Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis

Abstract

Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.

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From Adjustment to Thriving: Exploring Well-Being in Young Adult Survivors of Childhood Cancer and Their Siblings

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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AKT3 and breast tumor resistance

Acquired resistance to molecular targeted therapy represents a major challenge for the effective treatment of cancer. Hyperactivation of the PI3K/AKT pathway is frequently observed in virtually all human malignancies, and numerous PI3K and AKT inhibitors are currently under clinical evaluation. However, mechanisms of acquired resistance to AKT inhibitors have yet to be described. Here, we use a breast cancer preclinical model to identify resistance mechanisms to a small molecule allosteric AKT inhibitor MK2206. Using a step-wise and chronic high-dose exposure, breast cancer cell lines harboring oncogenic PI3K resistant to MK2206 were established. Using this model, we reveal that AKT3 expression is markedly upregulated in AKT inhibitor-resistant cells. Induction of AKT3 is regulated epigenetically by the bromodomain and extra terminal domain proteins. Importantly, knockdown of AKT3, but not AKT1 or AKT2, in resistant cells restores sensitivity to MK2206. AKT inhibitor-resistant cells also display an epithelial to mesenchymal transition phenotype as assessed by alterations in the levels of E-Cadherin, N-Cadherin and vimentin, as well as enhanced invasiveness of tumor spheroids. Notably, the invasive morphology of resistant spheroids is diminished upon AKT3 depletion. We also show that resistance to MK2206 is reversible since upon drug removal resistant cells regain sensitivity to AKT inhibition, accompanied by re-expression of epithelial markers and reduction of AKT3 expression, implying that epigenetic reprogramming contributes to acquisition of resistance. These findings provide a rationale for developing therapeutics targeting AKT3 to circumvent acquired resistance in breast cancer.

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Vemurafenib & PAC-1 are synergistic in mutant BRAF melanomas

The development of vemurafenib resistance limits the long-term efficacy of this drug for treatment of metastatic melanomas with the V600EBRAF mutation. Inhibition of downstream MAPK signaling with vemurafenib induces apoptotic cell death mediated by caspase-3, suggesting that addition of a procaspase-3 activator could enhance anticancer effects. Here we show that the combination of PAC-1, a procaspase-activating compound, and vemurafenib is highly synergistic in enhancing caspase-3 activity and apoptotic cell death in melanoma cell lines harboring the V600EBRAF mutation. In vivo, the combination displays a favorable safety profile in mice, and exerts significant antitumor effects. We further demonstrate that addition of PAC-1 to the clinically useful combination of vemurafenib and a MEK inhibitor, trametinib, starkly enhances the caspase-3 activity and proapoptotic effect of the combination. Moreover, addition of low concentration PAC-1 also delays the regrowth of cells following treatment with vemurafenib. Finally, PAC-1 remains potent against vemurafenib-resistant A375VR cells in cell culture and synergizes with vemurafenib to exert antitumor effects on A375VR cell growth in vivo. Collectively, our data suggest that inhibition of MAPK signaling combined with concurrent procaspase-3 activation is an effective strategy to enhance the antitumor activity of vemurafenib and mitigate the development of resistance.

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A new anti-CXCR4 antibody

The type-4 C-X-C-motif chemokine receptor (CXCR4) is expressed in a large variety of human cancers including hematological malignancies, and this receptor and its ligand, stromal-cell-derived factor-1 (SDF-1), play a crucial role in cancer progression. We generated a humanized immunoglobulin-G1 monoclonal antibody, hz515H7, which binds human CXCR4, efficiently competes for SDF-1 binding, and induces a conformational change in CXCR4 homodimers. Furthermore, it inhibits both CXCR4 receptor-mediated G-protein activation and β-arrestin-2 recruitment following CXCR4 activation. The binding of the hz515H7 antibody to CXCR4 inhibits the SDF-1-induced signaling pathway, resulting in reduced phosphorylation of downstream effectors such as Akt, Erk1/2, p38 and GSK3β. Hz515H7 also strongly inhibits cell migration and proliferation and, while preserving normal blood cells, induces both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against neoplastic cells. In mouse xenograft models, hz515H7 displays anti-tumor activities with multiple hematological tumor cell lines, with its Fc-mediated effector functions proving essential in this context. Furthermore hz515H7 binds to primary tumor cells from acute myeloid leukemia and multiple myeloma patients. Collectively, our results demonstrate two major mechanisms of action, making hz515H7 unique in this regard. Its potential as a best-in-class molecule is currently under investigation in a phase I clinical trial.

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Targeted PDT Treatment of Prostate Cancer

Prostatectomy has been the mainstay treatment for men with localized prostate cancer. Surgery, however, often can result in major side effects, which are caused from damage and removal of nerves and muscles surrounding the prostate. A technology that can help surgeons more precisely identify and remove prostate cancer resulting in a more complete prostatectomy is needed. Prostate-specific membrane antigen (PSMA), a type II membrane antigen highly expressed in prostate cancer, has been an attractive target for imaging and therapy. The objective of this study is to develop low molecular weight PSMA-targeted photodymanic therapy (PDT) agents, which would provide image-guidance for prostate tumor resection and allow for subsequent PDT to eliminate un-resectable or remaining cancer cells. Based on our highly negatively charged, urea-based PSMA ligand PSMA-1, we synthesized two PSMA-targeting PDT conjugates named PSMA-1-Pc413 and PSMA-1-IR700. In in vitro cellular uptake experiments and in vivo animal imaging experiments the two conjugates demonstrated selective and specific uptake in PSMA-positive PC3pip cells/tumors, but not in PSMA-negative PC3flu cells/tumors. Further in vivo photodynamic treatment proved that the two PSMA-1-PDT conjugates can effectively inhibit PC3pip tumor progression. The two PSMA-1-PDT conjugates reported here may have the potential to aid in the detection and resection of prostate cancers. It may also allow for the identification of unresectable cancer tissue and PDT ablation of such tissue after surgical resection with potentially less damage to surrounding tissues.

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Molecularly Defined Adult Granulosa Cell Tumor of the Ovary: The Clinical Phenotype

The histopathologic features of adult granulosa cell tumors (AGCTs) are relatively nonspecific, resulting in misdiagnosis of other cancers as AGCT, a problem that has not been well characterized. FOXL2 mutation testing was used to stratify 336 AGCTs from three European centers into three categories: 1) FOXL2 mutant molecularly defined AGCT (MD-AGCT) (n = 256 of 336), 2) FOXL2 wild-type AGCT (n = 17 of 336), 3) misdiagnosed other tumor types (n = 63 of 336). All statistical tests were two-sided. The overall and disease-specific survival of the misdiagnosed cases was lower than in the MD-AGCTs (P < .001). The misdiagnosed cases accounted for 71.9% of disease-specific deaths within five years. In the population-based cohort, overall survival of MD-AGCT patients was not different from age-matched, population-based controls. Even though 35.2% of all the MD-AGCT patients in our study experienced a relapse, AGCT is usually an indolent disease. The historical, premolecular data underpinning our clinical understanding of AGCT was likely skewed by inclusion of misdiagnosed cases, and future management strategies should reflect the potential for surgical cure and long survival even after relapse.

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Effect Modification by Time Since Blood Draw on the Association Between Circulating Fatty Acids and Prostate Cancer Risk

A recent meta-analysis suggested that circulating fatty acids do not play an important role in prostate carcinogenesis. We hypothesized that the relation between circulating fatty acids and prostate cancer (PCa) risk is modified by time between blood draw and diagnosis. We tested this hypothesis in a prospective case-control study of 476 PCa cases and matched control subjects nested in the Physicians' Health Study. The previously reported associations between fatty acids and PCa in this cohort were dramatically stronger among men diagnosed 10 or more years after blood collection. Statistically significant effect modification by time since blood collection was identified for mono-unsaturated and poly-unsaturated fatty acids and was more pronounced for aggressive tumors. Among men diagnosed fewer than 10 years since blood collection, the relative risks per interquartile range were 1.03 (95% confidence interval [CI] = 0.86 to 1.25) for total mono-unsaturated fatty acids (MUFA) and 0.95 (95% CI = 0.78 to 1.15) for total poly-unsaturated fatty acids (PUFA) whereas among men diagnosed 10 or more years after blood draw the relative risks per interquartile range were 1.69 (95% CI = 1.21 to 2.34) for MUFA (P_{heterogeneity} = .01) and 0.59 (95% CI = 0.42 to 0.83) for PUFA (P_{heterogeneity} = .02). These data suggest that the results of the meta-analysis may be partly explained by insufficient follow-up time. Furthermore, they suggest that some environmental and metabolic factors may play a role in prostate carcinogenesis decades before clinical identification of this disease.

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Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis

Abstract

Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.

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Immunomodulatory drugs reactivate lytic EBV.

Purpose:Lenalidomide, thalidomide, and pomalidomide (LTP) are immunomodulatory agents approved for use in multiple myeloma, but in some settings, especially with alkylating agents, an increase in Hodgkin's lymphoma (HL) and other secondary primary malignancies (SPM) has been noted. Some of these malignancies have been linked to Epstein-Barr virus (EBV), raising the possibility that immunomodulatory drugs disrupt latent EBV infection. Experimental Design:We studied the ability of LTP to reactivate latently infected EBV-positive cell lines in vitro and in vivo, and evaluated the EBV viral load in archived serum samples from patients who received a lenalidomide, thalidomide and dexamethasone (LTD) combination. Results:Treatment of EBV-infected B-cell lines with LTP at physiologically relevant concentrations induced the immediate early gene BZLF1, the early gene BMRF1, and the late proteins VCA and BCFR1. This occurred in the potency order pomalidomide>lenalidomide>thalidomide, and the nucleoside analogue ganciclovir enhanced the cytotoxic effects of lenalidomide and pomalidomide in Burkitt's lymphoma cells in vitro and in vivo. EBV reactivation was related to phosphatidylinositol-3 kinase (PI3K) stimulation and Ikaros suppression, and blocked by the PI3K- inhibitor idelalisib. Combinations of lenalidomide with dexamethasone or rituximab increased EBV reactivation compared to lenalidomide alone and, importantly, lenalidomide with melphalan produced even greater reactivation Conclusions:We conclude LTP may reactivate EBV-positive resting memory B-cells thereby enhancing EBV lytic cycle and host immune suppression.

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IL-18's immunotherapeutic effect on pancreatic cancer

Purpose:We sought to find new immune-based treatments for pancreatic cancer (PC). Experimental Design: We detected interleukin (IL)-18 expression in plasma and specimens from patients with PC. We then investigated whether IL-18 had a therapeutic effect for PC in vitro and in vivo, and any underlying mechanisms. Results: Higher plasma IL-18 was associated with longer overall survival, but higher IL-18 in PC tissues was associated with shorter overall survival and increased invasion and metastasis. Recombinant IL-18 alone had no antitumor effect in the syngeneic mice with orthotopically transplanted tumors and promoted tumors in immunocompromised mice; it also facilitated immune responses in vitro and in vivo by augmenting the activity of cytotoxic T cells and NK cells in peripheral bloods and lymph nodes. However, IL-18 promoted the proliferation and invasion of PC cells, in vitro and in vivo, through the NF-B pathway. Nevertheless, by co-administrating IL-18 with BAY11-7082, a NF-B inhibitor, we were able to prevent the pro-cancerous effects of IL-18 and prolong the survive time of the mice. Conclusions: IL-18 has both cancer-promoting and cancer-suppressing functions. Although its single-agent treatment has no therapeutic effect on PC, when combined with the NF-B pathway inhibitor, IL-18 improved survival in a murine PC model. Our study implies the possibility of a combinational immunotherapy that uses IL-18 and targets NF-B pathway.

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Study on the expression of PAK4 and P54 protein in breast cancer

Abstract

Background

Previous evidence have demonstrated that p21-activated kinase PAK4 was correlated with breast cancer. The aim of this paper is to study the expression and interaction of p21-activated kinase (pAK)-4 and P54 protein in breast cancer.

Methods

A total of 80 patients were enrolled in our study (breast fibroma n = 20, breast noninvasive cancer n = 20, early breast invasive cancer n = 20, and advanced breast invasive cancer). The expression of PAK4 was detected by immunohistochemical S-P method, and the relationship between them and the different pathological characteristics were compared. The subcellular localization of P54 and PAK4 in vitro was observed by immunofluorescence assay.

Results

The expression of both PAK4 and P54 in breast cancer was much higher than that in breast fibroma. Meanwhile, we found that both PAK4 and P54 increased gradually as breast cancer progressed (advanced invasive > early invasive > noninvasive). The positive staining of P54 were mainly located in the cytoplasm, especially around the nucleus. There was no significant stained region in the cell matrix. The P54 localization in the cytoplasm was verified by confocal experiment, and the PAK4 was co-localized.

Conclusions

PAK4 and P54 proteins may be used as molecular markers for diagnosis and treatment of breast cancer.

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Germline mutations of BRCA1 gene exon 11 are not associated with platinum response neither with survival advantage in patients with primary ovarian cancer: understanding the clinical importance of one of the biggest human exons. A study of the Tumor Bank Ovarian Cancer (TOC) Consortium

Abstract

Germline mutations in BRCA1 gene have been reported in up to 20 % of epithelial ovarian cancer (EOC) patients. Distinct clinical characteristics have been attributed to this special EOC population. We hypothesized that mutations in different BRCA1 gene exons may differently affect the clinical course of the disease. The aim of this study was to analyze, in a large cohort of primary EOCs, the clinical impact of mutations in BRCA1 gene exon 11, the largest exon of the gene sequence encoding the 60 % of BRCA1 protein. Two hundred sixty-three primary EOC patients, treated between 2000 and 2008 at Charité University Hospital of Berlin, were included. Patients' blood samples were obtained from the Tumor Ovarian Cancer (TOC) Network (www.toc-network.de). Direct sequencing of BRCA1 gene exon 11 was performed for each patient to detect mutations. Based on their BRCA1 exon 11 mutational status, patients were compared regarding clinico-pathological variables and survival. Mutations in BRCA1 exon 11 were found in 18 out of 263 patients (6.8 %). Further 10/263 (3.8 %) cases showed variants of uncertain significance (VUS). All exon 11 BRCA1-positive tumors (100 %) were Type 2 ovarian carcinomas (p = 0.05). Age at diagnosis was significantly younger in Type 2 exon 11 mutated patients (p = 0.01). On multivariate analysis, BRCA1 exon 11 mutational status was not found to be an independent predictive factor for optimal cytoreduction, platinum response, or survival. Mutations in BRCA1 gene exon 11 seem to predispose women to exclusively develop a Type 2 ovarian cancer at younger age. Exon 11 BRCA1-mutated EOC patients showed distinct clinico-pathological features but similar clinical outcome with respect to sporadic EOC patients.

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Preliminary results of robotic colorectal surgery at the National Cancer Institute, Cairo University

Publication date: Available online 13 June 2016
Source:Journal of the Egyptian National Cancer Institute
Author(s): Ashraf Saad Zaghloul, Ahmed Mostafa Mahmoud
BackgroundThe available literature on minimally invasive colorectal cancer demonstrates that laparoscopic approach is feasible and associated with better short term outcomes than open surgery while maintaining equivalent oncologic safety. Reports have shown that robotic surgery may overcome some of the pitfalls of laparoscopic intervention.Objective of the workTo evaluate early results of robotic colorectal surgery, in a cohort of Egyptian patients, regarding operative time, operative and early post-operative complications, hospital stay and pathological results.Patients and methodsA case series study which was carried out in surgical department at National Cancer Institute, Cairo University. Ten Egyptian cases of colorectal cancer (age ranged from 30 to 67, 5 males and 5 females) were recruited from the period of April 2013 to April 2014. Robotic surgery was performed to all cases.ResultsThree patients had low anterior resection, three anterior resection, one total proctectomy, one abdominoperineal resection, one left hemicolectomy and one colostomy. The study reported no mortalities and two morbidities. The mean operative time was 333min. The conversion to open was done in only one patient. A total mesorectal excision with negative circumferential margin was accomplished in all patients, distal margin was positive in one patient. Mean lymph nodes removed was 10.7. Mean hospital stay was 7.4days.ConclusionTo the best of our knowledge, this is the first study reporting the outcomes of robotic colorectal cancer intervention in Egyptian patients. Our preliminary results suggest that robotic-assisted surgery for colorectal cancer can be carried out safely and according to oncological principles.



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Erratum to: Absorption, distribution and excretion of intravenously injected 68 Ge/ 68 Ga generator eluate in healthy rats, and estimation of human radiation dosimetry

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177 Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model

Abstract

Background

¹⁷⁷Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of ¹⁷⁷Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications.

Results

¹⁷⁷Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq ¹⁷⁷Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of ¹⁷⁷Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels.

Conclusions

The ¹⁷⁷Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.

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Decreased brain-expressed X-linked 4 (BEX4) expression promotes growth of oral squamous cell carcinoma

Brain-expressed X-linked (BEX) 4 is a member of BEX family. The functional role of BEX4 in oral squamous cell carcinoma (OSCC) remains unknown.

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Osteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma

Abstract

Central nervous system lymphoma (CNSL) is diagnostically challenging. The identification of reliable and easy to measure biomarkers is desirable to facilitate diagnosis. Here, we evaluated the value of cerebrospinal fluid (CSF) osteopontin (OPN) as a diagnostic biomarker for CNSL. OPN concentrations in CSF from 37 patients with CNSL (29 with primary CNSL and 8 with secondary CNS involvement of systemic lymphoma) and 36 controls [6 patients with inflammatory CNS disease other than multiple sclerosis (MS), 8 with MS, 9 with glioblastoma (GBM) and 13 healthy controls] were determined using an enzyme-linked immunosorbent assay. Non-parametric tests and receiver operating characteristic (ROC) curves were performed for determination of diagnostic accuracy. Median CSF OPN level in all CNSL patients was 620 ng/mL and higher than in patients with inflammatory CNS disease (356 ng/mL); P < .05, MS (163 ng/mL); P < .01, GBM (41 ng/mL); P < .01, or healthy controls (319 ng/mL); P < .01. The area under the ROC curve was 0.865 [95 % confidence interval (CI) 0.745–0.985] for differentiating CNSL and patients with inflammatory CNS disease; 0.956 (95 % CI 0.898–1.000) for CNSL and MS patients; 0.988 (95 % CI 0.964–1.000) for CNSL and GBM patients, and 0.915 (95 % CI 0.834–0.996) for CNSL patients and healthy controls. In multivariate analysis, high CSF OPN level was associated with shorter progression-free (HR 1.61, 95 % CI 1.13–2.31; P = .009) and overall survival (HR 1.52, 95 % CI 1.04–2.21; P = .029). CSF OPN is a potential biomarker in CNSL.

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The transsylvian approach for resection of insular gliomas: technical nuances of splitting the Sylvian fissure

Abstract

Insular gliomas represent a unique surgical challenge due to the complex anatomy and nearby vascular elements associated within the Sylvian fissure. For certain tumors, the transsylvian approach provides an effective technique for achieving maximal safe resection. The goal of this manuscript and video are to present and discuss the surgical nuances and appropriate application of splitting the Sylvian fissure. Our hope is that this video highlights the safety and efficacy of the transsylvian approach for appropriately selected insular gliomas.

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PTEN mRNA expression is less pronounced in left- than right-sided colon cancer: a retrospective observational study

Abstract

Background

Several recent studies have reported that patients with metastatic colorectal cancer (CRC) whose primary tumor is located in left side of the colon have more favorable responses to anti-epidermal growth factor receptor (EGFR) antibody therapy than those with right-sided tumors. However, the mechanism for this phenomenon is unknown.

Methods

Fifty-two cases of primary CRC with liver metastases were analyzed in this retrospective study. The mRNA levels of 19 signal transduction genes in both primary tumor and liver metastases were measured by real-time reverse transcription polymerase chain reaction. The purposes of this study were (1) to determine the correspondence between signal transduction gene expressions in primary tumors and corresponding liver metastases, and (2) to determine whether expression levels of these genes differ by primary tumor location.

Results

mRNA expression levels of 14 of 19 signal transduction genes, including PTEN, ERBB2, MET, HGF, AREG, and EREG, showed significant correlations between the primary tumor and corresponding liver metastases. When the mRNA levels of the primary tumors were compared by tumor location, only PTEN mRNA expression differed significantly between left and right-sided CRC (median PTEN expression: left 1.00 vs. right 1.68; p = 0.017). When rectal cancers were separated from left-sided colon cancers, PTEN mRNA levels increased progressively from rectum to right-sided colon (median; rectum 0.84, left colon 1.23, right colon 1.68, p = 0.013). PTEN mRNA expression in liver metastases also differed significantly according to primary tumor location (median; left 0.92 vs. right 1.27, p = 0.048). There was no difference in overall survival between patients with high versus low levels of PTEN mRNA (p = 0.59).

Conclusions

Our data suggest that the PIK3/AKT/mTOR pathway is more active in left- than right-sided CRC, which provides a possible explanation for the fact that efficacy of anti-EGFR therapy differs by location of primary tumor.

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Molecular analyses of unselected head and neck cancer cases demonstrates that human papillomavirus transcriptional activity is positively associated with survival and prognosis

Abstract

Background

Human papillomavirus DNA detection in head and neck squamous cell carcinoma has been linked to improved patient prognosis. The main aims of the study was to test the hypotheses that HPV16 E6/E7 oncogene and p53 function within tumours were associated with the widely reported improved patient survival and prognosis in head and neck cancer.

Methods

HPV16 DNA, mRNA and p53 mRNA presence were analysed in a prospective study of 42 unselected HNSCC patients; correlating the data with patient age, tumour staging/grade, treatment response, disease recurrence and survival.

Results

HPV16 DNA and HPV16 mRNA were present in 45.2 % and 21.4 % of patients, respectively. There was a significant positive association between the detection of HPV16 E6/E7 mRNA and p53 mRNA (p = 0.032), but this was not replicated for HPV16 DNA. Five-year disease free survival for the whole cohort was 63 % (CI 52.5–73.5 %). Multivariable analysis revealed only HPV16 E6/E7 mRNA expression to have significant prognostic influence (p = 0.04).

Conclusions

Our study suggests that HPV16 oncogenic transcriptional activity within HNSCC tumours is associated with improved patient survival and better prognosis in a German population. Simple HPV DNA detection alone did not demonstrate this association. The significant association of full-length (wild-type) p53 with HPV16 E6/E7 mRNA is further evidence for a functional relationship, which could contribute to the widely reported improved survival and prognosis. Larger studies are required to validate the frequency of HPV16 mRNA expression in HNSCC.

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Associations of an abnormal Pap test result with attitudes and beliefs relevant to cervical cancer: a study of rural Appalachian women

Abstract

Purpose

To compare women who recall being informed of an abnormal Pap to those not having this experience relative to attitudes and beliefs pertaining to screening for cervical cancer.

Methods

Four hundred women were recruited from eight rural Appalachian counties, in 2013 and 2014. Women completed a paper-and-pencil survey after providing written informed consent. Bivariate associations and age-adjusted associations were calculated between the self-reported experience of being told of an abnormal Pap test result and eight attitudes/beliefs relative to the prevention of cervical cancer. Data analyses were performed in 2014.

Results

The mean age was 40.2 years (range 30–64 years). Eighteen women chose not to answer the question asking about ever having an abnormal Pap test result, leaving n = 382. Of the 382 women who did answer, 122 (30.6 %) indicated having an abnormal Pap test result and the remaining 260 (65.2 %) indicated never having this experience. With the exception of one item assessing knowledge that HPV is the cause of cervical cancer, between-group differences in attitudes, beliefs, and intent to have a Pap test the next time one is due were not observed.

Conclusions

Although we hypothesized that women ever having an abnormal Pap test may have actively sought to learn more about cervical cancer and its prevention, findings suggest that this is not the case. Informing women of an abnormal result could be coupled with a high-intensity counseling designed to improve attitudes and beliefs relative to women's role in protecting themselves from cervical cancer.

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Comparison of abdominal adiposity and overall obesity in relation to risk of small intestinal cancer in a European Prospective Cohort

Abstract

Background

The etiology of small intestinal cancer (SIC) is largely unknown, and there are very few epidemiological studies published to date. No studies have investigated abdominal adiposity in relation to SIC.

Methods

We investigated overall obesity and abdominal adiposity in relation to SIC in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective cohort of approximately half a million men and women from ten European countries. Overall obesity and abdominal obesity were assessed by body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Multivariate Cox proportional hazards regression modeling was performed to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Stratified analyses were conducted by sex, BMI, and smoking status.

Results

During an average of 13.9 years of follow-up, 131 incident cases of SIC (including 41 adenocarcinomas, 44 malignant carcinoid tumors, 15 sarcomas and 10 lymphomas, and 21 unknown histology) were identified. WC was positively associated with SIC in a crude model that also included BMI (HR per 5-cm increase = 1.20, 95 % CI 1.04, 1.39), but this association attenuated in the multivariable model (HR 1.18, 95 % CI 0.98, 1.42). However, the association between WC and SIC was strengthened when the analysis was restricted to adenocarcinoma of the small intestine (multivariable HR adjusted for BMI = 1.56, 95 % CI 1.11, 2.17). There were no other significant associations.

Conclusion

WC, rather than BMI, may be positively associated with adenocarcinomas but not carcinoid tumors of the small intestine.

Impact

Abdominal obesity is a potential risk factor for adenocarcinoma in the small intestine.

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Dietary inflammatory index, Mediterranean diet score, and lung cancer: a prospective study

Abstract

Purpose

To investigate prospectively the associations of Dietary Inflammatory Index (DII) and Mediterranean Diet Score (MDS) with lung cancer.

Methods

We used data from men and women aged 40–69 years at recruitment in 1990–1994, who were participants in the Melbourne Collaborative Cohort Study (n = 35,303). A total of 403 incident lung cancer cases were identified over an average 18-year follow-up. Hazard ratios (HR) were estimated using Cox regression, adjusting for smoking status and other risk factors, with age as the time metric.

Results

An inverse correlation was observed between the DII and MDS (ρ = −0.45), consistent with a higher DII being pro-inflammatory and less 'healthy,' while a high MDS reflects a 'healthier' diet. The DII was positively associated with risk of lung cancer in current smokers [HR_{Q4 vs Q1} = 1.70 (1.02, 2.82); P_trend = 0.008] (p interaction between DII quartiles and smoking status = 0.03). The MDS was inversely associated with lung cancer risk overall [HR_{7–9 vs 0–3} = 0.64 (0.45, 0.90); P_trend = 0.005] and for current smokers (HR_{7–9 vs 0–3} = 0.38 (0.19, 0.75); P_trend = 0.005) (p interaction between MDS categories and smoking status = 0.31).

Conclusions

The MDS showed an inverse association with lung cancer risk, especially for current smokers. A high DII, indicating a more pro-inflammatory diet, was associated with risk of lung cancer only for current smokers. A healthy diet may reduce the risk of lung cancer, especially in smokers.

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Maternal prenatal intake of one-carbon metabolism nutrients and risk of childhood leukemia

Abstract

Purpose

Folate, vitamins B12 and B6, riboflavin, and methionine are critical nutrients for the one-carbon metabolism cycle involved in DNA synthesis and epigenetic processes. We examined the association between maternal intake of these nutrients before pregnancy and risk of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in a matched case–control study.

Methods

Maternal dietary intake and vitamin supplement use in the year before pregnancy was assessed by food frequency questionnaire for 681 ALL cases, 103 AML cases, and 1076 controls. Principal component analysis was used to construct a variable representing combined nutrient intake, and conditional logistic regression estimated the odds ratio (OR) and 95% confidence interval (CI) for the association of ALL and AML with the principal component and each nutrient.

Results

Higher maternal intake of one-carbon metabolism nutrients from food and supplements combined was associated with reduced risk of ALL (OR for one-unit change in the principal component = 0.91, CI 0.84–0.99) and possibly AML (OR for the principal component = 0.83, CI 0.66–1.04). When analyzed separately, intake of supplements high in these nutrients was associated with a reduced risk of ALL in children of Hispanic women only.

Conclusions

In conclusion, these data suggest that higher maternal intake of one-carbon metabolism nutrients may reduce risk of childhood leukemia.

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Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis

Abstract

Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.

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Osteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma

Abstract

Central nervous system lymphoma (CNSL) is diagnostically challenging. The identification of reliable and easy to measure biomarkers is desirable to facilitate diagnosis. Here, we evaluated the value of cerebrospinal fluid (CSF) osteopontin (OPN) as a diagnostic biomarker for CNSL. OPN concentrations in CSF from 37 patients with CNSL (29 with primary CNSL and 8 with secondary CNS involvement of systemic lymphoma) and 36 controls [6 patients with inflammatory CNS disease other than multiple sclerosis (MS), 8 with MS, 9 with glioblastoma (GBM) and 13 healthy controls] were determined using an enzyme-linked immunosorbent assay. Non-parametric tests and receiver operating characteristic (ROC) curves were performed for determination of diagnostic accuracy. Median CSF OPN level in all CNSL patients was 620 ng/mL and higher than in patients with inflammatory CNS disease (356 ng/mL); P < .05, MS (163 ng/mL); P < .01, GBM (41 ng/mL); P < .01, or healthy controls (319 ng/mL); P < .01. The area under the ROC curve was 0.865 [95 % confidence interval (CI) 0.745–0.985] for differentiating CNSL and patients with inflammatory CNS disease; 0.956 (95 % CI 0.898–1.000) for CNSL and MS patients; 0.988 (95 % CI 0.964–1.000) for CNSL and GBM patients, and 0.915 (95 % CI 0.834–0.996) for CNSL patients and healthy controls. In multivariate analysis, high CSF OPN level was associated with shorter progression-free (HR 1.61, 95 % CI 1.13–2.31; P = .009) and overall survival (HR 1.52, 95 % CI 1.04–2.21; P = .029). CSF OPN is a potential biomarker in CNSL.

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The transsylvian approach for resection of insular gliomas: technical nuances of splitting the Sylvian fissure

Abstract

Insular gliomas represent a unique surgical challenge due to the complex anatomy and nearby vascular elements associated within the Sylvian fissure. For certain tumors, the transsylvian approach provides an effective technique for achieving maximal safe resection. The goal of this manuscript and video are to present and discuss the surgical nuances and appropriate application of splitting the Sylvian fissure. Our hope is that this video highlights the safety and efficacy of the transsylvian approach for appropriately selected insular gliomas.

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Stereotactic biopsy of brainstem lesions: 21 years experiences of a single center

Abstract

Stereotactic biopsies are procedures performed to obtain tumor tissue for diagnostic examinations. Cerebral lesions of unknown entities can safely be accessed and tissue can be examined, resulting in correct diagnosis and according treatment. Stereotactic procedures of lesions in highly eloquent regions such as the brainstem have been performed for more than two decades in our department. In this retrospective study we focus on results, approaches, modalities of anesthesia, and complications. We performed a retrospective analysis of our prospective database, including 26 patients who underwent stereotactic biopsy of the brainstem between April 1994 and June 2015. All of the patients underwent preoperative MRI. Riechert–Mundinger-frame was used before 2000, thereafter the Leksell stereotactic frame was used. After 2000 entry and target points were calculated by using BrainLab stereotactic system. We evaluated histopathological results as well as further treatment; additionally we compared complications of local versus general anesthesia and complications of a frontal versus a trans-cerebellar approach. Median age of all patients was 33 years, and median number of tissue samples taken was 12. In all patients a final histopathological diagnosis could be established. 5 patients underwent the procedure under local anesthesia, 21 patients in general anesthesia. In 19 patients a frontal approach was performed, while in 7 patients a trans-cerebellar approach was used. Complications occurred in five patients. Thereby no significant difference was found with regard to approach (frontal versus trans-cerebellar) or anesthesia (local versus general). Stereotactic biopsies even of lesions in the brainstem are a save way to obtain tumor tissue for final diagnosis, resulting in adequate treatment. Approach can be trans-cerebellar or frontal and procedure can be performed either under local or general anesthesia without significant differences concerning complication rate.

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Monte Carlo simulations of the clinical benefits from therapeutic drug monitoring of sunitinib in patients with gastrointestinal stromal tumours

Abstract

Purpose

Therapeutic drug monitoring (TDM) is being considered as a tool to individualise sunitinib treatment of gastrointestinal stromal tumours (GIST). Here, we used computer simulations to assess the expected impact of sunitinib TDM on the clinical outcome of patients with GIST.

Methods

Monte Carlo simulations were performed in R, based on previously published pharmacokinetic–pharmacodynamic models. Clinical trials with dose-limiting toxicity and patient dropout were simulated to establish the study size required to obtain sufficient statistical power for comparison of TDM-guided and fixed dosing.

Results

The simulations revealed that TDM might increase time to tumour progression by about 1–2 months (15–31 %) in eligible patients. However, the number of subjects required for a sufficient statistical power to quantify clinical benefit of TDM guided is likely to be prohibitively high (>1000).

Conclusion

Although data from randomised clinical trials on the clinical impact of sunitinib TDM are lacking, our findings support implementation of sunitinib TDM in clinical practice. For rare cancers with well-defined exposure–response relationships, modelling and simulation might allow the optimisation of dosing strategies when clinical trials cannot be performed due to low number of patients.

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Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis

Abstract

Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.

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Rad51C-ATXN7 fusion gene expression in colorectal tumors

Abstract

Background

Fusion proteins have unique oncogenic properties and their identification can be useful either as diagnostic or therapeutic targets. Next generation sequencing data have previously shown a fusion gene formed between Rad51C and ATXN7 genes in the MCF7 breast cancer cell line. However, the existence of this fusion gene in colorectal patient tumor tissues is largely still unknown.

Methods

We evaluated for the presence of Rad51C-ATXN7 fusion gene in colorectal tumors and cells by RT-PCR, PCR, Topo TA cloning, Real time PCR, immunoprecipitation and immunoblotting techniques.

Results

We identified two forms of fusion mRNAs between Rad51C and ATXN7 in the colorectal tumors, including a Variant 1 (fusion transcript between Rad51C exons 1–7 and ATXN7 exons 6–13), and a Variant 2 (between Rad51C exons 1–6 and ATXN7 exons 6–13). In silico analysis showed that the Variant 1 produces a truncated protein, whereas the Variant 2 was predicted to produce a fusion protein with molecular weight of 110 KDa. Immunoprecipitation and Western blot analysis further showed a 110 KDa protein in colorectal tumors. 5-Azacytidine treatment of LS-174 T cells caused a 3.51-fold increase in expression of the fusion gene (Variant 2) as compared to no treatment controls evaluated by real time PCR.

Conclusion

In conclusion we found a fusion gene between DNA repair gene Rad51C and neuro-cerebral ataxia Ataxin-7 gene in colorectal tumors. The in-frame fusion transcript of Variant 2 results in a fusion protein with molecular weight of 110 KDa. In addition, we found that expression of fusion gene is associated with functional impairment of Fanconi Anemia (FA) DNA repair pathway in colorectal tumors. The expression of Rad51C-ATXN7 in tumors warrants further investigation, as it suggests the potential of the fusion gene in treatment and predictive value in colorectal cancers.

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Monte Carlo simulations of the clinical benefits from therapeutic drug monitoring of sunitinib in patients with gastrointestinal stromal tumours

Abstract

Purpose

Therapeutic drug monitoring (TDM) is being considered as a tool to individualise sunitinib treatment of gastrointestinal stromal tumours (GIST). Here, we used computer simulations to assess the expected impact of sunitinib TDM on the clinical outcome of patients with GIST.

Methods

Monte Carlo simulations were performed in R, based on previously published pharmacokinetic–pharmacodynamic models. Clinical trials with dose-limiting toxicity and patient dropout were simulated to establish the study size required to obtain sufficient statistical power for comparison of TDM-guided and fixed dosing.

Results

The simulations revealed that TDM might increase time to tumour progression by about 1–2 months (15–31 %) in eligible patients. However, the number of subjects required for a sufficient statistical power to quantify clinical benefit of TDM guided is likely to be prohibitively high (>1000).

Conclusion

Although data from randomised clinical trials on the clinical impact of sunitinib TDM are lacking, our findings support implementation of sunitinib TDM in clinical practice. For rare cancers with well-defined exposure–response relationships, modelling and simulation might allow the optimisation of dosing strategies when clinical trials cannot be performed due to low number of patients.

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Molecular Bases of Aberrant miR-182 Expression in Ovarian Cancer

Abstract

The molecular bases of miR-182 deregulation in epithelial ovarian cancers (EOCs) remain unknown and its diagnostic or prognostic role in EOCs is still unclear.

We performed miR-182 expression analysis using a microarray approach and real-time PCR (qPCR). We also used array comparative genomic hybridization and methylated DNA immunoprecipitation to study copy number changes and methylation aberrations within coding locus/promoter sequences of miR-182 in EOC tissues, respectively.

We have found that miR-182 expression is significantly increased in EOC (P<0.00001) and that higher miR-182 expression in EOC is linked with significantly shorter overall survival (P=0.026). The methylation of miR-182 promoter was significantly associated with lower miR-182 expression in EOC tissues (P=0.045). miR-182 over-expression is connected with copy number (CN) gains of this miRNA coding sequences in EOC (P=0.002), and the number of PRDM5 copies is significantly and inversely correlated with miR-182 expression evaluated by qPCR (R=-0.615, P=0.009). We conclude that the aberrant miR-182 expression in EOC may be due to CN gains within its coding locus. The miR-182 promoter is rarely methylated in EOC, and its methylation status is associated with lower miR-182 expression. Deletion of the PRDM5 locus may play a supportive role in miR-182 overexpression in EOC. miR-182 is an unfavorable prognostic factor in EOC. This article is protected by copyright. All rights reserved.

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Analysis of Alternative Lengthening of Telomere Markers in BRCA1 Defective Cells

Abstract

Telomeres are specialised structures responsible for the chromosome end protection. Previous studies have revealed that defective BRCA1 may lead to elevated telomere fusions and accelerated telomere shortening. In addition, BRCA1 associates with promyelocytic leukemia (PML) bodies in alternative lengthening of telomeres (ALT) positive cells. We report here elevated recombination rates at telomeres in cells from human BRCA1 mutation carriers and in mouse embryonic stem cells lacking both copies of functional Brca1. An increased recombination rate at telomeres is one of the signs of ALT. To investigate this possibility further we employed the C-circle assay that identifies ALT unequivocally. Our results revealed elevated levels of ALT activity in Brca1 defective mouse cells. Similar results were obtained when the same cells were assayed for the presence of another ALT marker, namely the frequency of PML bodies. These results suggest that BRCA1 may act as a repressor of ALT. This article is protected by copyright. All rights reserved.

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Decreased brain-expressed X-linked 4 (BEX4) expression promotes growth of oral squamous cell carcinoma

Abstract

Background

Brain-expressed X-linked (BEX) 4 is a member of BEX family. The functional role of BEX4 in oral squamous cell carcinoma (OSCC) remains unknown.

Methods

Expression level of BEX family members (BEX1-5) in OSCC tissues and the paired normal epithelial were examined. Functions of epigenetic changes (DNA methylation and histone modifications) on BEX4 suppression in OSCC were examined by zebularine and trichostatin A (TSA) treatment on OSCC cell lines. Lentivector containing full-length BEX4 was used to generate OSCC cell lines with stable BEX4 expression. Effects of BEX4 expression on OSCC proliferation were monitored with xCELLigence RTCA real-time cell analyzer. BEX4-overexpressing CAL27 was implanted into nude mice to evaluate the effects on tumor growth in vivo. The signaling pathways regulated by BEX4 in OSCC was explored using human whole-transcript expression microarray.

Results

Among the 5 BEX family members, BEX1 and BEX4 showed significant down-regulation in OSCC (P < 0.001). BEX3, in comparison, was overexpressed in the primary tumor. BEX4 expression in OSCC cell lines was re-activated after zebularine and TSA treatment. High BEX4 expression could suppress proliferation of OSCC in vitro. Subcutaneous tumor volume of BEX4-overexpressing CAL27 was remarkably reduced in nude mice. Microarray experiment showed that S100A family members (S100A7, S100A7A, S100A8, S100A9 & S100A12) might be the downstream targets of BEX4 in OSCC.

Conclusions

BEX4 functions as tumor suppressor by inhibiting proliferation and growth of oral cancer. Decreased BEX4 contributes to the increased proliferative propensity of OSCC.

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Navigating your career path in pediatric hematology/oncology: On and off the beaten track

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Loss of OLFM4 promotes tumor migration through inducing interleukin-8 expression and predicts lymph node metastasis in early gastric cancer

Loss of OLFM4 promotes tumor migration through inducing interleukin-8 expression and predicts lymph node metastasis in early gastric cancer

Oncogenesis 5, e234 (June 2016). doi:10.1038/oncsis.2016.42

Authors: J Zhao, P Shu, F Duan, X Wang, L Min, Z Shen, Y Ruan, J Qin, Y Sun & X Qin

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Improvement of gemcitabine sensitivity of p53-mutated pancreatic cancer MiaPaCa-2 cells by RUNX2 depletion-mediated augmentation of TAp73-dependent cell death

Improvement of gemcitabine sensitivity of p53-mutated pancreatic cancer MiaPaCa-2 cells by RUNX2 depletion-mediated augmentation of TAp73-dependent cell death

Oncogenesis 5, e233 (June 2016). doi:10.1038/oncsis.2016.40

Authors: M Nakamura, H Sugimoto, T Ogata, K Hiraoka, H Yoda, M Sang, M Sang, Y Zhu, M Yu, O Shimozato & T Ozaki

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Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model

Abstract

Podoplanin (Aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin monoclonal antibody, NZ-1, and a rat-human chimeric anti-human podoplanin antibody, NZ-8, derived from NZ-1, which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against podoplanin-positive MPM cell lines. In this study, we demonstrated the antitumor effect of NZ-1, NZ-8, and NZ-12, a novel rat-human chimeric anti-human podoplanin antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a⁺) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human NK (CD56⁺) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ-12 induced potent ADCC mediated by human MNC, compared with either NZ-1 or NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56⁺) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ-12 mediated by human NK (CD56⁺) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that a combination therapy of both podoplanin-targeting immunotherapy using NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM.

This article is protected by copyright. All rights reserved.

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Knowledge of, attitudes toward, and use of low-dose computed tomography for lung cancer screening among family physicians

BACKGROUND

The results of the National Lung Screening Trial showed a 20% reduction in lung cancer mortality and a 6.7% reduction in all-cause mortality when high-risk patients were screened with low-dose computed tomography (LDCT) versus chest x-ray (CXR). The US Preventive Services Task Force has issued a grade B recommendation for LDCT screening, and the Centers for Medicare and Medicaid Services and private insurers now cover the screening cost under certain conditions. The purpose of this study was to assess the knowledge of, attitudes toward, and use of LDCT screening for lung cancer among family physicians.

METHODS

A 32-item questionnaire was distributed to members of the South Carolina Academy of Family Physicians in 2015. Descriptive statistics were calculated.

RESULTS

There were 101 respondents, and most had incorrect knowledge about which organizations recommended screening. Many physicians continued to recommend CXR for lung cancer screening. Most felt that LDCT screening increased the odds of detecting disease at earlier stages (98%) and that the benefits outweighed the harms (75%). Concerns included unnecessary procedures (88%), stress/anxiety (52%), and radiation exposure (50%). Most physicians discussed the risks/benefits of screening with their patients in some capacity (76%); however, more than 50% reported making 1 or no screening recommendations in the past year.

CONCLUSIONS

Most family physicians report discussing LDCT with patients at high risk for lung cancer; however, referrals remain low. There are gaps in physician knowledge about screening guidelines and reimbursement, and this indicates a need for further educational outreach. The development of decision aids may facilitate shared decision-making discussions about screening, and targeted interventions may improve knowledge gaps. Cancer 2016. © 2016 American Cancer Society.

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Two decades of lung cancer through the pages of Cancer Cytopathology

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Issue Information

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Gladwyn Leiman: An appreciation

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Caging the pack

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2016 publication schedule

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Cardiac MRI: a Translational Imaging Tool for Characterizing Anthracycline-Induced Myocardial Remodeling

Abstract

Cardiovascular side effects of cancer therapeutics are the leading causes of morbidity and mortality in cancer survivors. Anthracyclines (AC) serve as the backbone of many anti-cancer treatment strategies, but dose-dependent myocardial injury limits their use. Cumulative AC exposure can disrupt the dynamic equilibrium of the myocardial microarchitecture while repeated injury and repair leads to myocyte loss, interstitial myocardial fibrosis, and impaired contractility. Although children are assumed to have greater myocardial plasticity, AC exposure at a younger age portends worse prognosis. In older patients, there is lower overall survival once they develop cardiovascular disease. Because aberrations in the myocardial architecture predispose the heart to a decline in function, early detection with sensitive imaging tools is crucial and the implications for resource utilization are substantial. As a comprehensive imaging modality, cardiac magnetic resonance (CMR) imaging is able to go beyond quantification of ejection fraction and myocardial deformation to characterize adaptive microstructural and microvascular changes that are important to myocardial tissue health. Herein, we describe CMR as an established translational imaging tool that can be used clinically to characterize AC-associated myocardial remodeling.

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The Role of Intravoxel Incoherent Motion MRI in Predicting Early Treatment Response to Chemoradiation for Metastatic Lymph Nodes in Nasopharyngeal Carcinoma

Abstract

Introduction

Pilot studies have suggested potential clinical applications for intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) in head and neck cancers. This study aimed to characterize metastatic lymph nodes using IVIM MRI, and to evaluate the role of IVIM MRI in the prediction of the early treatment response of lymph node metastasis from nasopharyngeal carcinoma (NPC).

Methods

A total of 122 patients with metastatic lymph nodes from NPC underwent two MRI examinations, pre-treatment and post-treatment (at 4 weeks and at ≥2 years from the end of chemoradiotherapy). Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. Differences in the initial IVIM parameters [pure molecular diffusion (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f)] between nodes with a partial response (PR) and a complete response (CR) were analyzed in 102 patients after the exclusion of 20.

Results

The initial D*, D, and apparent diffusion coefficient (ADC) did not reveal a significant difference between nodes showing a PR or a CR. The mean initial f value was significantly higher in patients with a PR relative to patients with a CR (p = 0.003), and its sensitivity and specificity in predicting treatment response to chemoradiotherapy were 86.7% and 100%, respectively.

Conclusions

The present study indicated that the initial f value may be more accurate than the initial D*, D, and ADC in the early prediction of treatment response to chemoradiotherapy for metastatic lymph nodes in patients with NPC.

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Unusual association of non-anaplastic Wilms tumor and Cornelia de Lange syndrome: case report

Abstract

Background

Cornelia de Lange syndrome is the prototype for cohesinopathy disorders, which are characterized by defects in chromosome segregation. Kidney malformations, including nephrogenic rests, are common in Cornelia de Lange syndrome. Only one post-mortem case report has described an association between Wilms tumor and Cornelia de Lange syndrome. Here, we describe the first case of a living child with both diseases.

Case presentation

Non-anaplastic triphasic nephroblastoma was diagnosed in a patient carrying a not yet reported mutation in NIPBL (c.4920 G > A). The patient had the typical facial appearance and intellectual disability associated with Cornelia de Lange syndrome in absence of limb involvement. The child's kidneys were examined by ultrasound at 2 years of age to exclude kidney abnormalities associated with the syndrome. She underwent pre-operative chemotherapy and nephrectomy. Seven months later she was healthy and without residual detectable disease.

Conclusion

The previous report of such co-occurrence, together with our report and previous reports of nephrogenic rests, led us to wonder if there may be any causal relationship between these two rare entities. The wingless/integrated (Wnt) pathway, which is implicated in kidney development, is constitutively activated in approximately 15–20 % of all non-anaplastic Wilms tumors. Interestingly, the Wnt pathway was recently found to be perturbed in a zebrafish model of Cornelia de Lange syndrome. Mutations in cohesin complex genes and regulators have also been identified in several types of cancers. On the other hand, there is no clear evidence of an increased risk of cancer in Cornelia de Lange syndrome, and no other similar cases have been published since the fist one reported by Cohen, and this prompts to think Wilms tumor and Cornelia de Lange syndrome occurred together in our patient by chance.

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Stereotactic biopsy of brainstem lesions: 21 years experiences of a single center

Abstract

Stereotactic biopsies are procedures performed to obtain tumor tissue for diagnostic examinations. Cerebral lesions of unknown entities can safely be accessed and tissue can be examined, resulting in correct diagnosis and according treatment. Stereotactic procedures of lesions in highly eloquent regions such as the brainstem have been performed for more than two decades in our department. In this retrospective study we focus on results, approaches, modalities of anesthesia, and complications. We performed a retrospective analysis of our prospective database, including 26 patients who underwent stereotactic biopsy of the brainstem between April 1994 and June 2015. All of the patients underwent preoperative MRI. Riechert–Mundinger-frame was used before 2000, thereafter the Leksell stereotactic frame was used. After 2000 entry and target points were calculated by using BrainLab stereotactic system. We evaluated histopathological results as well as further treatment; additionally we compared complications of local versus general anesthesia and complications of a frontal versus a trans-cerebellar approach. Median age of all patients was 33 years, and median number of tissue samples taken was 12. In all patients a final histopathological diagnosis could be established. 5 patients underwent the procedure under local anesthesia, 21 patients in general anesthesia. In 19 patients a frontal approach was performed, while in 7 patients a trans-cerebellar approach was used. Complications occurred in five patients. Thereby no significant difference was found with regard to approach (frontal versus trans-cerebellar) or anesthesia (local versus general). Stereotactic biopsies even of lesions in the brainstem are a save way to obtain tumor tissue for final diagnosis, resulting in adequate treatment. Approach can be trans-cerebellar or frontal and procedure can be performed either under local or general anesthesia without significant differences concerning complication rate.

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MicroRNA-132 targets PEA-15 and suppresses the progression of astrocytoma in vitro

Abstract

Gliomas are highly malignant tumors, the most common of which are astrocytomas. A growing number of studies suggest that dysregulation of miRNAs is a frequent event contributing to the pathogenesis of gliomas. In this study, we found that over-expression of miR-132 inhibited cell proliferation and migration and triggered apoptosis, while knockdown of miR-132 showed opposite effects. PEA-15 was identified as a direct target of miR-132. Reintroduction of PEA-15 without 3′UTR region reversed the inhibitory effects of miR-132 on cell proliferation, migration, and apoptosis. MiR-132 was inversely correlated with the PEA-15 expression. CREB (cAMP response element binding protein) and KLF (Krüppel-like factor 8) were conformed as transcription factors of miR-132, which bidirectionally regulate the expression of miR-132. Our study suggests that miR-132 is an important tumor suppressor of astrocytoma progression by targeting PEA-15, while CREB and KLF can modulate the expression of miR-132, thus providing new insight into the molecular mechanisms underlying astrocytoma progression in vitro.

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