. We investigated whether simplified salivary and swallowing structure contouring can still lead to good OAR sparing in automated head and neck cancer (HNC) plans.

https://ift.tt/2pP0ixi

Susceptibility-weighted magnetic resonance imaging of cerebrovascular sequelae after radiotherapy for pediatric brain tumors

Due to sensitive neuroimaging techniques, cerebrovascular complications such as cerebral microbleeds (CMB) and cerebral cavernous malformations (CCM) are increasingly recognized as considerable late effects after treatment for pediatric brain tumor. The aim of this study was to analyze CMB in a cohort of patients after cranial irradiation therapy for medulloblastoma or other pediatric brain tumors using susceptibility-weighted magnetic resonance imaging (SWI).

https://ift.tt/2GigtJW

ESTRO ACROP guidelines for target volume definition in the treatment of locally advanced non-small cell lung cancer

Radiotherapy (RT) plays a major role in the curative treatment of locally advanced non-small cell lung cancer (NSCLC). Therefore, the ACROP committee was asked by the ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)radiotherapy (RT) and adjuvant RT for locally advanced NSCLC. The guidelines given here are a result of the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing procedure within the committee.

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Prospective evaluation of serum IL-16 and risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Abstract

Background

Sexually transmitted infections and chronic inflammation have been associated with an increased risk of prostate cancer. Inflammatory mediators, such as cytokines and free radicals, have been hypothesized to play a role.

Methods

To explore the role of inflammation in prostate cancer risk further, we examined the association between pre-diagnostic serum levels of interleukin-16 (IL-16), an important pleiotropic cytokine, and prostate cancer risk among 932 Caucasian cases and 942 controls and 154 African-American cases and 302 controls in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Serum IL-16 was quantified using enzyme-linked immunoassay. Logistic regression was used to estimate associations between IL-16 and prostate cancer risk, separately by race.

Results

Although no association between IL-16 and prostate cancer overall was observed among Caucasians (p = 0.27), a significantly increased risk of high-grade prostate cancer, defined as Gleason ≥ 7 (p_het = 0.02), was observed with increasing levels of IL-16 (OR_{3rd vs. 1st tertile} = 1.37, 95% CI 1.04–1.81, p_trend = 0.02). We also discovered a significant interaction between IL-16 and history of gonorrhea (p = 0.04). Among Caucasian men with a history of gonorrhea, elevated IL-16 levels were associated with an increased risk of prostate cancer (OR_{3rd vs. 1st tertile} = 3.64, 95% CI 1.14–11.6) but no association was seen among those without a history of gonorrhea (OR_{3rd vs. 1st tertile} = 1.06, 95% CI 0.83–1.34). No associations were observed among African-Americans.

Conclusions

This study found evidence that higher pre-diagnostic IL-16 levels may be associated with increased risk of high-grade disease, supporting inflammation as potential mechanism by which sexually transmitted diseases may increase risk.

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Prospective evaluation of serum IL-16 and risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Abstract

Background

Sexually transmitted infections and chronic inflammation have been associated with an increased risk of prostate cancer. Inflammatory mediators, such as cytokines and free radicals, have been hypothesized to play a role.

Methods

To explore the role of inflammation in prostate cancer risk further, we examined the association between pre-diagnostic serum levels of interleukin-16 (IL-16), an important pleiotropic cytokine, and prostate cancer risk among 932 Caucasian cases and 942 controls and 154 African-American cases and 302 controls in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Serum IL-16 was quantified using enzyme-linked immunoassay. Logistic regression was used to estimate associations between IL-16 and prostate cancer risk, separately by race.

Results

Although no association between IL-16 and prostate cancer overall was observed among Caucasians (p = 0.27), a significantly increased risk of high-grade prostate cancer, defined as Gleason ≥ 7 (p_het = 0.02), was observed with increasing levels of IL-16 (OR_{3rd vs. 1st tertile} = 1.37, 95% CI 1.04–1.81, p_trend = 0.02). We also discovered a significant interaction between IL-16 and history of gonorrhea (p = 0.04). Among Caucasian men with a history of gonorrhea, elevated IL-16 levels were associated with an increased risk of prostate cancer (OR_{3rd vs. 1st tertile} = 3.64, 95% CI 1.14–11.6) but no association was seen among those without a history of gonorrhea (OR_{3rd vs. 1st tertile} = 1.06, 95% CI 0.83–1.34). No associations were observed among African-Americans.

Conclusions

This study found evidence that higher pre-diagnostic IL-16 levels may be associated with increased risk of high-grade disease, supporting inflammation as potential mechanism by which sexually transmitted diseases may increase risk.

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…why remifentanil?

https://ift.tt/2I81fHV

Sensitization of recombinant human tumor necrosis factor-related apoptosis-inducing ligand-resistant malignant melanomas by quercetin

Malignant melanoma is the most commonly diagnosed skin cancer associated with a high rate of metastasis. Low-stage melanoma is easily treated, but metastatic malignant melanoma is an extremely treatment-resistant malignancy with low survival rates. The application of recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) for the treatment of metastatic malignant melanoma holds considerable promise because of its selective proapoptotic activity towards cancer cells and not nontransformed cells. Unfortunately, the clinical utilization of rhTRAIL has been terminated due to the resistance of many cancer cells to undergo apoptosis in response to rhTRAIL. However, rhTRAIL-resistance can be abrogated through the cotreatment with compounds derived from 'Mother Nature' such as quercetin that can modulate cellular components responsible for rhTRAIL-resistance. Here, we show that rhTRAIL-resistant malignant melanomas are sensitized by quercetin. Quercetin action is manifested by the upregulation of rhTRAIL-binding receptors DR4 and DR5 on the surface of cancer cells and by increased rate of the proteasome-mediated degradation of the antiapoptotic protein FLIP. Our data provide for a new efficient and nontoxic treatment of malignant melanoma. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. https://ift.tt/1hexVwJ Present address: Katherine A. Turner: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA Correspondence to Michael Kalafatis, PhD, Department of Chemistry, Cleveland State University, 2351 Euclid Avenue, Science and Research Center SR370, Cleveland, OH 44115, USA Tel: +1 216 687 2460; fax: +1 216 687 9298; e-mail: m.kalafatis@csuohio.edu Received August 8, 2017 Accepted February 20, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Targeted ultrasound and fine-needle aspiration cytology for sentinel node diagnostics in early-stage melanoma: a validation study

Ultrasound-guided fine-needle aspiration cytology (US-FNAC) is used to evaluate the involvement of lymph nodes in various malignant diseases. Its value in detecting sentinel lymph node (SN) metastasis preoperatively in melanoma patients is controversial and is the subject of this study. In this prospective validation study, 91 consecutive patients with melanoma clinical stage I (n=64) and II (n=27) were examined with US-FNAC before SN biopsy from 2012 to 2014 at a tertiary center. All patients underwent lymphoscintigraphy before the US-FNAC. Lymph nodes that showed any of the Berlin morphologic criteria on ultrasonography were examined using FNAC. The median Breslow thickness of the melanomas was 1.22 mm (range: 0.47–11.5 mm). Twenty-two percent of the patients had metastases in their SNs, 90% of which were smaller than 2 mm in largest diameter. The percentages of metastases with a size more than 1 mm were 50 and 29%, respectively, in the true-positive and false-negative US groups. The sensitivity, specificity, positive predictive value, and negative predictive value for overall US examination were 30, 81, 24, and 83%, respectively. None of the FNACs contained conclusive malignant cells. The specificity of the FNAC was 76%. Our results show that US-FNAC was not a useful diagnostic tool in our setting as it did not add significantly to the staging and management of patients with mainly thin cutaneous melanomas, perhaps because of the often small size of the SN metastases. It may be useful in the early diagnosis of lymph node metastases in a subgroup of melanoma patients with larger metastases. Correspondence to Annette H. Chakera, MD, PhD, Department of Plastic Surgery, Herlev University Hospital, Copenhagen, Herlev Ringvej 75, Herlev 2730, Denmark Tel: +45 38 682 838; fax: +45 38 683 955;e-mail: annette.hougaard.chakera@regionh.dk Received November 22, 2017 Accepted February 23, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Radiothérapie des métastases osseuses en France : étude descriptive rétrospective monocentrique

Publication date: Available online 27 March 2018
Source:Cancer/Radiothérapie
Author(s): C. Le Fèvre, D. Antoni, A. Thiéry, A. Keller, P. Truntzer, C. Vigneron, J.-B. Clavier, S. Guihard, M. Pop, C. Schumacher, P. Salze, G. Noël
IntroductionLes métastases osseuses sont source de douleurs et altèrent la qualité de vie des patients. La radiothérapie est un des traitements antalgiques de référence. L'objectif de cette étude était de comparer les pratiques courantes d'un service de radiothérapie français pour le traitement des métastases osseuses non compliquées avec les données de la littérature dans le but d'améliorer et d'optimiser la prise en charge des patients.Matériel et méthodesUne étude rétrospective monocentrique des patients ayant bénéficié d'une irradiation palliative de métastases osseuses non compliquées a été menée.RésultatsQuatre-vingt-onze patients ont bénéficié de 116 radiothérapies de métastases osseuses non compliquées sur la période étudiée, dont 44 hommes (48 %) et 47 femmes (52 %), âgés en moyenne de 63 ans (25–88 ans). Les tumeurs primitives les plus fréquemment retrouvées étaient mammaires (35 %), pulmonaires (16 %) et prostatiques (12 %). Les schémas thérapeutiques utilisés étaient dans 29 % des cas 30Gy en dix fractions, dans 21 % des cas 20Gy en cinq fractions, dans 22 % des cas 8Gy en une séance et dans 28 % des cas 23,31Gy en trois fractions en conditions stéréotaxiques. L'état général du patient (indice de performance selon l'Organisation mondiale de la santé et indice de Karnofsky) (p<0,001), le score de la douleur et la consommation d'antalgiques (p<0,001), son profil oligométastatique (p=0,003) et l'expérience du praticien (p<0,001) étaient des facteurs influençant le choix du schéma d'irradiation. L'âge (p=0,46), le sexe (p=0,14), les traitements anticancéreux en cours (p=0,56), l'hospitalisation concomitante (p=0,14) et la distance entre le centre de radiothérapie et le domicile (p=0,87) n'influençaient pas la décision significativement. En tout, trois cas de compression médullaire et un de fracture post-thérapeutique ont été observés, survenant respectivement entre un et 128jours et 577jours après l'irradiation. Huit pour cent de l'ensemble des métastases irradiées ont été ré-irradiées entre 13 et 434jours. Le taux de ré-irradiation était significativement plus important après un traitement par 8Gy (p=0,02). Le taux de décès était significativement moins important (p<0,001) et la probabilité de survie globale significativement plus importante après radiothérapie stéréotaxique (p<0,001).ConclusionCette étude a montré que la population des patients analysée était comparable aux populations de différentes études. Des facteurs prédictifs de choix du schéma thérapeutique ont été identifiés. Le traitement non fractionné était sous-utilisé, alors que le traitement en conditions stéréotaxiques était de plus en plus prescrit, ce qui montre une évolution dans la prise en charge des patients.PurposeBone metastases cause pain and affect patients' quality of life. Radiation therapy is one of the reference analgesic treatments. The objective of this study was to compare the current practices of a French radiotherapy department for the treatment of uncomplicated bone metastases with data from the literature in order to improve and optimize the management of patients.Material and methodsA retrospective monocentric study of patients who underwent palliative irradiation of uncomplicated bone metastases was performed.ResultsNinety-one patients had 116 treatments of uncomplicated bone metastases between January 2014 and December 2015, including 44 men (48%) and 47 women (52%) with an average age of 63years (25–88years). Primary tumours most commonly found were breast cancer (35%), lung cancer (16%) and prostate cancer (12%). The regimens used were in 29% of cases 30Gy in ten fractions (group 30Gy), in 21% of cases 20Gy in five fractions (group 20Gy), in 22% of cases 8Gy in one fraction (group 8Gy) and in 28% of cases 23.31Gy in three fractions of stereotactic body irradiation (stereotactic group). The general condition of the patient (P<0.001), pain score and analgesic (P<0.001), oligometastatic profile (P=0.003) and practitioner experience (P<0.001) were factors influencing the choice of the regimen irradiation. Age (P=0.46), sex (P=0.14), anticancer treatments (P=0.56), concomitant hospitalization (P=0.14) and the distance between the radiotherapy centre and home (P=0.87) did not influence the decision significantly. A total of three cases of spinal compression and one case of post-therapeutic fracture were observed, occurring between one and 128days and 577days after irradiation, respectively. Eight percent of all irradiated metastases were reirradiated with a delay ranging between 13 and 434days after the first irradiation. The re-irradiation rate was significantly higher after 8Gy (P=0.02). The rate of death was significantly lower in the stereotactic arm (P<0.001) and overall survival was significantly greater in the stereotactic arm (P<0.001).ConclusionThis study showed that patients' analysed was comparable to the population of different studies. Predictive factors for the choice of the treatment regimen were identified. Non-fractionnated therapy was underutilised while stereotactic treatment was increasingly prescribed, showing an evolution in the management of patients.



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