Fellatio-associated erythema of the soft palate: an incidental finding during a routine dental evaluation

Oral lesions can have widely variable aetiology, hence, the importance of a comprehensive history and oral examination. We describe the case of a 47-year-old man who presented with an incidental erythematous lesion of the soft palate. The diagnosis was established during a routine dental examination. We found the lesion to be associated with the practice of fellatio. Oral sex is a very common sexual practice, and as clinicians we should consider it as a potential cause of palatal lesions in our differential diagnosis. This should also raise our suspicion for sexually transmitted diseases in high-risk patients.

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Recurrent meningitis caused by idiopathic cerebrospinal fluid rhinorrhoea from the sphenoid sinus

Description

A 41-year-old woman with 7 days of fever and headache had loss of consciousness 1 day prior to presentation. Despite the absence of trauma or other significant medical history, she had two episodes of meningitis in the previous 6 months. Physical examination showed no nuchal rigidity or abnormal findings on nasal endoscopy. Lumbar puncture showed a cerebrospinal fluid cell count of 750/μl. CT showed a bony defect of the posterior wall of the sphenoid sinus, which was filled with a soft tissue density. MRI showed fluid intensity in the same area (figure 1A, B). The diagnosis was recurrent meningitis due to possible idiopathic cerebrospinal fluid rhinorrhoea. Although a cisternogram is normally recommended, emergency drainage of the sphenoid sinus with antibiotic treatment was prioritised because of her deteriorating condition. With various possible diagnoses, an experienced surgeon operated on the patient. 

Figure 1

A bony defect of...

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Management of placenta percreta in a Jehovahs Witness patient

Placenta percreta is increasing in incidence and is associated with the risk of life-threatening haemorrhage. Patients who do not accept blood products present a unique challenge to obstetrician-gynaecologists. In this case report, we present the case of a 42-year-old pregnant Jehovah's Witness with a complete placenta previa and confirmed percreta at 26 weeks' gestation. Due to her religious beliefs against the use of blood products, she was managed with a stepwise surgical approach which involved caesarean delivery with internal iliac (hypogastric) artery ligation, weekly methotrexate and delayed hysterectomy 6 weeks later. Non-traditional, alternative approaches to the management of abnormal placentation in patients declining blood products warrant exploration.

https://ift.tt/2l5DOpe

Persistent elevation of carcinoembryonic antigen as first presentation of a medullary thyroid carcinoma

Carcinoembryonic antigen (CEA) is still the most widely used tumour marker for gastrointestinal cancer. CEA was originally thought to be a specific marker for colorectal cancer, but it turned out to be a non-specific marker for further studies. CEA levels can be elevated in breast, lung and liver cancers, among others, including medullary thyroid cancer. The authors report a case of a 73-year-old woman who had a right hemicolectomy for an ascending colon adenocarcinoma and showed a persistent elevation in the CEA marker during follow-up. After several imaging tests, recurrence of the colon cancer was not found, but the presence of thyroid nodules had been detected. The diagnosis of a medullary thyroid carcinoma was made after the finding of a high value of calcitonin. The patient had a total thyroidectomy with resection of the central and lateral lymph nodes.

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Bronchogenic cyst infection presenting as pleuropericarditis

Description 

A 17-year-old woman was admitted to the emergency department with a 3-day history of dyspnoea (New York Heart Association Class II) and typical pleuritic pain following a 1-week history of cough and fever. Pneumonia was diagnosed based on a chest X-ray (figure 1A), and amoxicillin–clavulanate treatment was initiated. After 48 hours, the patient developed hypotension and tachycardia. Given hypotension, ongoing fever and rising C reactive protein despite antibiotic treatment, she was referred to the intensive care unit. On admission, an echocardiography was performed. A circumferential pericardial effusion with 14 mm maximum diameter adjacent to the right ventricle was detected, without haemodynamic compromise at the time. Besides, left pleural effusion was evidenced. An ultrasound-guided thoracentesis was conducted. Pleural fluid testing revealed the following findings: white blood cells (WBC) count 11.10⁹/Literwith 90% neutrophils, proteins 38 g/L, pH 7.36, glucose 6.3 mmol/L and lactate dehydrogenase (LDH) 492 IU/L. The culture exhibited no organism,...

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Septic arthritis of the temporomandibular joint leading to an epidural abscess

Septic arthritis of the temporomandibular joint (TMJ) is rare, but patients with this diagnosis are at high risk for significant morbidity. We present a case of a 15-year-old man who presented with increasing trismus for 3 days. He had only minimal discomfort and swelling of the right cheek and temporal region, and pericoronitis of an impacted wisdom tooth was suspected. Under intravenous antibiotics, pain subsided, but trismus and a slight swelling remained. CT scan showed septic arthritis of the TMJ with an abscess formation penetrating into the epidural space. Immediate drainage and craniotomy were performed. Under intravenous antibiotics, the patient made a full recovery. The source of infection remained undetermined. To our knowledge, this is the first reported case of septic arthritis of the TMJ spreading into the epidural space.

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Dentin dysplasia: diagnostic challenges

Dentin dysplasia(DD) is a rare autosomal dominant disorder associated with disturbance of the dentin. While the crowns appear clinically normal, on radiography, the pulp spaces appear partially or completely obliterated, with short blunted roots, and multiple periapical radiolucencies affecting the apparently sound teeth. Clinical signs include spontaneous abscess formation or increased tooth mobility which can lead to exfoliation. DD can therefore have a significant impact on the patient's dentition, and treatment is often challenging. Shields' classification of dentin disorders has been recently criticised for failing to consider differential variations and expressions of these disorders. This paper describes a case of a 23-year-old woman with previously undiagnosed DD, who presented with clinical and histological features belonging to several of these diseases, thus highlighting the potential diagnostic challenges faced with Shields' classification.

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Osteoporosis and malignancy: a dicey combination

Osteoporosis is the most common metabolic bone disorder worldwide, especially in women. Postmenopausal status is the most common risk factor for osteoporosis in elderly women. The operational diagnosis of osteoporosis is usually made with the help of central dual energy X-ray absorptiometry scan. Clinically, osteoporosis is suspected in the background of one or more fractures of the hip, vertebra, proximal humerus or pelvis in the absence of local disease or high-energy trauma. Serious underlying illness can present with vertebral fractures and can be missed if other clues from clinical examination and investigations are overlooked. We report a case emphasising this aspect.

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Primary carnitine deficiency in a 57-year-old patient with recurrent exertional rhabdomyolysis

Rhabdomyolysis is an emergency requiring rapid diagnosis and suitable aetiological treatment. We describe the case of a 57-year-old man with recurrent exertional rhabdomyolysis who was diagnosed with systemic primary carnitine deficiency (SPCD). Clinical examination was normal, creatine kinase levels were elevated, plasma free carnitine concentration was mildly decreased, muscle biopsy demonstrated lipid accumulation, carnitine uptake in cultured fibroblasts was decreased and genetic analysis identified a homozygous pathologic c.1181_1183del in the SLC22A5 gene. Rhabdomyolysis did not recur after treatment with oral L-carnitine was introduced. SPCD is a rare autosomal recessive disorder of carnitine transportation usually manifesting as an infantile (hepatic) or a childhood myopathic (cardiac) condition and rarely affecting adults. Our case indicates that SPCD should be considered in the aetiological evaluation of adult patients with recurrent exertional rhabdomyolysis, even in the absence of myopathy and cardiomyopathy.

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Horseshoe kidney with unilateral single ectopic ureter

The horseshoe kidney (HSK) is not an uncommon entity with an incidence of about 1 in 400 or 0.25% of the general population. It is also more commonly found in men as compared with women in a ratio of 2:1.An increased association of genitourinary anomalies have been found with HSK.Duplication of ureters occurs in 10% of HSKs. However, the association of HSK with single-system ectopic ureter is extremely rare. To our knowledge, no case with similar presentation has been reported in literature. Most cases of HSK with bilateral single ectopic ureters have been described. The aim of this report is to highlight the radiological and surgical findings in a case of HSK with unilateral single ectopic ureter.

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Traumatic corneal perforation with exteriorisation of Ahmed glaucoma valve tube

We report a rare case of traumatic corneal perforation with Ahmed glaucoma valve (AGV) tube. A 5-year-old female child, diagnosed with refractory glaucoma, had undergone AGV implantation, presented with the posterior migration of AGV tube after trauma to the eye. The detailed ocular history, ophthalmic findings, clinical course and surgical management are discussed.

https://ift.tt/2l2D6cg

Metachronous renal Ewing sarcoma/primitive neuroectodermal tumour in a survivor of Burkitt lymphoma

We present a case of a 14-year-old girl who was diagnosed with Burkitt lymphoma in 2014. She was managed with chemotherapy and remained in remission for 3 years. On her surveillance imaging in 2017, a left-sided renal neoplastic mass was incidentally discovered. She underwent nephrectomy and pathology of the resected specimen revealed small cell tumour of the kidney with features favouring renal Ewing sarcoma/primitive neuroectodermal tumour. Molecular genetic analysis by fluorescence in situ hybridisation was performed which showed translocation of 22q12, thereby confirming the diagnosis. This is a rare secondary malignancy and an unusual association. This case highlights the importance and diagnostic dilemmas of rare secondary tumours in patients with such haematological malignancies and discusses its possible pathogenetic aspects.

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Actinium-225 for Targeted α Therapy: Coordination Chemistry and Current Chelation Approaches

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


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Cancer-associated fibroblasts promote gastric tumorigenesis through EphA2 activation in a ligand-independent manner

Abstract

Purpose

Under physiologic conditions, the binding of erythropoietin-producing hepatocellular (Eph) A2 receptor and its ligand ephrinA1 results in decreased EphA2 level and tumor suppression. However, EphA2 and ephrinA1 are highly expressed in human cancers including gastric adenocarcinoma. In this study, we tested our hypothesis that cancer-associated fibroblasts (CAFs) promote gastric tumorigenesis through EphA2 signaling in a ligand-independent manner.

Methods

Expression of EphA2 protein in primary tumor tissues of 91 patients who underwent curative surgery for gastric adenocarcinoma was evaluated by immunohistochemistry and western blotting. Conditioned medium of cancer-associated fibroblasts (CAF-CM) was used to evaluate the tumorigenic effect of CAFs on gastric cancer cell lines. Epithelial–mesenchymal transition (EMT), cell proliferation, migration, and invasion were assessed. EphrinA1-Fc ligand was used to determine the suppressor role of EphA2 receptor-ligand binding.

Results

CAF-CM-induced EMT and promoted cancer cell motility even without cell–cell interaction. Treatment with a selective EphA2 inhibitor (ALW-II-41-27) or EphA2-targeted siRNA markedly reduced CAF-CM-induced gastric tumorigenesis. EphrinA1-Fc ligand treatment showing ligand-dependent tumor suppression diminished the EphA2 expression and EMT progression. In contrast, ephrinA1-targeted siRNA did not significantly affect CAF-CM-mediated increases in EphA2 expression and EMT progression. Treatment with VEGF showed effects like CAF-CM in terms of EphA2 activation and EMT progression.

Conclusion

CAFs may contribute to gastric tumorigenesis by activating EphA2 signaling pathway in a ligand-independent manner. Our results suggest that ligand-independent activation of EphA2 was triggered by VEGF released from CAF-CM. Our result may partially explain why ligand-dependent tumor suppressor roles of EphA2 are not evident in gastric cancer despite the prominent level of ephrinA1.

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Diagnosis of Richter transformation in chronic lymphocytic leukemia: histology tips the scales

Abstract

Development of diffuse large B-cell lymphoma in chronic lymphocytic leukemia, so-called Richter transformation (RT), occurs in 2–5% of patients and is associated with poor outcome. The clinical features of RT are fairly non-specific and unable to discriminate transformation from other mimics. In case of clinically suspected RT, a CT/MRT is recommended, and FDG-PET/CT may help to select the site of biopsy. Radiological features suggestive of RT have been defined, but there are only limited data about their predictive value, and histological confirmation is still considered the gold standard for RT diagnosis. We retrospectively analyzed 34 patients with clinically suspected RT and available radiological and histological data. A histopathological diagnosis of RT with concordant clinical and radiological findings was obtained in 13 patients. In 18 patients, CT did not show features of transformation, concordant with lack of RT in the biopsy. Of interest, a distinct lymphoma other than DLBCL was identified in two of these cases. A false-positive radiological diagnosis of RT was rendered in two patients, including a case of Herpes simplex virus lymphadenitis. In conclusion, our findings confirm the central role of tissue biopsy in the diagnostic work up in case of clinically suspected RT.

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Androgen receptor in triple negative breast cancer: A potential target for the targetless subtype

Publication date: Available online 11 June 2018
Source:Cancer Treatment Reviews
Author(s): L. Gerratana, D. Basile, G. Buono, S. De Placido, M. Giuliano, S. Minichillo, A. Coinu, F. Martorana, I. De Santo, L. Del Mastro, M. De Laurentiis, F. Puglisi, G. Arpino
Triple negative breast cancer (TNBC) represents the 15-20% of all breast cancers (BC) and is characterized by a very aggressive behavior. Recent data suggest that TNBC is not a single disease, but it is rather an umbrella for different ontology-profiles such as basal like 1 and 2, mesenchymal, and the luminal androgen receptor (LAR). The LAR subtype is characterized by the expression of the Androgen Receptor (AR) and its downstream effects. Notwithstanding the role of the AR in several signaling pathways, its impact on a biological and clinical standpoint is still controversial. The LAR subtype has been associated with better prognosis, less chemotherapy responsiveness and lower pathologic complete response after neoadjuvant treatment. Clinical evidence suggests a role for anti-androgen therapies such as bicalutamide, enzalutamide and abiraterone, offering an interesting chemo-free alternative for chemo-unresponsive patients, and therefore potentially shifting current treatment strategies.



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Fallopian Tube Tumorigenesis and Clinical Implications for Ovarian Cancer Risk-Reduction

Publication date: Available online 11 June 2018
Source:Cancer Treatment Reviews
Author(s): Allison Gockley, Kevin M. Elias
Ovarian cancer remains the leading cause of gynecologic cancer death among American women. Prevention is the only proven approach to reduce the incidence of the disease. Oral contraception, tubal ligation, and risk-reducing salpingo-oophorectomy (rrBSO) for high-risk groups are all established risk reduction strategies. This paradigm is changing as recent biologic studies suggest that many ovarian cancers, especially high-grade serous ovarian cancers, originate in the distal end of the fallopian tube rather than the ovarian surface epithelium. A putative precursor lesion has been identified called the serous tubal intraepithelial carcinoma (STIC). Theoretically, removal of the fallopian tubes alone may prevent these lesions and prevent overt disease. Opportunistic salpingectomy during benign gynecologic surgery appears to be safe and may offer some protection from ovarian cancer without compromising ovarian endocrine function. Despite a lack of evidence for efficacy, several professional societies now recommend this approach for average-risk women. Whether salpingectomy can also serve as a temporizing measure to delay risk-reducing oophorectomy in women with a genetic predisposition to ovarian cancer remains to be seen. Several ongoing non-randomized clinical trials will test the feasibility of this approach. Therefore, the societal impact of increasing salpingectomy rates on ovarian cancer incidence will be an area of intense focus for the next 10-20 years.



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Intra vs Inter Cross-Resistance Determines Treatment Sequence between Taxane and AR-Targeting Therapies in Advanced Prostate Cancer

Current treatments for castration resistant prostate cancer (CRPC) largely fall into two major classes; AR-targeted therapies such as the next-generation anti-androgen therapies (NGATs), enzalutamide and abiraterone, and taxanes such as docetaxel and cabazitaxel. Despite improvements in outcomes, patients still succumb to the disease due to the development of resistance. Further complicating the situation is lack of a well-defined treatment sequence and potential for cross-resistance between therapies. We have developed several models representing CRPC with acquired therapeutic resistance. Here, we utilized these models to assess putative cross-resistance between treatments. We find that resistance to enzalutamide induces resistance to abiraterone and vice versa but resistance to neither alters sensitivity to taxanes. Acquired resistance to docetaxel induces cross-resistance to cabazitaxel but not to enzalutamide or abiraterone. Correlating responses with known mechanisms of resistance indicates that androgen receptor (AR) variants are associated with resistance to NGATs while the membrane efflux protein ABCB1 is associated with taxane resistance. Mechanistic studies show that AR variant-7 (AR-v7) is involved in NGAT resistance but not resistance to taxanes. Our findings suggest the existence of intra cross-resistance within a drug class (i.e., within NGATs or within taxanes), while inter cross-resistance between drug classes does not develop. Furthermore, our data suggests resistance mechanisms differ between drug classes. These results may have clinical implications by showing that treatments of one class can be sequenced with those of another, but caution should be taken when sequencing similar classed drugs. Additionally, the development and use of biomarkers indicating resistance will improve patient stratification for treatment.

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Intratumoral delivery of an adenoviral vector carrying the SOCS-1 gene enhances T cell-mediated anti-tumor immunity by suppressing PD-L1

Ovarian cancer (OvCa) is the leading cause of gynecological cancer-related deaths and novel therapeutic strategies are required. Programmed cell death 1 and programmed cell death ligand 1 (PD-L1), which are key mediators of host immune tolerance, are associated with OvCa progression. Recent evidence indicates the importance of IFN--induced PD-L1 for immune tolerance in OvCa. This study aimed to reveal the therapeutic potential of suppressor of cytokine signaling 1 (SOCS-1), an endogenous inhibitor of the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, for the treatment of OvCa. Immunohistochemical assessment revealed that OvCa patients with high intratumoral STAT1 activation exhibited poor prognosis compared with patients with low STAT1 activation (P < 0.05). Stimulation of OVISE, OVTOKO, OV2944-HM-1 (HM-1) and CT26 cell lines with IFN- induced STAT1 phosphorylation and PD-L1 expression. Adenovirus-mediated SOCS-1 gene delivery (AdSOCS-1) in HM-1 and CT26 cells in vitro potently inhibited IFN--induced STAT1 phosphorylation and PD-L1 upregulation, similar to the addition of JAK inhibitor I, but failed to inhibit their proliferation. Notably, intratumoral injection of AdSOCS-1, but not AdLacZ, significantly inhibited the tumor growth of HM-1 and CT26 cells subcutaneously transplanted in immunocompetent syngeneic mice. AdSOCS-1 reduced PD-L1 expression on tumors and restored the activation of tumor-infiltrating CD8 T cells. Moreover, the anti-tumor effect of AdSOCS-1 was significantly attenuated by PD-L1 Fc-fusion protein administration in vivo, suggesting that the effect of AdSOCS-1 is mainly attributable to enhancement of tumor immunity. This study highlights the potential clinical utility of SOCS-1 as an immune checkpoint inhibitor.

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The ATR inhibitor AZD6738 synergizes with gemcitabine in vitro and in vivo to induce pancreatic ductal adenocarcinoma regression

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers and overall survival rates have barely improved over the past five decades. The antimetabolite gemcitabine remains part of the standard-of-care, but shows very limited anti-tumor efficacy. Ataxia telangiectasia and Rad3-related protein (ATR), the apical kinase of the intra-S-phase DNA damage response (DDR), plays a central role in safeguarding cells from replication stress (RS) and can therefore limit the efficacy of antimetabolite drug therapies. We investigated the ability of the ATR inhibitor, AZD6738, to prevent the gemcitabine-induced intra-S-phase checkpoint activation and evaluated the anti-tumor potential of this combination in vitro and in vivo. In PDAC cell lines, AZD6738 inhibited gemcitabine-induced Chk1 activation, prevented cell cycle arrest and restrained RRM2 accumulation, leading to the strong induction of replication stress markers only with the combination. Moreover, synergistic growth inhibition was identified in a panel of 5 mouse and 7 human PDAC cell lines using both Bliss Independence and Loewe models. In clonogenic assays, the combination abrogated survival at concentrations for which single agents had minor effects. In vivo, AZD6738 in combination with gemcitabine was well tolerated and induced tumor regression in a subcutaneous allograft model of a KrasG12D; Trp53R172H; Pdx-Cre (KPC) mouse cancer cell line, significantly extending survival. Remarkably, the combination also induced regression of a subgroup of KPC autochthonous tumors, which generally do not respond well to conventional chemotherapy. Altogether, our data suggest that AZD6738 in combination with gemcitabine merits evaluation in a clinical trial in patients with PDAC.

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AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells

Aldo-keto reductase 1C3 (AKR1C3) also known as type 5 17 β-hydroxysteroid dehydrogenase is responsible for intratumoral androgen biosynthesis, contributing to the development of castration-resistant prostate cancer (CRPC) and eventual chemotherapeutic failure. Significant upregulation of AKR1C3 is observed in CRPC patient samples and derived CRPC cell lines. As AKR1C3 is a downstream steroidogenic enzyme synthesizing intratumoral testosterone (T) and 5α-dihydrotestosterone (DHT), the enzyme represents a promising therapeutic target to manage CRPC and combat the emergence of resistance to clinically employed androgen deprivation therapy. Herein, we demonstrate the antineoplastic activity of a potent, isoform selective and hydrolytically stable AKR1C3 inhibitor (E)-3-(4-(3-methylbut-2-en-1-yl)-3-(3-phenylpropanamido)phenyl)acrylic acid (KV-37) which reduces prostate cancer cell growth in vitro and in vivo, and sensitizes CRPC cell lines (22Rv1 and LNCaP1C3) towards the anti-tumor effects of enzalutamide. Crucially, KV-37 does not induce toxicity in non-malignant WPMY-1 prostate cells nor does it induce weight loss in mouse xenografts. Moreover, KV-37 reduces androgen receptor (AR) transactivation and prostate specific antigen (PSA) expression levels in CRPC cells lines indicative of a therapeutic effect in prostate cancer. Combination studies of KV-37 with enzalutamide reveal a very high degree of synergistic drug interaction that induces significant reduction in prostate cancer cell viability via apoptosis, resulting in >200-fold potentiation of enzalutamide action in drug resistant 22Rv1 cells. These results demonstrate a promising therapeutic strategy for the treatment of drug resistant CRPC that invariably develops in prostate cancer patients following initial treatment with AR antagonists such as enzalutamide.

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Anti-PSMA/CD3 Bispecific Antibody Delivery And Anti-Tumor Activity Using A Polymeric Depot Formulation

Small therapeutic proteins represent a promising novel approach to treat cancer. Nevertheless, their clinical application is often adversely impacted by their short plasma half-life. Controlled long-term delivery of small biologicals has become a challenge because of their hydrophilic properties and in some cases their limited stability. Here, an in-situ forming depot injectable polymeric system was used to deliver BiJ591, a Bispecific T-cell Engager (BiTE) targeting both prostate-specific membrane antigen (PSMA) and the CD3 T-cell receptor in prostate cancer. BiJ591 induced T-cell activation, prostate cancer directed cell lysis and tumor growth inhibition. The use of diblock and triblock biodegradable polyethylene glycol - poly(lactic acid) (PEG-PLA) copolymers solubilized in tripropionin, a small chain triglyceride, allowed maintenance of BiJ591 stability and functionality in the formed depot and controlled its release. In mice, after a single subcutaneous injection, one of the polymeric candidates, TB1/DB4, provided the most sustained release of BiJ591 for up to 21 days. Moreover, the use of BiJ591-TB1/DB4 formulation in prostate cancer xenograft models showed significant therapeutic activity in both low and high PSMA expressing tumors whereas daily intravenous administration of BiJ591 was less efficient. Collectively, the present data provide new insights into the development of controlled delivery of small therapeutic proteins in cancer.

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STAT3 Cyclic Decoy Demonstrates Robust Antitumor Effects in Non-Small Cell Lung Cancer

Constitutively activated STAT3 plays a critical role in non-small cell lung carcinoma (NSCLC) progression by mediating proliferation and survival. STAT 3 activation in normal cells is transient, making it an attractive target for NSCLC therapy. The therapeutic potential of blocking STAT3 in NSCLC was assessed utilizing a decoy approach by ligating a double-stranded 15-mer oligonucleotide that corresponds to the STAT3 response element of STAT3-target genes, to produce a cyclic STAT3 decoy (CS3D). The decoy was evaluated using NSCLC cells containing either wild-type (WT) EGFR (201T) or mutant EGFR with an additional EGFRi resistance mutation (H1975). These cells are resistant to EGFR inhibitors and require an alternate therapeutic approach. CS3D activity was compared to an inactive cyclic control oligonucleotide (CS3M) that differs by a single base pair, rendering it unable to bind to STAT3 protein. Transfection of 0.3 µM of CS3D caused a 50% inhibition in proliferation in 201T and H1975 cells, relative to CS3M, and a 2-fold increase in apoptotic cells. Toxicity was minimal in normal cells. CS3D treatment caused a significant reduction of mRNA and protein expression of the STAT3 target gene c-Myc, and inhibited colony formation by 70%. The active decoy decreased the nuclear pool of STAT3 compared to the mutant. In a xenograft model, treatments with CS3D (5 mg/kg) caused a potent 96.5% and 81.7% reduction in tumor growth in 201T (P<0.007) and H1975 models (P<.0001), respectively, and reduced c-Myc and p-STAT3 proteins. Targeting STAT3 with the cyclic decoy could be an effective therapeutic strategy for NSCLC.

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Bone Marrow Versus Peripheral Blood as a Graft Source for Haploidentical Donor Transplantation in Adults Using Post-Transplant Cyclophosphamide—A Systematic Review and Meta-Analysis

Publication date: Available online 11 June 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Xiaotong Yu, Liping Liu, Zhenwei Xie, Chongya Dong, Libo Zhao, Jingru Zhang, Hong-Hu Zhu, Jian Gu
BackgroundPeripheral-blood (PB) and bone marrow (BM) are both widely used in hematopoietic stem cell transplantation (HSCT). However, it is unclear whether PB or BM produces a more satisfactory outcome in haploidentical HSCT, particularly for patients using post-transplant cyclophosphamide (PTCy), which is the standard therapy. However, to date, no meta-analysis focusing on this issue has been published.MethodsWe systematically searched PubMed, MEDLINE, Web of Science, the Cochrane Library and the ClinicalTrials.gov website for studies regarding the use of BM or PB in haploidentical HSCT for hematological malignancies in adults using PTCy. Data were analyzed using Open Meta-Analyst statistical software.ResultsFourteen studies were extracted including four comparative retrospective reports and ten single-arm reports, with a total of 1759 patients received PTCy haploidentical HSCT (462 patients received PBSCT, 1297 patients received BMT). The pooled outcomes of comparative retrospective studies showed significantly higher incidence of grade III-IV acute graft-versus-host disease (GVHD) (OR = 1.741, 95%CI 1.032-2.938), incidence of grade II-IV acute GVHD (OR = 1.778, 95%CI 1.314, 2.406) and engraftment rate (OR = 1.843, 95%CI 1.066-3.185) in the PB group. No significant differences were found on the incidence of relapse, 2-year overall survival (OS) and disease-free survival (DFS), acute II-IV GVHD and chronic GVHD between PBSCT or BMT.ConclusionThe efficacy of PB is not inferior to BM for patients undergoing PTCy haploidentical HSCT with regard to primary outcomes, including OS, DFS, NRM and relapse. However, with regards to convenience and pain relief, PB graft is suitable for haploidentical HSCT, but with a higher risk of acute GVHD.



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Targeting the cellular schizophrenia. Likely employment of the antipsychotic agent pimozide in treatment of refractory cancers and glioblastoma

Publication date: Available online 11 June 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Ilhan Elmaci, Meric A. Altinoz
Pimozide is currently being used in clinic as a neuroleptic and exerts versatile biological actions. Pimozide is a cationic amphiphilic drug (CAD); CADs block the synthesis of neutral lipids, impair cholesterol homeostasis of cancer cells and increase accumulation of diacylglycerol-3-phosphate. Pimozide exerts tumoricidal activity which was first shown for melanoma and neuroblastoma via proposed anti- dopaminergic effects. Recently, pancreas cancers are shown to elevate dopamine receptor-2 synthesis, which is blocked by pimozide leading growth inhibition. Besides binding to inner mitochondrial membrane and reducing cellular respiration, pimozide also inhibits calmodulin, T-type calcium channels and σ-receptors which all correlate with tumor-inhibitory functions. Pimozide also exerts chemotherapy and radiotherapy-sensitizing effects in cancer cells and acts as an inhibitor of STAT-3 and STAT-5 signaling proteins with potential activity in leukemia, liver and prostate cancer. Pimozide also blocks stem cell features and Wnt-β/catenin signaling in liver cancer. Pimozide interferes with Fatty Acid Protein Binding-4 and activates PPAR-γ and it was proposed to alleviate cancer cachexia. Besides mechanisms of calmodulin and σ-receptor associated pathways, pimozide was proposed to inhibit glioblastoma via serotonin receptor 5-HT7. Pimozide is a selective inducer of autophagy and also inhibits ubiquitine specific protease (USP-1) which may associate with its chemosensizing potential in lung cancer and glioblastoma. Via versatile mechanisms of tumoricidal actions and due to its highly traversing capability through the blood-brain barrier, pimozide highly deserves to be studied in animal models of drug resistant refractory cancers and glioblastoma, which have very poor prognosis.



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Pembrolizumab exposure-response assessments challenged by association of cancer cachexia and catabolic clearance

Purpose: To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non-small cell carcinoma (NSCLC). Experimental Design: PK dependencies in OS were evaluated across three pembrolizumab studies of either 200mg or 2-10 mg/kg Q3W. Kaplan-Meier (K-M) plots of OS, stratified by dose, exposure, and baseline clearance were assessed per indication and study. A Cox Proportional Hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL</SPAN>₀<SPAN style="font-family: Arial, sans-serif;"> subgroups. </SPAN>Results: <SPAN style="font-family: 'Arial','sans-serif';">1453 subjects were included, 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose-independent from 2-10 mg/kg for pembrolizumab-treated melanoma <SPAN style="background: white;">(</SPAN>HR=0.98; 95%CI, 0.94-1.02<SPAN style="background: white;">)</SPAN></SPAN> <SPAN style="font-family: 'Arial','sans-serif'; background: white;">and NSCLC (</SPAN><SPAN style="font-family: 'Arial','sans-serif';">HR=0.98; 95%CI, 0.95-1.01<SPAN style="background: white;">)</SPAN>; however, a strong CL₀-OS association was identified for both cancer types</SPAN> <SPAN style="font-family: 'Arial','sans-serif';">(unadjusted melanoma HR=2.56; 95%CI, 1.72-3.80 and NSCLC HR=2.64; 95%CI, 1.94-3.57). Decreased OS in subjects with higher pembrolizumab CL₀ paralleled disease severity markers associated with end-stage cancer-anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL₀-OS association (multivariate-adjusted CL₀ HR=1.64; 95%CI, 1.06-2.52 for melanoma; HR=1.88; 95%CI, 1.22-2.89 for NSCLC). Conclusions: These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2-10 mg/kg. An association of pembrolizumab CL₀ with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure-response confounding may be a broader phenomenon generalizable to antineoplastic monoclonal antibodies.

https://ift.tt/2JQNGB0

The spatio-temporal evolution of lymph node spread in early breast cancer

Purpose: The most significant prognostic factor in early breast cancer is lymph node involvement. This stage between localised and systemic disease is key to understanding breast cancer progression, however our knowledge of the evolution of lymph node malignant invasion remains limited, as most currently available data derive from primary tumours. Experimental design: In 11 treatment-naïve node positive early breast cancer patients without clinical evidence of distant metastasis, we investigated lymph node evolution using spatial multi-region sequencing (n=78 samples) of primary and lymph node deposits and genomic profiling of matched longitudinal circulating tumour DNA (ctDNA). Results: Linear evolution from primary to lymph node was rare (1/11) whereas the majority of cases displayed either early divergence between primary and nodes (4/11), or no detectable divergence (6/11) where both primary and nodal cells belonged to a single recent expansion of a metastatic clone. Divergence of metastatic subclones was driven in part by APOBEC. Longitudinal ctDNA samples from 2 of 7 subjects with evaluable plasma taken peri-operatively reflected the two major evolutionary patterns and demonstrate that private mutations can be detected even from early metastatic nodal deposits. Moreover, node removal resulted in disappearance of private lymph node mutations in ctDNA. Conclusions: This study sheds new light on a crucial evolutionary step in the natural history of breast cancer, demonstrating early establishment of axillary lymph node metastasis in a substantial proportion of patients.

https://ift.tt/2HFrapQ

Integrated genomic classification of melanocytic tumors of the central nervous system using mutation analysis, copy number alterations and DNA methylation profiling

Purpose: In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria can be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis. Experimental Design: Targeted next-generation-sequencing, array-based genome-wide methylation analysis and BAP1 immunohistochemistry was performed on the largest cohort of central nervous system melanocytic tumors analyzed to date, incl. 47 primary tumors of the central nervous system, 16 uveal melanomas. 13 cutaneous melanoma metastasis and 2 blue nevus-like melanomas. Gene mutation, DNA-methylation and copy-number profiles were correlated with clinicopathological features. Results: Combining mutation, copy-number and DNA-methylation profiles clearly distinguished cutaneous melanoma metastases from other melanocytic tumors. Primary leptomeningeal melanocytic tumors, uveal melanomas and blue nevus-like melanoma showed common DNA-methylation, copy-number alteration and gene mutation signatures. Notably, tumors demonstrating chromosome 3 monosomy and BAP1 alterations formed a homogeneous subset within this group. Conclusions: Integrated molecular profiling aids in distinguishing primary from metastatic melanocytic tumors of the central nervous system. Primary leptomeningeal melanocytic tumors, uveal melanoma and blue nevus-like melanoma share molecular similarity with chromosome 3 and BAP1 alterations markers of poor prognosis.

https://ift.tt/2JQNAt8

Evaluation of efficacy and safety of sorafenib in kidney cancer patients aged 75 years and older: a propensity score-matched analysis

Evaluation of efficacy and safety of sorafenib in kidney cancer patients aged 75 years and older: a propensity score-matched analysis

Evaluation of efficacy and safety of sorafenib in kidney cancer patients aged 75 years and older: a propensity score-matched analysis, Published online: 12 June 2018; doi:10.1038/s41416-018-0129-3

Evaluation of efficacy and safety of sorafenib in kidney cancer patients aged 75 years and older: a propensity score-matched analysis

https://ift.tt/2Midjcz

Erratum: Periphere Regionalanästhesie ohne Komplikationen – Ein Traum wird wahr?!

Anästhesiol Intensivmed Notfallmed Schmerzther
DOI: 10.1055/a-0629-0254

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

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Fludarabine and busulfan plus low-dose TBI as reduced intensity conditioning in older patients undergoing allogeneic hematopoietic cell transplant for myeloid malignancies

Abstract

We have been using a combination of fludarabine/busulfan plus low-dose total body irradiation (TBI) as the reduced-intensity conditioning (RIC) regimen for patients age ≥ 60 years undergoing allogeneic hematopoietic cell transplantation (HCT) for myeloid malignancies. We retrospectively analyzed outcomes of 116 older patients (median age 64 years) who underwent HCT from 2006 to 2015 for myeloid malignancies, including acute myeloid leukemia (AML) in first complete remission (CR1). On univariate analysis, overall survival (OS) for the cohort at 3 years was 33% (95% CI 25–42). Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 3 years were 24% (95% CI 16–32) and 43% (95% CI 34–52), respectively. Multivariable analysis for OS demonstrated AML patients to have superior outcome (HR 1.60 for other myeloid, 95% CI 1.01–2.54, p = 0.045), as well as related donors (HR 1.92 for unrelated, 95% CI 1.22–3.03, p = 0.005). For NRM, AML patients had superior outcome (HR 1.76 for other myeloid, 95% CI 1.03–3.01, p = 0.038), as well as patients with related donors (HR 1.81 for unrelated, 95% CI 1.07–3.07, p = 0.028). We then demonstrated that AML patients with related donors (n = 45) had superior 3-year OS of 51% (95% CI 36–65), compared to 21% (95% CI 12–32) for all other patients (p = 0.0003). We conclude that the RIC regimen used is effective for older patients, particularly AML patients in CR1 with matched related donors.

https://ift.tt/2MlSY5U

Evaluation of efficacy and safety of sorafenib in kidney cancer patients aged 75 years and older: a propensity score-matched analysis

https://ift.tt/2LFFfpy

Aberrant FGFR tyrosine kinase signaling enhances the Warburg effect by reprogramming LDH isoform expression and activity in prostate cancer

The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression. How it contributes to PCa progression is not fully understood, although it is known to confer a growth advantage and promote cell survival. Here we report that FGFR1 tyrosine kinase reprograms the energy metabolism of PCa cells by regulating expression of lactate dehydrogenase (LDH) isozymes. FGFR1 increased LDHA stability through tyrosine phosphorylation and reduced LDHB expression by promoting its promoter methylation, thereby shifting cell metabolism from oxidative phosphorylation to aerobic glycolysis. LDHA depletion compromised, whereas LDHB depletion enhanced the tumorigenicity of prostate cancer cells. Furthermore, FGFR1 overexpression and aberrant LDH isozyme expression were associated with short overall survival and biochemical recurrence times in patients with PCa. Our results indicate that ectopic FGFR1 expression reprograms the energy metabolism of PCa cells, representing a hallmark change in PCa progression.

https://ift.tt/2HEHYgG

Licofelone enhances the efficacy of paclitaxel in ovarian cancer by reversing drug resistance and tumor stem-like properties

Drug development for front-line treatment of epithelial ovarian cancer (EOC) has been stagnant for almost three decades. Traditional cell culture methods for primary drug screening do not always accurately reflect clinical disease. To overcome this barrier, we grew a panel of EOC cell lines in three-dimensional (3D) cell cultures to form multicellular tumor spheroids (MCTS). We characterized these MCTS for molecular and cellular features of EOC and performed a comparative screen with cells grown using two-dimensional (2D) cell culture to identify previously unappreciated anti-cancer drugs. MCTS exhibited greater resistance to chemotherapeutic agents, showed signs of senescence and hypoxia, and expressed a number of stem cell-associated transcripts including ALDH1A and CD133. Using a library of clinically repurposed drugs, we identified candidates with preferential activity in MCTS over 2D cultured cells. One of the lead compounds, the dual COX/LOX inhibitor licofelone, reversed the stem-like properties of ovarian MCTS. Licofelone also synergized with paclitaxel in ovarian MCTS models and in a patient-derived tumor xenograft (PDX) model. Importantly, the combination of licofelone with paclitaxel prolonged the median survival of mice (>141 days) relative to paclitaxel (115 days), licofelone (37 days), or vehicle (30 days). Increased efficacy was confirmed by Mantel-Haenszel hazard ratio compared to vehicle (HR=0.037) and paclitaxel (HR=0.017). These results identify for the first time an unappreciated, anti-inflammatory drug that can reverse chemotherapeutic resistance in ovarian cancer, highlighting the need to clinically evaluate licofelone in combination with front-line chemotherapy in primary and chemotherapy-refractory EOC.

https://ift.tt/2Jsg11n

TET1-mediated hypomethylation activates oncogenic signaling in triple-negative breast cancer

Both gains and losses of DNA methylation are common in cancer, but the factors controlling this balance of methylation remain unclear. Triple-negative breast cancer (TNBC), a subtype that does not overexpress hormone receptors or HER2/NEU, is one of the most hypomethylated cancers observed. Here we discovered that the TET1 DNA demethylase is specifically overexpressed in about 40% of patients with TNBC, where it is associated with hypomethylation of up to 10% of queried CpG sites and a worse overall survival. Through bioinformatic analyses in both breast and ovarian cancer cell line panels, we uncovered an intricate network connecting TET1 to hypomethylation and activation of cancer-specific oncogenic pathways including PI3K, EGFR, and PDGF. TET1 expression correlated with sensitivity to drugs targeting the PI3K-mTOR pathway, and CRISPR-mediated deletion of TET1 in two independent TNBC cell lines resulted in reduced expression of PI3K pathway genes, upregulation of immune response genes, and substantially reduced cellular proliferation, suggesting dependence of oncogenic pathways on TET1 overexpression. Our work establishes TET1 as a potential oncogene that contributes to aberrant hypomethylation in cancer and suggests that TET1 could serve as a druggable target for therapeutic intervention.

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Programmatic comparison and dissemination of an audit of single fraction radiotherapy prescribing practices for bone metastases is associated with a meaningful and lasting change in practice on a population level

Publication date: Available online 11 June 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Robert Olson, Matthew Chan, Neelam Minhas, Gurkirat Kandola, Manpreet Tiwana, Shilo Lefresne, Ross Halperin, Devin Schellenberg, Elaine Wai, Nissar Ahmed, Scott Tyldesley
PurposeThere is ample evidence that single fraction radiation therapy (SFRT) is equally efficacious as more costly and morbid multi-fraction regimens. We previously demonstrated that an audit-based intervention increased the use of SFRT in all regional cancer centers the year following. However, other investigators have demonstrated interventions were only associated with a transient one-year change in prescribing practices. We sought to determine if our intervention resulted in a more lasting impact.MethodsIn 2012 we performed an audit of prescribing practices of individual physicians, which were then presented to leaders and oncologists as an intervention to increase SFRT. We then compared the use of SFRT from 2007-2011 (pre-intervention) and 2013-2016 (post-intervention) in all 31,192 patients treated in our provincial program.ResultsThe use of SFRT increased from 49.2% to 58.9% post intervention (p<0.001), with rates in 2007-2011 of 51, 51, 48, 49, and 48%, while post intervention in 2013-2016 they were 60, 62, 59, and 56%. Post intervention, half of the centers prescribed SFRT in a relatively narrow range (55-58%). However, across all centers, there was still a broad range, with the lowest and highest users at 35% and 81% respectively, though the lowest utilizing center still showed a significant increase (26% to 35%; p <0.001).ConclusionOur audit and educational based intervention resulted in a lasting and meaningful 10% change in practice. Our provincial rate is similar to a previously recommended benchmark rate of 60%, though we continue to see significant variation by center, suggesting further room for improvement in provincial standardization. With emerging evidence in support of ablative radiotherapy for select populations of patients with bone metastases, future benchmark rates of SFRT should be readdressed, though our data suggest programmatic comparison and dissemination of SFRT prescribing practices can achieve a population-based SFRT utilization rate near 60%.

Teaser

After an audit-based educational intervention in our population-based provincial radiotherapy program, we demonstrate a lasting and meaningful 10% increase in the prescription of SFRT for bone metastases. Other jurisdictions should consider using similar programmatic audit-based educational approaches in an effort to increase the use of this cost-effective treatment which has been historically used well below evidence-based benchmarks internationally. Our data suggests that the benchmark of 60% use of SFRT for bone metastases is feasible.


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Role of daily plan adaptation in MR-guided stereotactic ablative radiotherapy for adrenal metastases

Publication date: Available online 11 June 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): M.A. Palacios, O. Bohoudi, A.M.E. Bruynzeel, J.R. van Sörnsen-de Koste, P. Cobussen, B.J. Slotman, F.J. Lagerwaard, S. Senan
PurposeTo study inter-fractional organ changes during MR-guided stereotactic ablative radiotherapy (SABR) for adrenal metastases and to evaluate the dosimetric advantages of online plan adaptation.Methods and MaterialsSeventeen patients underwent a total of 84 fractions of video-assisted, respiration-gated MR-guided adaptive radiotherapy to deliver either 50 Gy (5 fractions), 60 Gy (8 fractions) or 24 Gy (3 fractions). An MR scan was repeated prior to each fraction, followed by rigid co-registration to the GTV on the pre-treatment MR scan. Contour deformation, PTV (GTV+3mm) expansion and online plan re-optimization were then performed. Re-optimized plans were compared to baseline treatment plans recalculated on the anatomy-of-the-day ('predicted plans').Inter-fractional changes in OARs were quantified according to OAR volume changes within a 3 cm distance from PTV surface, centre of mass (COM) displacements and the Dice Similarity Coefficient (DSC). Plan quality evaluation was based on target coverage (GTV and PTV), and also high dose sparing of all OARs (V36Gy, V33Gy and V25Gy).ResultsSubstantial COM displacements were observed for stomach, bowel and duodenum of 17, 27 and 36 mm, respectively. Maximum volume changes for the stomach, bowel and duodenum within 3 cm of PTV were 23.8, 20.5 and 20.9 cc, respectively. DSC values for OARs ranged from 0.0 to 0.9 for all fractions.Baseline plans recalculated on anatomy-of-the-day revealed underdosage of target volumes, and variable OAR sparing, leading to a failure to meet institutional constraints in a third of fractions. Online re-optimization improved target coverage in 63% of fractions, and reduced the number of fractions not meeting the V95% objective for GTV and PTV. Re-optimized plans exhibited significantly better sparing of OAR.ConclusionsSignificant inter-fractional changes in OARs positions were observed despite breath-hold SABR delivery under MR-guidance. Online re-optimization of treatment plans led to significant improvements in target coverage and OAR sparing.

Teaser

Stereotactic ablative radiotherapy (SABR) delivered during shallow inspiration breath-hold under MR-guidance, was implemented for adrenal gland metastases. We studied inter-fractional changes in GTV and OARs, and also the role of online plan re-optimization in ensuring both adequate target coverage and OAR sparing. Online plan adaptation led to improved target coverage in 63% of treatment fractions, and significantly reduced OAR doses. Our results indicate that online plan adaptation is beneficial in adrenal SABR.


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Cytomegalovirus reactivation in a critically ill patient: a case report

The aim of this case report is to discuss diagnostic workup and clinical management of cytomegalovirus reactivation in a critically ill immunocompetent pediatric patient.

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Oncology Research Program

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NCCN News

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Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology

This selection from the NCCN Guidelines for Merkel Cell Carcinoma (MCC) focuses on areas impacted by recently emerging data, including sections describing MCC risk factors, diagnosis, workup, follow-up, and management of advanced disease with radiation and systemic therapy. Included in these sections are discussion of the new recommendations for use of Merkel cell polyomavirus as a biomarker and new recommendations for use of checkpoint immunotherapies to treat metastatic or unresectable disease. The next update of the complete version of the NCCN Guidelines for MCC will include more detailed information about elements of pathology and addresses additional aspects of management of MCC, including surgical management of the primary tumor and draining nodal basin, radiation therapy as primary treatment, and management of recurrence.

https://ift.tt/2HFrTXZ

Movin On Up!

https://ift.tt/2Jucu2n

Early Versus Delayed Initiation of Salvage Androgen Deprivation Therapy and Risk of Prostate Cancer-Specific Mortality

Background: This study sought to ascertain whether there is an association between prostate cancer (PC)–specific mortality (PCSM) and timing of salvage androgen deprivation therapy (ADT) among men with short versus long prostate-specific antigen doubling times (PSA-DTs). Methods: The study cohort was selected from 206 men with localized unfavorable-risk PC randomized to radiation therapy (RT) or RT plus 6 months of ADT between 1995 and 2001. A total of 54 men who received salvage ADT for PSA failure after a median follow-up of 18.72 years following randomization defined the study cohort. The Fine-Gray competing risks regression model was used to analyze whether the timing of salvage ADT was associated with an increased risk of PCSM after adjusting for age, comorbidity, known PC prognostic factors, and previously identified interactions. Results: After a median follow-up of 5.68 years (interquartile range, 3.05–9.56) following salvage ADT, 49 of the 54 men (91%) died, of which 27 from PC (54% of deaths). Increasing PSA-DT as a continuous covariate (per month increase) was associated with a decreasing risk of PCSM (adjusted hazard ratio [HR], 0.33; 95% CI, 0.13–0.82; P=.02). Among men with a long PSA-DT (≥6 months), initiating salvage ADT later (PSA level >12 ng/mL, upper quartile) versus earlier was associated with an increased risk of PCSM (adjusted HR, 8.84; 95% CI, 1.99–39.27; P=.004), whereas for those with a short PSA-DT (<6 months; adjusted HR, 1.16; 95% CI, 0.38–3.54; P=.79) this was not true. Conclusions: Early initiation of salvage ADT for post-RT PSA failure in men with a PSA-DT of ≥6 months may reduce the risk of PCSM.

https://ift.tt/2LK0U03

Integrated Histogenetic Analysis Reveals BAP1-Mutated Epithelioid Mesothelioma in a Patient With Cancer of Unknown Primary

This case report presents a male patient with epithelioid mesothelioma that was initially misdiagnosed as cancer of unknown primary (CUP) and correctly identified using molecular panel sequencing. The patient had a prior history of colon and breast cancer. To assess the enlarged mediastinal lymph nodes, retrosternal lymphadenectomy was performed in 2016. The lymph nodes were histologically deemed unrelated to the known breast cancer by the reference pathologist, thus leading to the diagnosis of a CUP syndrome. When the patient presented to our center, targeted deep sequencing of both breast cancer and presumed CUP was performed to address the clonal relationship between both malignancies. A missense mutation in BAP1 was revealed in both samples, with coverage data indicating a germline event. The patient was subsequently counseled by a human geneticist and underwent genetic testing, which confirmed the germline nature of this mutation. Collectively, these data led to the diagnosis of BAP1 (BRCA1-associated protein-1) tumor predisposition syndrome (TPDS). With the knowledge of an underlying BAP1 mutation and its known frequent association with epithelioid mesothelioma, the histology was reassessed and the diagnosis was revised to epithelioid mesothelioma. At this point, peritoneal involvement of mesothelioma could be diagnosed and histologically confirmed. This case illustrates the potential of integrated histopathologic and molecular diagnostics in helping to decipher CUP syndromes and establish the correct diagnosis. Additionally, this case highlights typical features of BAP1 TPDS with its general susceptibility to cancers, with pleural and peritoneal mesotheliomas as most prevalent clinical entities and the typically more benign course of these epithelioid mesotheliomas compared with BAP1-unrelated cases of mesotheliomas.

https://ift.tt/2JsUwNL

Advances in Immunotherapy for Metastatic Merkel Cell Carcinoma: A Clinician's Guide

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer. The clinical impact of MCC has been increasing due to steadily rising incidence rates. Since 2001, more than 24,000 cases of MCC have been reported to the US National Program of Cancer Registries database, and in 2018, more than 2,500 incident cases are expected. MCC is highly aggressive, and one-third of patients will either present with or develop metastatic disease. Outcomes in patients with metastatic MCC have historically been poor; median time to progression with cytotoxic chemotherapy is only 3 months. MCC has long been appreciated to be immunogenic, with reports of spontaneous regression and responsiveness to immunotherapy. However, the mechanisms of this immunogenicity have only been understood over the past decade, with approximately 80% of cases in the United States associated with the Merkel cell polyomavirus (MCPyV) and expression of viral antigens (virus-positive [VP] MCC), and the remaining 20% of cases caused by UV radiation–induced damage leading to a high mutational burden and expression of neoantigens (virus-negative [VN] MCC). These insights have led to multiple successful trials of immunotherapies for MCC. PD-1 axis checkpoint inhibitors are now regarded as the preferred frontline systemic therapy in eligible patients (including both VP- and VN-MCC), with impressive frequency, durability, and depth of objective responses, which compare favorably to those of most solid tumors. This article reviews the safety and efficacy data from the key clinical trials of immune checkpoint inhibitors for metastatic MCC, and discusses several issues relevant to the clinical use of these agents. Finally, emerging immunotherapies for MCC, including cellular therapies and adjuvant systemic therapies, are reviewed.

https://ift.tt/2LHFXmb

Metachronous Medulloblastoma in a Child With Successfully Treated Neuroblastoma: Case Report and Novel Findings of DNA Sequencing

Metachronous neoplasms have rarely been reported in patients with neuroblastoma. This report presents the clinical case of a 23-month-old child who was diagnosed with an anaplastic medulloblastoma 5 months after completing treatment for stage IV neuroblastoma. The patient was treated with complete surgical resection and adjuvant chemoradiation followed by maintenance chemotherapy at an outside institution and came to our institution for further management. A pathologic diagnosis and review of both the suprarenal and posterior fossa masses were performed, as well as a genetic analysis of both cerebellar tumor tissue and blood using next-generation gene sequencing. At our institution, the patient was submitted to induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation and remains free of disease 2 years after completion of treatment. Genetic analysis revealed multiple somatic copy number variations with most deleted genes located in 2q37, a region which harbors genes involved in epigenetic regulation and tumor suppression. A homozygous deletion was found in the TSC2 gene, which is a clinically actionable gene, and patients with activating deletions in TSC2 can potentially be eligible for basket clinical trials with mTOR inhibitors. Germline single nucleotide variants were also identified in multiple genes involved in cancer (ALK, FGFR3, FLT3/4, HNF1A, NCOR1, and NOTCH2/3), cancer predisposition (TP53, TSC1, and BRCA1/2), and genes involved in DNA repair (MSH6, PMS2, POLE, and ATM). Metachronous neoplasms are rare and challenging to treat, hence genetic analysis and referral are needed to exclude hereditary cause. DNA sequencing of the tumor and germline can help identify alterations that increase predisposition or can be used to guide treatment decisions on recurrence and when standard options fail.

https://ift.tt/2JuFiYO

Outcomes From a Patient-Centered, Interprofessional, Palliative Consult Team in Oncology

Background: Palliative care aims to improve suffering and quality of life for patients with life-limiting disease. This study evaluated an interdisciplinary palliative consultation team for outpatients with advanced cancer at the Tom Baker Cancer Centre. This team traditionally offered palliative medicine and recently integrated a specialized psychosocial clinician. Historic patient-reported clinical outcomes were reviewed. There were no a priori hypotheses. Methods: A total of 180 chart reviews were performed in 8 sample months in 2015 and 2016; 114 patients were included. All patients were referred for management of complex cancer symptomatology by oncology or palliative care clinicians. Patients attended initial interviews in person; palliative medicine follow-ups were largely performed by telephone, and psychosocial appointments were conducted in person for those who were interested and had psychosocial concerns. Chart review included collection of demographics, medical information, and screening for distress measures at referral, initial consult, and discharge. Results: A total of 51% of the patient sample were men, 81% were living with a partner, and 87% had an advanced cancer diagnosis. Patients were grouped based on high, moderate, or low scores for 5 symptoms (pain, fatigue, depression, anxiety, and well-being). High scores on all 5 symptoms decreased from referral to discharge. Pain and anxiety decreased in the moderate group. All 5 low scores increased significantly. Sleep, frustration/anger, sense of burdening others, and sensitivity to cold were less frequently endorsed by discharge. Conclusions: Patients who completed this interdisciplinary palliative consult service appeared to experience a reduction in their most severe symptoms. Visits to patients during existing appointments or having them attend a half-day clinic appears to have reached those referred. With interdisciplinary integration, clinicians are able to collaborate to address patient care needs. Considerations include how to further integrate palliative and psychosocial care to achieve additional benefits and ongoing monitoring of changes in symptom burden.

https://ift.tt/2HCZYrz

NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018

The NCCN Guidelines for Neuroendocrine and Adrenal Tumors provide recommendations for the management of adult patients with neuroendocrine tumors (NETs), adrenal gland tumors, pheochromocytomas, and paragangliomas. Management of NETs relies heavily on the site of the primary NET. These NCCN Guidelines Insights summarize the management options and the 2018 updates to the guidelines for locoregional advanced disease, and/or distant metastasis originating from gastrointestinal tract, bronchopulmonary, and thymus primary NETs.

https://ift.tt/2JuF5F0

Weekend Effect in Emergency Colon and Rectal Cancer Surgery: A Prospective Study Using Data From the Dutch ColoRectal Audit

Background: It is unclear whether emergency weekend colon and rectal cancer surgery are associated with worse outcomes (ie, weekend effect) because previous studies mostly used administrative data, which may insufficiently adjust for case-mix. Materials and Methods: Prospectively collected data from the 2012–2015 Dutch ColoRectal Audit (n=5,224) was used to examine differences in 30-day mortality and severe complication and failure-to-rescue rates for emergency weekend (Saturday and Sunday) versus Monday surgery, stratified for colon and rectal cancer. Analyses were adjusted for age, sex, body mass index, Charlson comorbidity index, American Society of Anesthesiologists classification score, tumor stage, presence of metastasis, preoperative complication, additional resection for metastasis or locally advanced tumor, location primary colon tumor, type of rectal surgery (lower anterior resection or abdominal perineal resection), and type of neoadjuvant therapy (short-course radiotherapy or chemoradiotherapy). Results: A total of 5,052 patients undergoing colon cancer surgery and 172 undergoing rectal cancer surgery were included. Patients undergoing colon or rectal cancer surgery during weekends had significantly more preoperative tumor complications compared with those undergoing surgery on a weekday. Additionally, differences in year of surgery and location of primary tumor were found for colon cancer surgery. Emergency colon cancer surgery during the weekend was associated with increased 30-day mortality (odds ratio [OR], 1.66; 95% CI, 1.10–2.50) and severe complications (OR, 1.29; 95% CI, 1.03–1.63) compared with surgery on Monday. Estimates for emergency weekend rectal cancer surgery were similar but not statistically significant, likely explained by small numbers. Conclusions: Weekend emergency colon cancer surgery was associated with higher mortality and severe complication rates. More research is needed to understand which factors explain and contribute to these differences.

https://ift.tt/2HF9kTY

Receipt of Guideline-Concordant Care Among Older Women With Stage I-III Breast Cancer: A Population-Based Study

Background: This study examined receipt of guideline-concordant care (GCC) according to evidence-based treatment guidelines and quality measures and specific types of treatment among older women with breast cancer. Patients and Methods: A total of 142,433 patients aged ≥66 years diagnosed with stage I–III breast cancer between 2007 and 2011 were identified in the SEER-Medicare linked database. Algorithms considering cancer characteristics and the appropriate course of care as per guidelines versus actual care received determined receipt of GCC. Multivariable logistic regression estimated the likelihood of GCC and specific types of treatment for women aged ≥75 versus 66 to 74 years. Results: Overall, 39.7% of patients received GCC. Patients diagnosed at stage II or III, with certain preexisting conditions, and of nonwhite race were less likely to receive GCC. Patients with hormone-negative tumors, higher grade tumors, and greater access to oncology care resources were more likely to receive GCC. Patients aged ≥75 years were approximately 40% less likely to receive GCC or adjuvant endocrine therapy, 78% less likely to have any surgery, 61% less likely to have chemotherapy, and about half as likely to have radiation therapy than those aged 66 to 74 years. Conclusions: Fewer than half of older women with breast cancer received GCC, with the lowest rates observed among the oldest age groups, racial/ethnic minorities, and women with later-stage cancers. However, patients with more aggressive tumor characteristics and greater access to oncology resources were more likely to receive GCC. Considering that older women have the highest incidence of breast cancer and that many are diagnosed at stages requiring more aggressive treatment, efforts to increase rates of earlier stage diagnosis and the development of less toxic treatments could help improve GCC and survival while preserving quality of life.

https://ift.tt/2JtodOO

Radiotherapy in the Multidisciplinary Management of Merkel Cell Carcinoma

The management of Merkel cell carcinoma (MCC) requires multidisciplinary care for optimal patient outcomes. Radiotherapy (RT) is most commonly used as adjuvant therapy to improve locoregional control in patients with MCC who undergo surgery. Additionally, it can sometimes be used as definitive monotherapy for patients who decline or are not candidates for surgery and as palliative treatment in those with metastatic MCC. This article discusses the indications, treatment considerations, and recommended dose prescriptions for RT in the management of early- and advanced-stage disease. Considerable hope exists that immunotherapy advances will synergize with RT to further enhance clinical outcomes.

https://ift.tt/2HCYY6Y

Clinical Impact of Local Progression in Pancreatic Cancer

Background: The high prevalence of distant metastatic disease among patients with pancreatic cancer often draws attention away from the local pancreatic tumor. This study aimed to define the complications and hospitalizations from local versus distant disease progression among a retrospective cohort of patients with pancreatic cancer. Methods: Records of 298 cases of pancreatic cancer treated at a single institution from 2004 through 2015 were retrospectively reviewed, and cancer-related symptoms and complications requiring hospitalization were recorded. Hospitalizations related to pancreatic cancer were attributed to either local or distant progression. Cumulative incidence analyses were used to estimate the incidence of hospitalization, and multivariable Fine-Gray regression models were used to identify factors predictive of hospitalizations. Results: The 1-year cumulative incidences of hospitalization due to local versus distant disease progression were 31% and 24%, respectively. Among 509 recorded hospitalizations, leading local etiologies included cholangitis (10%), biliary obstruction (7%), local procedure complication (7%), and gastrointestinal bleeding (7%). On multivariable analysis, significant predictors of hospitalization from local progression included unresectable disease (subdistribution hazard ratio [SDHR], 2.42; P<.01), black race (SDHR, 3.34; P<.01), younger age (SDHR, 1.02 per year; P=.01), tumor in the pancreatic head (SDHR, 2.19; P<.01), and larger tumor size (SDHR, 1.13 per centimeter; P=.02). Most patients who died in the hospital from pancreatic cancer (56%) were admitted for complications of local disease progression. Conclusions: Patients with pancreatic cancer experience significant complications of local tumor progression. Although distant metastatic progression represents a hallmark of pancreatic cancer, future research should also focus on improving local therapies.

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Palliative Care: Who is Responsible?

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Epigenetic ConFUSION: SS18-SSX Fusion Rewires BAF Complex to Activate Bivalent Genes in Synovial Sarcoma

Publication date: 11 June 2018
Source:Cancer Cell, Volume 33, Issue 6
Author(s): Marc A. Morgan, Ali Shilatifard
In this issue of Cancer Cell, McBride and colleagues report that the synovial sarcoma SS18-SSX fusion drives BAF complex recruitment to bivalent domains repressed by PRC2 complex to orchestrate aberrant transcriptional activation. Redistribution of BAF localization is a major driver of synovial sarcoma proliferation and presents a promising therapeutic target.

Teaser

In this issue of Cancer Cell, McBride and colleagues report that the synovial sarcoma SS18-SSX fusion drives BAF complex recruitment to bivalent domains repressed by PRC2 complex to orchestrate aberrant transcriptional activation. Redistribution of BAF localization is a major driver of synovial sarcoma proliferation and presents a promising therapeutic target.


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BAI1 Suppresses Medulloblastoma Formation by Protecting p53 from Mdm2-Mediated Degradation

Publication date: 11 June 2018
Source:Cancer Cell, Volume 33, Issue 6
Author(s): Dan Zhu, Satoru Osuka, Zhaobin Zhang, Zachery R. Reichert, Liquan Yang, Yonehiro Kanemura, Ying Jiang, Shuo You, Hanwen Zhang, Narra S. Devi, Debanjan Bhattacharya, Shingo Takano, G. Yancey Gillespie, Tobey Macdonald, Chalet Tan, Ryo Nishikawa, William G. Nelson, Jeffrey J. Olson, Erwin G. Van Meir
Adhesion G protein-coupled receptors (ADGRs) encompass 33 human transmembrane proteins with long N termini involved in cell-cell and cell-matrix interactions. We show the ADGRB1 gene, which encodes Brain-specific angiogenesis inhibitor 1 (BAI1), is epigenetically silenced in medulloblastomas (MBs) through a methyl-CpG binding protein MBD2-dependent mechanism. Knockout of Adgrb1 in mice augments proliferation of cerebellar granule neuron precursors, and leads to accelerated tumor growth in the Ptch1^+/− transgenic MB mouse model. BAI1 prevents Mdm2-mediated p53 polyubiquitination, and its loss substantially reduces p53 levels. Reactivation of BAI1/p53 signaling axis by a brain-permeable MBD2 pathway inhibitor suppresses MB growth in vivo. Altogether, our data define BAI1's physiological role in tumorigenesis and directly couple an ADGR to cancer formation.

Graphical abstract

Teaser

Zhu et al. identify epigenetic silencing of ADGRB1 in medulloblastoma (MB) and show that Adgrb1 loss in a transgenic mouse MB model accelerates tumor growth. ADGRB1 encodes BAI1, which prevents MDM2-mediated p53 polyubiquitination. Rescue of BAI1 expression increases p53 levels and suppresses MB growth.


https://ift.tt/2HJ001q

ROS Promotes Cancer Cell Survival through Calcium Signaling

Publication date: 11 June 2018
Source:Cancer Cell, Volume 33, Issue 6
Author(s): Colleen R. Reczek, Navdeep S. Chandel
To avoid reactive oxygen species (ROS)-induced cell death, cancer cells increase their antioxidant defense system. In this issue of Cancer Cell, Takahashi et al. identify a novel, non-canonical oxidative stress defense mechanism involving TRPA1, a redox-sensitive Ca²⁺ channel, and the upregulation of anti-apoptotic pathways to promote cancer cell survival.

Teaser

To avoid reactive oxygen species (ROS)-induced cell death, cancer cells increase their antioxidant defense system. In this issue of Cancer Cell, Takahashi et al. identify a novel, non-canonical oxidative stress defense mechanism involving TRPA1, a redox-sensitive Ca²⁺ channel, and the upregulation of anti-apoptotic pathways to promote cancer cell survival.


https://ift.tt/2Ju8eQr

Non-conventional Inhibitory CD4+Foxp3−PD-1hi T Cells as a Biomarker of Immune Checkpoint Blockade Activity

Publication date: 11 June 2018
Source:Cancer Cell, Volume 33, Issue 6
Author(s): Roberta Zappasodi, Sadna Budhu, Matthew D. Hellmann, Michael A. Postow, Yasin Senbabaoglu, Sasikanth Manne, Billel Gasmi, Cailian Liu, Hong Zhong, Yanyun Li, Alexander C. Huang, Daniel Hirschhorn-Cymerman, Katherine S. Panageas, E. John Wherry, Taha Merghoub, Jedd D. Wolchok
A significant proportion of cancer patients do not respond to immune checkpoint blockade. To better understand the molecular mechanisms underlying these treatments, we explored the role of CD4⁺Foxp3⁻ T cells expressing PD-1 (4PD1^hi) and observed that 4PD1^hi accumulate intratumorally as a function of tumor burden. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1^hi increases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect and improves anti-tumor activity. We found that lack of effective 4PD1^hi reduction after anti-PD-1 correlates with poor prognosis. Mechanistically, we provide evidence that mouse and human circulating and intra-tumor 4PD1^hi inhibit T cell functions in a PD-1/PD-L1 dependent fashion and resemble follicular helper T cell (TFH)-like cells. Accordingly, anti-CTLA-4 activity is improved in TFH deficient mice.

Graphical abstract

Teaser

Zappasodi et al. show that a subset of CD4⁺Foxp3⁻ T cells with high PD-1 expression, designated 4PD1^hi cells, inhibits T cell functions. CTLA-4 blockade increases intratumoral and systemic 4PD1^hi cells, while combination with PD-1 blockade reduces the increase of 4PD1^hi cells and improves anti-tumor activity.


https://ift.tt/2HFVBMs

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

Publication date: 11 June 2018
Source:Cancer Cell, Volume 33, Issue 6
Author(s): Jeremy D. Waight, Dhan Chand, Sylvia Dietrich, Randi Gombos, Thomas Horn, Ana M. Gonzalez, Mariana Manrique, Lukasz Swiech, Benjamin Morin, Christine Brittsan, Antoine Tanne, Belinda Akpeng, Ben A. Croker, Jennifer S. Buell, Robert Stein, David A. Savitsky, Nicholas S. Wilson
The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs). In the case of mAbs targeting CTLA-4 and TIGIT, the interaction with FcγR on APCs enhanced antigen-specific T cell responses and tumoricidal activity. This mechanism extended to an anti-CD45RB mAb, which led to FcγR-dependent regulatory T cell expansion in mice.

Graphical abstract

Teaser

Waight et al. report an FcγR-dependent, but independent of Treg depletion, mechanism of action of anti-CTLA-4 antibodies and show that Fc-FcγR co-engagement by anti-CTLA-4 antibodies improves T cell signaling and function. This mechanism also applies to anti-TIGIT and anti-CD45RB antibodies.


https://ift.tt/2Js0Oxj

Th9 Cells Represent a Unique Subset of CD4+ T Cells Endowed with the Ability to Eradicate Advanced Tumors

Publication date: 11 June 2018
Source:Cancer Cell, Volume 33, Issue 6
Author(s): Yong Lu, Qiang Wang, Gang Xue, Enguang Bi, Xingzhe Ma, Aibo Wang, Jianfei Qian, Chen Dong, Qing Yi
The antitumor effector T helper 1 (Th1) and Th17 cells represent two T cell paradigms: short-lived cytolytic Th1 cells and "stem cell-like" memory Th17 cells. We report that Th9 cells represent a third paradigm—they are less-exhausted, fully cytolytic, and hyperproliferative. Only tumor-specific Th9 cells completely eradicated advanced tumors, maintained a mature effector cell signature with cytolytic activity as strong as Th1 cells, and persisted as long as Th17 cells in vivo. Th9 cells displayed a unique Pu.1-Traf6-NF-κB activation-driven hyperproliferative feature, suggesting a persistence mechanism rather than an antiapoptotic strategy. Th9 antitumor efficacy depended on interleukin-9 and upregulated expression of Eomes and Traf6. Thus, tumor-specific Th9 cells are a more effective CD4⁺ T cell subset for adoptive cancer therapy.

Graphical abstract

Teaser

Lu et al. report that adaptively transferred tumor-specific CD4⁺ Th9 cells eradicate large established murine tumors and protect surviving mice against tumor rechallenge. Th9 cells maintain a mature effector cell signature with cytolytic activity as strong as Th1 cells and persist as long as Th17 cells in vivo.


https://ift.tt/2LIgwRo

Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling

Publication date: 11 June 2018
Source:Cancer Cell, Volume 33, Issue 6
Author(s): Debanjan Dhar, Laura Antonucci, Hayato Nakagawa, Ju Youn Kim, Elisabeth Glitzner, Stefano Caruso, Shabnam Shalapour, Ling Yang, Mark A. Valasek, Sooyeon Lee, Kerstin Minnich, Ekihiro Seki, Jan Tuckermann, Maria Sibilia, Jessica Zucman-Rossi, Michael Karin
How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Once expressed, CD44 potentiates AKT activation to induce the phosphorylation and nuclear translocation of Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to escape p53-induced death and senescence and respond to proliferative signals that promote fixation of mutations and their transmission to daughter cells that go on to become HCC progenitors.

Graphical abstract

Teaser

Dhar et al. show that CD44 expression induced in carcinogen-exposed hepatocytes potentiates AKT signaling to activate Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to respond to proliferative signals, leading their daughter cells to become HCC progenitors.


https://ift.tt/2JxI5R7

Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

Publication date: 11 June 2018
Source:Cancer Cell, Volume 33, Issue 6
Author(s): Ewa Gogola, Alexandra A. Duarte, Julian R. de Ruiter, Wouter W. Wiegant, Jonas A. Schmid, Roebi de Bruijn, Dominic I. James, Sergi Guerrero Llobet, Daniel J. Vis, Stefano Annunziato, Bram van den Broek, Marco Barazas, Ariena Kersbergen, Marieke van de Ven, Madalena Tarsounas, Donald J. Ogilvie, Marcel van Vugt, Lodewyk F.A. Wessels, Jirina Bartkova, Irina Gromova, Miguel Andújar-Sánchez, Jiri Bartek, Massimo Lopes, Haico van Attikum, Piet Borst, Jos Jonkers, Sven Rottenberg
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.

Graphical abstract

Teaser

Gogola et al. show loss of poly(ADP-ribose) glycohydrolase (PARG) confers resistance of BRCA2-deficient tumor cells to PARP inhibition by restoring PAR formation, controlled DNA replication fork progression, and the recruitment of downstream DNA repair factors while sensitizing them to ionizing radiation and temozolomide.


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CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis

Publication date: 11 June 2018
Source:Cancer Cell, Volume 33, Issue 6
Author(s): Sarah M. Greenblatt, Na Man, Pierre-Jacques Hamard, Takashi Asai, Daniel Karl, Concepcion Martinez, Daniel Bilbao, Vasileios Stathais, Anna McGrew-Jermacowicz, Stephanie Duffort, Madhavi Tadi, Ezra Blumenthal, Samantha Newman, Ly Vu, Ye Xu, Fan Liu, Stephan C. Schurer, Michael T. McCabe, Ryan G. Kruger, Mingjiang Xu, Feng-Chun Yang, Daniel Tenen, Justin Watts, Francisco Vega, Stephen D. Nimer
Chromatin-modifying enzymes, and specifically the protein arginine methyltransferases (PRMTs), have emerged as important targets in cancer. Here, we investigated the role of CARM1 in normal and malignant hematopoiesis. Using conditional knockout mice, we show that loss of CARM1 has little effect on normal hematopoiesis. Strikingly, knockout of Carm1 abrogates both the initiation and maintenance of acute myeloid leukemia (AML) driven by oncogenic transcription factors. We show that CARM1 knockdown impairs cell-cycle progression, promotes myeloid differentiation, and ultimately induces apoptosis. Finally, we utilize a selective, small-molecule inhibitor of CARM1 to validate the efficacy of CARM1 inhibition in leukemia cells in vitro and in vivo. Collectively, this work suggests that targeting CARM1 may be an effective therapeutic strategy for AML.

Graphical abstract

Teaser

Greenblatt et al. show that loss of the protein arginine methyltransfersase CARM1 minimally impacts normal hematopoiesis but strongly impairs leukemogenesis by regulating cell-cycle progression, myeloid differentiation, and apoptosis. Targeting CARM1 reduces AML growth in primary patient samples and mouse models.


https://ift.tt/2JuIaoA

Bloodstream infection in patients with head and neck cancer: a major challenge in the cetuximab era

Abstract

Purpose

To assess the impact of bloodstream infection (BSI) in patients with head and neck cancer (HNC) in the cetuximab era.

Methods

We prospectively analysed the epidemiology, microbiology and outcomes of 51 BSI episodes occurring in 48 patients with HNC (2006–2017). We performed a retrospective matched-cohort study (1:2) to determine the risk factors for BSI. Finally, we compared patients who died with those who survived to identify risk factors for mortality.

Results

The most frequent HNC localization was the oropharynx (43%), and pneumonia was the most frequent source (25%). Gram-positive BSI occurred in 55% cases, mainly due to Streptococcus pneumoniae (21%), and among Gram-negatives, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae were the most frequent. Hypoalbuminemia (OR 8.4; 95% CI, 3.5–19.9), previous chemotherapy (OR, 3.2; 95% CI, 1.3–7.4) and cetuximab therapy (OR, 2.8; 95% CI, 1.6–6.7) were significant risk factors for BSI. Patients with BSI had a higher overall case-fatality rate than patients without BSI (OR, 4.4; 95% CI, 1.7–11.8). Hypoalbuminemia was an independent risk factor for the early (7 day) and overall (30 day) case-fatalities, with ORs of 0.8 (95% CI, 0.6–0.9) and 0.8 (95% CI, 0.7–0.97), respectively. The presence of comorbidities (OR, 7; 95% CI, 1.4–34) was also an independent risk factor for overall case-fatality.

Conclusions

BSI causes high mortality in patients with HNC and is most often secondary to pneumonia. It occurs mainly among patients with hypoalbuminemia who receive treatment with cetuximab or chemotherapy. The development of BSI in patients with HNC impairs their outcome, especially in the presence of hypoalbuminemia and comorbidities.

https://ift.tt/2l4hGva

Maximizing the Prospects for Progress Against Cancer

NCI Director Dr. Ned Sharpless highlights some of the important research findings from the 2018 American Society of Clinical Oncology annual meeting and discusses the rapid pace of progress in cancer research.

https://ift.tt/2y4HUqY

Autologous Stem Cell Transplantation for Multiple Myeloma: Underutilized but Highly Effective

In the current issue of the Journal, Rosenberg et al. describe the results of a population-based study regarding the role of autologous stem cell transplantation (ASCT) for patients with newly diagnosed multiple myeloma (MM) between 1998 and 2012 (1). This time period represents an important era, noteworthy for the development and implementation of several new classes of efficacious myeloma therapies, including immunomodulatory agents (eg, lenalidomide) and proteasome inhibitors (eg, bortezomib), which called into question the role of autologous stem cell transplantation as consolidation for myeloma patients following induction therapy (1–4).

https://ift.tt/2MfBPuJ

Association Between Autologous Stem Cell Transplant and Survival Among Californians With Multiple Myeloma

Abstract

Background

Autologous hematopoietic stem cell transplant (aHSCT) is an efficacious treatment for newly diagnosed multiple myeloma patients. However, as rapid advances have resulted in other highly efficacious and less intensive therapies, the role of aHSCT has been questioned.

Methods

We utilized population-based data to identify 13 494 newly diagnosed patients younger than age 80 years between 1998 and 2012. Patient characteristics of aHSCT and non-aHSCT groups were balanced using inverse probability weighting of a propensity score predicting aHSCT use. Multivariable models adjusted for baseline comorbidities, demographics, and socioeconomic status estimated the adjusted hazard ratio (aHR) and 95% confidence intervals (CIs) of death.

Results

Twenty point eight percent (2807) of patients underwent aHSCT, and this rate increased over time from 15.4% in 1998–2002 to 23.9% in 2008–2012. aHSCT was utilized among 37.6% and 11.5% of patients younger than age 60 years and 60 to 79 years, respectively. The median time to aHSCT was 9.4 months, and 89% of all aHSCTs occurred within two years of diagnosis. The median overall survival from time of aHSCT was 72.9 months (95% confidence interval [CI] = 68 to 78). Autologous HSCT at any time was associated with improved survival (aHR = 0.83, 95% CI = 0.75 to 0.92). Among aHSCT recipients, transplant more than 12 months after diagnosis (vs ≤12 months) was associated with worse survival (aHR = 1.33, 95% CI = 1.16 to 1.51). The positive effect of aHSCT on overall survival was similar across study time periods and age groups.

Conclusion

In the era of highly efficacious induction therapies, aHSCT remained infrequently used but continued to be associated with improved survival for multiple myeloma patients and should be considered for newly diagnosed patients.

https://ift.tt/2y1QeHQ

Effect of starvation on brain glucose metabolism and 18 F-2-fluoro-2-deoxyglucose uptake: an experimental in-vivo and ex-vivo study

Abstract

Background

The close connection between neuronal activity and glucose consumption accounts for the clinical value of 18F-fluoro-2-deoxyglucose (FDG) imaging in neurodegenerative disorders. Nevertheless, brain metabolic response to starvation (STS) might hamper the diagnostic accuracy of FDG PET/CT when the cognitive impairment results in a severe food deprivation.

Methods

Thirty six-week-old BALB/c female mice were divided into two groups: "control" group (n = 15) were kept under standard conditions and exposed to fasting for 6 h before the study; the remaining "STS" mice were submitted to 48 h STS (absence of food and free access to water) before imaging. In each group, nine mice were submitted to dynamic micro-PET imaging to estimate brain and skeletal muscle glucose consumption (C- and SM-MRGlu*) by Patlak approach, while six mice were sacrificed for ex vivo determination of the lumped constant, defined as the ratio between CMRGlu* and glucose consumption measured by glucose removal from the incubation medium (n = 3) or biochemical analyses (n = 3), respectively.

Results

CMRGlu* was lower in starved than in control mice (46.1 ± 23.3 vs 119.5 ± 40.2 nmol × min⁻¹ × g⁻¹, respectively, p < 0.001). Ex vivo evaluation documented a remarkable stability of lumped constant as documented by the stability of GLUT expression, G6Pase activity, and kinetic features of hexokinase-catalyzed phosphorylation. However, brain SUV in STS mice was even (though not significantly) higher with respect to control mice. Conversely, a marked decrease in both SM-MRGlu* and SM-SUV was documented in STS mice with respect to controls.

Conclusions

STS markedly decreases brain glucose consumption without altering measured FDG SUV in mouse experimental models. This apparent paradox does not reflect any change in lumped constant. Rather, it might be explained by the metabolic response of the whole body: the decrease in FDG sequestration by the skeletal muscle is as profound as to prolong tracer persistence in the bloodstream and thus its availability for brain uptake.

https://ift.tt/2y2AHYn

The renal blood flow reserve in healthy humans and patients with atherosclerotic renovascular disease measured by positron emission tomography using [ 15 O]H 2 O

Abstract

Background

Microvascular function plays an important role in ARVD (atherosclerotic renovascular disease). RFR (renal flow reserve), the capacity of renal vasculature to dilate, is known to reflect renal microvascular function. In this pilot study, we assessed PET (positron emission tomography)-based RFR values of healthy persons and renal artery stenosis patients.

Seventeen patients with ARVD and eight healthy subjects were included in the study. Intravenous enalapril 1 mg was used as a vasodilatant, and the maximum response (blood pressure and RFR) to it was measured at 40 min. Renal perfusion was measured by means of oxygen-15-labeled water PET. RFR was calculated as a difference of stress flow and basal flow and was expressed as percent [(stress blood flow − basal blood flow)/basal blood flow] × 100%.

Results

RFR of the healthy was 22%. RFR of the stenosed kidneys of bilateral stenosis patients (27%) was higher than that of the stenosed kidneys of unilateral stenosis patients (15%). RFR of the contralateral kidneys of unilateral stenosis patients was 21%. There was no difference of statistical significance between RFR values of ARVD subgroups or between ARVD subgroups and the healthy. In the stenosed kidneys of unilateral ARVD patients, stenosis grade of the renal artery correlated negatively with basal (p = 0.04) and stress flow (p = 0.02). Dispersion of RFR values was high.

Conclusions

This study is the first to report [¹⁵O]H₂O PET-based RFR values of healthy subjects and ARVD patients in humans. The difference between RFR values of ARVD patients and the healthy did not reach statistical significance perhaps because of high dispersion of RFR values. [¹⁵O]H₂O PET is a valuable non-invasive and quantitative method to evaluate renal blood flow though high dispersion makes imaging challenging. Larger studies are needed to get more information about [¹⁵O]H₂O PET method in evaluation of renal blood flow.

https://ift.tt/2JKP3Bm

Simplifying [ 18 F]GE-179 PET: are both arterial blood sampling and 90-min acquisitions essential?

Abstract

Introduction

The NMDA receptor radiotracer [¹⁸F]GE-179 has been used with 90-min scans and arterial plasma input functions. We explored whether (1) arterial blood sampling is avoidable and (2) shorter scans are feasible.

Methods

For 20 existing [¹⁸F]GE-179 datasets, we generated (1) standardised uptake values (SUVs) over eight intervals; (2) volume of distribution (V_T) images using population-based input functions (PBIFs), scaled using one parent plasma sample; and (3) V_T images using three shortened datasets, using the original parent plasma input functions (ppIFs).

Results

Correlations with the original ppIF-derived 90-min V_Ts increased for later interval SUVs (maximal ρ = 0.78; 80–90 min). They were strong for PBIF-derived V_Ts (ρ = 0.90), but between-subject coefficient of variation increased. Correlations were very strong for the 60/70/80-min original ppIF-derived V_Ts (ρ = 0.97–1.00), which suffered regionally variant negative bias.

Conclusions

Where arterial blood sampling is available, reduction of scan duration to 60 min is feasible, but with negative bias. The performance of SUVs was more consistent across participants than PBIF-derived V_Ts.

https://ift.tt/2JEQMon

Long-term oncologic outcomes of radiotherapy combined with maximal androgen blockade for localized, high-risk prostate cancer

Abstract

Background

To assess the oncologic outcomes of radiation therapy (RT) combined with maximal androgen blockade (MAB) and prostate-specific antigen (PSA) kinetics in patients with localized, high-risk prostate carcinoma (PCa).

Methods

Three-hundred twenty individuals with localized PCa who underwent RT + MAB in 2001–2015 were evaluated retrospectively. All patients had received 36 months of MAB therapy and 45 Gy of pelvic irradiation, plus a dose-escalated external beam radiation therapy (DE-EBRT) boost to 76~81 Gy (MAB + EBRT group), or a low-dose-rate prostate permanent brachytherapy (LDR-PPB) boost to 110 Gy with I-125 (MAB + EBRT + PPB group).

Results

Follow-up median is 90 months, ranging from 12 to 186 months; 117 (36.6%) and 203 (63.4%) cases underwent MAB + EBRT and MAB + EBRT + PPB, respectively. Multivariate Cox regression showed that the PPB regimen and PSA kinetics were positive indicators of oncologic outcomes. Compared with MAB + EBRT, MAB + EBRT + PPB remarkably improved PSA kinetics more pronouncedly: PSA nadir (1.3 ± 0.7 vs 0.11 ± 0.06 ng/mL); time of PSA decrease to nadir (7.5 ± 1.8 vs 3.2 ± 2.1 months); PSA doubling time (PSADT; 15.6 ± 4.2 vs 22.6 ± 6.1 months); decrease in PSA (84.6 ± 6.2% vs 95.8 ± 3.4%). Additionally, median times of several important oncologic events were prolonged in the MAB + EBRT + PPB group compared with the MAB + EBRT group: overall survival (OS; 12.3 vs 9.1 years, P < 0.001), biochemical recurrence-free survival (BRFS; 9.8 vs 6.5 years, P < 0.001), skeletal-related event (SRE; 10.4 vs 8.2 years, P < 0.001), and cytotoxic chemotherapy (CCT; 11.6 vs 8.8 years, P = 0.007).

Conclusion

MAB + EBRT + PPB is extremely effective in patients with localized, high-risk PCa, indicating that PPB may play a synergistic role in improving PSA kinetics and independently predicts oncologic outcomes.

https://ift.tt/2LEKt4S

Childhood cancer registration in New Zealand: A registry collaboration to asssess and improve data quality

Publication date: August 2018
Source:Cancer Epidemiology, Volume 55
Author(s): Kirsten R. Ballantine, Susan Hanna, Scott Macfarlane, Peter Bradbeer, Lochie Teague, Sarah Hunter, Siobhan Cross, Jane Skeen
AimTo evaluate the completeness and accuracy of child cancer registration in New Zealand.MethodsRegistrations for children aged 0–14 diagnosed between 1/1/2010 and 31/12/2014 were obtained from the New Zealand Cancer Registry (NZCR) and the New Zealand Children's Cancer Registry (NZCCR). Six key data fields were matched using National Health Index numbers in order to identify and resolve registration discrepancies. Capture-recapture methods were used to assess the completeness of cancer registration. RESULTS: 794 unique cases were reported; 718 from the NZCR, 721 from the NZCCR and 643 from both registries. 27 invalid cancer registrations were identified, including 19 residents of the Pacific Islands who had travelled to New Zealand for treatment. The NZCCR provided 55 non-malignant central nervous system tumour and 16 Langerhans cell histiocytosis cases which were not registered by the NZCR. The NZCR alerted the NZCCR to 18 cases missed due to human error and 23 cases that had not been referred to the specialist paediatric oncology centres. 762 cases were verified as true incident cases, an incidence rate of 166.8 per million. Registration accuracy for six key data fields was 98.6%. According to their respective inclusion criteria case completeness was 99.3% for the NZCR and 94.4% for the NZCCR. For childhood malignancies covered by both registries, capture-recapture methods estimated case ascertainment at greater than 99.9%. CONCLUSION: With two national registries covering childhood cancers, New Zealand is uniquely positioned to undertake regular cooperative activities to ensure high quality data is available for research and patient care.



https://ift.tt/2sWBUe5

Tumor budding and human chorionic gonadotropin-β expression correlate with unfavorable patient outcome in colorectal carcinoma

Abstract

Tumor budding is thought to represent a manifestation of epithelial-to-mesenchymal transition (EMT) and it has been correlated with poor patient outcomes in colorectal cancer (CRC). Our group recently demonstrated that human chorionic gonadotropin-β (hCGβ) modulates EMT in CRC. In the current study, based on the likely relationships between tumor budding and hCGβ expression, we examined their clinicopathologic significance in CRC. Twenty-eight of 80 (35.0%) CRC showed tumor budding. Tumor budding significantly correlated with lymph node metastasis (P < 0.01), pathologic stage (P < 0.01), lymphatic invasion (P = 0.044), and vascular invasion (P = 0.013). Thirteen of 80 (16.3%) CRC were hCGβ positive on immunohistochemistry. More tumor buds were present in the hCGβ-positive cases (P < 0.01), and tumor budding was significantly correlated with hCGβ positivity (P < 0.01). Cases with both tumor budding and hCGβ expression had the poorest prognosis compared with all other groups (P < 0.01). In conclusion, tumor budding and hCGβ expression are closely associated with EMT, and they are independent prognostic factors in CRC. They identify patients with an "EMT phenotype" who may respond to targeted molecular therapies.

https://ift.tt/2l3hYml