Mutational analysis of the RB1 gene and the inheritance patterns of retinoblastoma in Jordan

Abstract

Retinoblastoma (RB) is a childhood cancer developing in the retina due to RB1 pathologic variant. Herein we are evaluating the oncogenic mutations in the RB1 gene and the inheritance patterns of RB in the Jordanian patients. In this prospective study, the peripheral blood of 50 retinoblastoma patients was collected, genomic DNA was extracted, mutations were identified using Quantitative multiplex PCR (QM-PCR), Allele-specific PCR, Next Generation Sequencing analysis, and Sanger sequencing. In this cohort of 50 patients, 20(40%) patients had unilateral RB and 30(60%) were males. Overall, 36(72%) patients had germline disease, 17(47%) of whom had the same RB1 pathologic variant detected in one of the parents (inherited disease). In the bilateral group, all (100%) patients had germline disease; 13(43%) of them had inherited mutation. In the unilateral group, 6(30%) had germline disease, 4(20%) of them had inherited mutation. Nonsense mutation generating a stop codon and producing a truncated non-functional protein was the most frequent detected type of mutations (n = 15/36, 42%). Only one (2%) of the patients had mosaic mutation, and of the 17 inherited cases, 16(94%) had an unaffected carrier parent. In conclusion, in addition to all bilateral RB patients in our cohort, 30% of unilateral cases showed germline mutation. Almost half (47%) of germline cases had inherited disease from affected (6%) parent or unaffected carrier (94%). Therefore molecular screening is critical for the genetic counseling regarding the risk for inherited RB in both unilateral and bilateral cases including those with no family history.

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Childhood body mass index and height in relation to site-specific risks of colorectal cancers in adult life

Abstract

As colorectal cancers have a long latency period, their origins may lie early in life. Therefore childhood body mass index (BMI; kg/m²) and height may be associated with adult colorectal cancer. Using a cohort design, 257,623 children from The Copenhagen School Health Records Register born from 1930 to 1972 with measured heights and weights at ages 7 to 13 years were followed for adult colon and rectal adenocarcinomas by linkage to the Danish Cancer Registry. Hazard ratios (HRs) with 95% confidence intervals (CI) were estimated by Cox proportional hazard regressions. During follow-up, 2676 colon and 1681 rectal adenocarcinomas were diagnosed. No sex differences were observed in the associations between child BMI or height and adult colon or rectal cancers. Childhood BMI and height were positively associated with colon cancer; at age 13 years the HRs were 1.09 (95% CI 1.04–1.14) and 1.14 (95% CI 1.09–1.19) per z-score, respectively. Children who were persistently taller or heavier than average, had increased risk of colon cancer. Similarly, growing taller or gaining more weight than average was positively associated with colon cancer. No associations were observed between BMI or height and rectal cancer. Childhood BMI and height, along with above average change during childhood are significantly and positively associated with adult colon cancers, but not with rectal cancer, suggesting different etiologies.

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Traditional Chinese medicine as adjunctive therapy improves the long-term survival of lung cancer patients

Abstract

Purpose

Traditional Chinese medicine is one of the popular alternative treatments for cancer, mainly enhancing host immune response and reducing adverse effect of chemotherapy. This study first explored traditional Chinese medicine treatment effect on long-term survival of lung cancer patients.

Methods

This study evaluated whether traditional Chinese medicine combined with conventional cancer treatment improved overall survival of lung cancer patients. We had conducted a retrospective cohort study on 111,564 newly diagnosed lung cancer patients in 2000–2009 from National Health Insurance Program database.

Results

A total of 23,803 (21.31%) patients used traditional Chinese medicine for lung cancer care. Eligible participants were followed up until 2011 with a mean follow-up period of 1.96 years (standard deviation 2.55) for non-TCM users and 3.04 years (2.85) for traditional Chinese medicine users. Patients with traditional Chinese medicine utilization were significantly more likely to have a 32% decreased risk of death [hazard ratio = 0.62; 95% confidence interval = 0.61–0.63], compared with patients without traditional Chinese medicine utilization after multivariate adjustment. We also observed a similar significant reduction risk across various subgroups of chronic lung diseases. Qing Zao Jiu Fei Tang was the most effective traditional Chinese medicine agent for mortality reduction both in the entire lung cancer (0.81; 0.72–0.91) and matched populations (0.86; 0.78–0.95).

Conclusion

This study demonstrated adjunctive therapy with traditional Chinese medicine may improve overall survival of lung cancer patients. This study also suggested traditional Chinese medicine may be used as an adjunctive therapy for cancer treatment. These observational findings need being validated by future randomized controlled trials to rule out the possibility of effect due to holistic care.

http://ift.tt/2wRfZFj

INST OX-05-024: first line gemcitabine, oxaliplatin, and erlotinib for primary hepatocellular carcinoma and bile duct cancers: a multicenter Phase II trial

Abstract

Hepatocellular Carcinoma (HCC) incidence is increasing in the USA. Gemcitabine (G) and oxaliplatin (O) are active in HCC and biliary duct cancer (BDC). Erlotinib (E) is an EGFR tyrosine kinase inhibitor (TKI) with known activity against both. We sought to evaluate the efficacy of the combination G+O+E. Patients with either of the two diagnosis were treated in a phase II trial. Simons 2 stage design was used. A disease-control rate (DCR), complete response (CR) + partial response (PR)+ stable disease (SD) at 24 weeks of ≤20% and >40% (P0 and P1 of 0.2 and 0.4, respectively) were set as undesirable (null) and desirable results. 26 HCC and 7 BDC patients were accrued. In HCC, 1 PR, 10 SD, and 9 PDs were seen. DCR in HCC was 42%. Among seven (7) patients with BDC, one patient was not evaluable; one achieved a long lasting PR, and five patients had SD and DCR was 86%. Median overall survival (OS) times and progression-free survivals (PFS) were 196 and 149 days in HCC and 238 days and not reached in BDC. PFS at 26 weeks in HCC was 41% and at 21 weeks in BDC was 60%. Grade 3 toxicities in >5% of patients were fatigue (12.9%), neutropenia (9.6%), thrombocytopenia (9.6%), and diarrhea (6.4%). G+O+E exceeded both preset P0a and P1 of the primary objective with a PFS of 41% at 26 weeks for HCC and preliminary BDC data may warrant further investigations.

This is a phase II trial in the first line setting with gemcitabine, oxaliplatin, and erlotinib for primary hepatocellular carcinoma and bile duct cancer. The trial shows interesting results specially in the bile duct cancer arm and this combination should be tested in a randomized setting in comparison with standard of care.

http://ift.tt/2uPd3b7

Mediating burden and stress over time: Caregivers of patients with primary brain tumor

Abstract

There is a growing literature on the effects of cancer caregiving on the well-being of informal family caregivers. However, there has been little longitudinal research on caregivers of patients with the complex, rapidly-changing disease of primary malignant brain tumor (PBT).

Objective

Our objective was to model longitudinal relationships between caregiver burden, social support, and distress within caregivers of patients with PBT.

Methods

Caregiver participants were recruited from a neuro-oncology clinic. Caregiver questionnaire data, including socio-demographics, social support, depression, anxiety, and caregiving burden, were collected at four time points (diagnosis, +4, +8, and +12 months). Using the stress process model as a guide, we hypothesized that early burden would predict later depression and anxiety and this would be mediated by social support.

Results

Using data from 147 participants, we found support for the stress process model in caregivers of patients with PBT. Greater burden at diagnosis was associated with lower social support at 4 months and lower social support was related to higher depression and anxiety at 8 months, as well as to changes in anxiety between 8 and 12 months.

Conclusion

We found evidence of the stress process model in caregivers of PBT patients unfolding over the course of a year after diagnosis. Our findings emphasize the potential importance of early programs for caregivers to ensure low initial levels of burden, which may have a positive effect on social support, depression, and anxiety.

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In Response.

No abstract available

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In Response: Concerns With Rate of Rise of Carbon Dioxide During Apnea With Buccal Oxygenation.

No abstract available

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The Subtleties of Language as a Reason for Failure to Follow Preoperative Fasting Guidelines: The Differences Between Restricting, Allowing, and Encouraging.

No abstract available

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Core Temperature Monitoring in Obstetric Spinal Anesthesia Using an Ingestible Telemetric Sensor.

BACKGROUND: Perioperative hypothermia may affect maternal and neonatal outcomes after obstetric spinal anesthesia. Core temperature is often poorly monitored during spinal anesthesia, due to the lack of an accurate noninvasive core temperature monitor. The aim of this study was to describe core temperature changes and temperature recovery during spinal anesthesia for elective cesarean delivery. We expected that obstetric spinal anesthesia would be associated with a clinically relevant thermoregulatory insult (core temperature decrease >1.0[degrees]C). METHODS: A descriptive study was conducted in 28 women. An ingestible telemetric temperature sensor was used to record core temperature over time (measured every 10 seconds). The primary outcome was the maximum core temperature decrease after spinal anesthetic injection. The secondary outcomes were lowest absolute core temperature, time to lowest temperature, time to recovery of core temperature, hypothermic exposure (degree-hours below 37.0[degrees]C), and the time-weighted hypothermic exposure (median number of degrees below 37.0[degrees]C per hour). Basic descriptive statistics, median spline smooth, and integration of the area below the 37.0[degrees]C line of the temperature-over-time curve were utilized to analyze the data. RESULTS: Intestinal temperature decreased by a mean (standard deviation) of 1.30[degrees]C (0.31); 99% confidence interval (CI), 1.14 to 1.46 after spinal anesthetic injection. The median (interquartile range [IQR]) time to temperature nadir was 0.96 (0.73-1.32) hours (95% CI, 0.88-1.22). Fourteen of the 28 participants experienced intestinal temperatures below 36.0[degrees]C after spinal injection. Temperature was monitored for a minimum of 8 hours after spinal injection. In 8 of 28 participants, intestinal temperature did not recover to baseline during the monitored period. A median (IQR) of 4.59 (3.38-5.92) hours (95% CI, 3.45-5.90) was required for recovery to baseline intestinal temperature in the remaining 20 patients. Participants experienced a median (IQR) of 1.97 (1.00-2.68) degree-hours of hypothermic exposure (95% CI, 1.23-2.45). The median (IQR) number of degrees below 37.0[degrees]C per hour was 0.45 (0.35-0.60) (95% CI, 0.36-0.58). CONCLUSIONS: During cesarean delivery under spinal anesthesia, women experienced a rapid decrease in core temperature. Using an intestinal telemetric sensor, the perioperative thermal insult and recovery were documented with high resolution. Fifty percent of participants in this study became hypothermic. Although the surgical procedure is typically of short duration, women undergoing spinal anesthesia for cesarean delivery experience significant hypothermic exposure and compromised thermoregulation for several hours. (C) 2017 International Anesthesia Research Society

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Respiratory Outcomes in Preterm Infants: From Infancy Through Adulthood.

No abstract available

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Reducing Mortality in Acute Kidney Injury.

No abstract available

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EGFR-amplification plus gene expression profiling predicts response to combined radiotherapy with EGFR-inhibition: A preclinical trial in 10 HNSCC-tumour-xenograft models

Improvement of the results of radiotherapy by EGFR inhibitors is modest, suggesting significant intertumoural heterogeneity of response. To identify potential biomarkers, a preclinical trial was performed on ten different human squamous cell carcinoma xenografts of the head and neck (HNSCC) studying in vivo and ex vivo the effect of fractionated irradiation and EGFR inhibition. Local tumour control and tumour growth delay were correlated with potential biomarkers, e.g. EGFR gene amplification and radioresponse-associated gene expression profiles.

http://ift.tt/2hSbR5r

Palliative external beam radiotherapy for the treatment of tumor bleeding in inoperable advanced gastric cancer

Abstract

Background

To assess the outcomes and prognostic factors associated with palliative external beam radiotherapy (EBRT), administered to patients with advanced gastric cancer.

Methods

Forty-two patients with bleeding gastric tumors that received EBRT for palliation were analyzed. The response to EBRT was assessed by the palliation of tumor bleeding. Patients were classified as either responders, or non-responders to EBRT. The prognostic utility of clinical and dosimetric variables was examined in a multivariate logistic regression model. The optimal dose cutoff to classify the two groups was determined with receiver operating characteristic analysis.

Results

The palliation of gastric tumor bleeding after EBRT was achieved in 29 patients (69.0%). The time to resolve tumor bleeding ranged from 1 to 84 days (median, 15 days). The median duration of palliation was 14.9 weeks. The median EBRT dose was 40 Gy in responders vs. 21 Gy in non-responders, with the difference being significant (p < 0.001). The biologically effective dose (using α/β = 10, BED₁₀) for responders was significantly higher than the BED₁₀ for non-responders (median 48 Gy vs. 26.4 Gy, p < 0.001), and the optimal cut off value to separate the two groups was 36 Gy (p < 0.001). The absence of distant metastasis and the use of concurrent chemotherapy generally showed a better EBRT response (p = 0.079 and p = 0.079, respectively). In the multivariate analysis, BED₁₀ ≥ 36 Gy was the most significant factor associated with EBRT response (p = 0.001). Overall survival (OS) and re-bleeding-free survival was median 12.6 weeks and 14.9 weeks. The responders to EBRT showed superior OS (16.6 vs. 5.1 months, p < 0.001). Neither acute nor chronic toxicities of grade 3 or higher were observed.

Conclusions

EBRT is an effective method for treating tumor bleeding in advanced gastric cancer, and does not induce severe toxicity.

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Technique of Laparoscopic Hysterectomy and Pelvic Lymphadenectomy for Endometrial Cancer

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Breast Cancer Immunotherapy: Facts and Hopes

Immunotherapy is revolutionizing the management of multiple solid tumors, and early data have revealed the clinical activity of PD-1/PD-L1 antagonists in small numbers of metastatic breast cancer patients. Clinical activity appears more likely if the tumor is triple negative, PD-L1+, and/or harbors higher levels of TILs. Responses to atezolizumab and pembrolizumab appear to be durable in metastatic triple negative breast cancer (TNBC), suggesting these agents may transform the lives of responding patients. Current clinical efforts are focused on developing immunotherapy combinations that convert non-responders to responders, deepen those responses that do occur, and surmount acquired resistance to immunotherapy. Identifying biomarkers that can predict the potential for response to single agent immunotherapy, identify the best immunotherapy combinations for a particular patient, and guide salvage immunotherapy in patients with progressive disease are high priorities for clinical development. Smart clinical trials testing rational immunotherapy combinations that include robust biomarker evaluations will accelerate clinical progress, moving us closer to effective immunotherapy for almost all breast cancer patients.

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Simultaneous targeting of two distinct epitopes on MET effectively inhibits MET- and HGF-driven tumor growth by multiple mechanisms

Increased MET activity is linked with poor prognosis and outcome in several human cancers currently lacking targeted therapies. Here we report on the characterization of Sym015, an antibody mixture composed of two humanized IgG1 antibodies against non-overlapping epitopes of MET. Sym015 was selected by high-throughput screening searching for antibody mixtures with superior growth inhibitory activity against MET-dependent cell lines. Synergistic inhibitory activity of the antibodies comprising Sym015 was observed in several cancer cell lines harboring amplified MET locus and was confirmed in vivo. Sym015 was found to exert its activity via multiple mechanisms. It disrupted interaction of MET with the HGF ligand and prompted activity-independent internalization and degradation of the receptor. In addition, Sym015 induced high levels of CDC and ADCC in vitro. The importance of these effector functions was confirmed in vivo using an Fc-effector-function attenuated version of Sym015. The enhanced effect of the two antibodies in Sym015 on both MET degradation and CDC and ADCC is predicted to render Sym015 superior to single antibodies targeting MET. Our results demonstrate strong potential for use of Sym015 as a therapeutic antibody mixture for treatment of MET-driven tumors. Sym015 is currently being tested in a phase I dose escalation clinical trial (NCT02648724)

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The combination of metformin and valproic acid induces synergistic apoptosis in the presence of p53 and androgen signaling in prostate cancer

We investigated the potential of combining the hypoglycemic drug metformin (MET) and the anti-epileptic drug valproic acid (VPA), which act via different biochemical pathways, to provide enhanced anti-tumor responses in prostate cancer. Prostate cancer cell lines (LNCaP and PC-3), normal prostate epithelial cells (PrEC), and patient-derived prostate tumor explants were treated with MET and/or VPA. Proliferation and apoptosis were assessed. The role of p53 in response to MET+VPA was assessed in cell lines using RNA interference in LNCaP (p53⁺) and ectopic expression of p53 in PC-3 (p53^-). The role of the androgen receptor (AR) was investigated using the AR antagonist, Enzalutamide. The combination of MET and VPA synergistically inhibited proliferation in LNCaP and PC-3, with no significant effect in PrEC. LNCaP, but not PC-3, demonstrated synergistic intrinsic apoptosis in response to MET+VPA. Knock-down of p53 in LNCaP (p53⁺, AR⁺) reduced the synergistic apoptotic response as did inhibition of AR. Ectopic expression of p53 in PC-3 (p53^-, AR^-) increased apoptosis in response to MET+VPA. In patient-derived prostate tumor explants, MET+VPA also induced a significant decrease in proliferation and an increase in apoptosis in tumor cells. In conclusion, we demonstrate that MET+VPA can synergistically kill more prostate cancer cells than either drug alone. The response is dependent on the presence of p53 and AR signaling which have critical roles in prostate carcinogenesis. Further in vivo/ex vivo pre-clinical studies are required to determine the relative efficacy of MET+VPA as a potential treatment for prostate cancer.

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TDP1 is critical for the repair of DNA breaks induced by sapacitabine, a nucleoside also targeting ATM- and BRCA-deficient tumors

2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes beta-elimination that generates single-strand breaks with abnormal 3'-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes non-phosphorylated 3'-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1-/- DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC. We also identified BRCA1, FANCD2 and PCNA in the DNA repair pathways to CNDAC. Comparing CNDAC with the chemically related arabinosyl nucleoside analog, cytosine arabinoside (cytarabine, AraC) and the topoisomerase I inhibitor camptothecin (CPT), which both generate 3'-end blocking DNA lesions that are also repaired by TDP1, we found that inactivation of BRCA2 renders cells hypersensitive to CNDAC and CPT but not to AraC. By contrast, cells lacking PARP1 were only hypersensitive to CPT but not to CNDAC or AraC. Examination of TDP1 expression in the cancer cell line databases (CCLE, GDSC, NCI-60) and human cancers (TCGA) revealed a broad range of expression of TDP1, which was correlated with PARP1 expression, TDP1 gene copy number and promoter methylation. Thus, the present study identifies the importance of TDP1 as a novel determinant of response to CNDAC across various cancer types (especially non-small cell lung cancers), and demonstrates the differential involvement of BRCA2, PARP1 and TDP1 in the cellular responses to CNDAC, AraC and CPT.

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Exploiting radiation-induced signaling to increase the susceptibility of resistant cancer cells to targeted drugs: AKT and mTOR inhibitors as an example

Implementing targeted drug therapy in radio-oncologic treatment regimens has greatly improved the outcome of cancer patients. However, the efficacy of molecular targeted drugs such as inhibitory antibodies or small molecule inhibitors essentially depends on target expression and activity, which both can change during the course of treatment. Radiotherapy has previously been shown to activate pro-survival pathways which can help tumor cells to adapt and thereby survive treatment. Therefore, we aimed to identify changes in signaling induced by radiation and evaluate the potential of targeting these changes with small molecules to increase the therapeutic efficacy on cancer cell survival. Analysis of "The Cancer Genome Atlas" (TCGA) database disclosed a significant overexpression of AKT1, AKT2, and MTOR genes in human prostate cancer samples compared with normal prostate gland tissue. Multifractionated radiation of 3D-cultured prostate cancer cell lines with a dose of 2 Gy/day as a clinically relevant schedule resulted in an increased protein phosphorylation and enhanced protein-protein interaction between AKT and mTOR, while gene expression of AKT, MTOR, and related kinases was not altered by radiation. Similar results were found in a xenograft model of prostate cancer. Pharmacological inhibition of mTOR/AKT signaling after activation by multifractionated radiation was more effective than treatment prior to radiotherapy. Taken together, our findings provide a proof-of-concept that targeting signaling molecules after activation by radiotherapy may be a novel and promising treatment strategy for cancers treated with multifractionated radiation regimens such as prostate cancer to increase the sensitivity of tumor cells to molecular targeted drugs.

http://ift.tt/2vNMRSO

MicroRNA-720 regulates E-cadherin-{alpha}E-catenin complex and promotes renal cell carcinoma.

MicroRNAs are implicated in regulating cancer progression and metastasis. Here we show that miR-720 is positively associated with renal cell carcinoma (RCC). Elevated levels of miR-720 were observed in a panel of RCC cell lines and clinical tissues compared to non-malignant cell line and normal samples. Loss of miR-720 function inhibited proliferation, migration and invasion and induced apoptosis in RCC cell lines in vitro and repressed tumor growth in xenograft mouse model. Conversely, gain of miR-720 function in non-malignant HK-2 cells induced pro-cancerous characteristics. Silencing of miR-720 caused a marked induction in the levels of endogenous αE-catenin and E-cadherin protein levels in anti720 transfected cells compared to control. Whereas, miR-720 overexpression in RCC cell lines reduced activity of a luciferase reporter gene fused to the wild-type αE-catenin or E-cadherin 3' UTR compared to non-specific 3' UTR control indicating that αE-catenin-E-cadherin complex is a direct and functional target of miR-720 in RCC. We also observed attenuation of β-Catenin, CD44 and Akt expression in RCC cells transfected with miR-720 inhibitor compared to control. Further, miR-720 exhibited clinical significance in RCC. Expression of miR-720 significantly distinguished malignant from normal samples. Elevated miR-720 levels positively correlated with higher Fuhrman grade, pathological stage and poor overall survival of RCC patients. These findings uncover a new regulatory network in RCC involving metastasis-promoting miR-720 that directly targets expression of key metastasis-suppressing proteins E-cadherin and αE-catenin complex. These results suggest that therapeutic regulation of miR-720 may provide an opportunity to regulate EMT and metastasis in RCC.

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Anticancer drugs and the regulation of Hedgehog genes GLI1 and PTCH1, a comparative study in nonmelanoma skin cancer cell lines.

Nonmelanoma skin cancer is the most common cancer in humans, comprising mainly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC proliferation is highly dependent on the Hedgehog signaling pathway. We aimed to investigate a panel of anticancer drugs with known activity against skin cancer for their therapeutic potential in localized, enhanced topical treatment of SCC and BCC. Cytotoxicity profiles for vismodegib, 5-fluorouracil (5-FU), methotrexate (MTX), cisplatin, bleomycin, and vorinostat were established in terms of half maximal inhibitory concentration values in a panel of immortalized keratinocytes (HaCaT), BCC (UWBCC1 and BCC77015), and SCC (A431 and SCC25) cell lines. The impact of treatment on the regulation of Hedgehog pathway target genes (GLI1 and PTCH1), measured by real-time PCR, was compared between UWBCC1 and HaCaT. Varying cell line sensitivity profiles to the examined anticancer drugs were observed. Generally, 24-h drug exposure was sufficient to reduce cell viability. We found that 5-FU, MTX, and cisplatin significantly downregulated the expression of two genes controlled by the Hedgehog pathway (

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Focal Increased Tc-99m MDP Uptake in the Nutrient Foramen of the Femoral Diaphysis on Bone SPECT/CT

Abstract

We present images of an 83-year-old female with a history of osteoporosis and bilateral total knee replacement arthroplasty, referred for bone scintigraphy and single-photon emission computed tomography (SPECT)/computed tomography (CT), owing to left knee pain. No trauma to, or intense exercise of, the knee was reported. The bone scan and SPECT/CT revealed a focally increased Tc-99m methylene diphosphonate (MDP) uptake in the medial cortex of the left femoral diaphysis with matched linear radiolucency on CT images. This was misinterpreted as atypical femoral stress fracture; however, focal stress reaction injury to the nutrient foramen was confirmed on contrast-enhanced magnetic resonance imaging.

http://ift.tt/2uwHbN8

Successful long-term extracorporeal membrane oxygenation for invasive pulmonary aspergillosis: a case report

Extracorporeal membrane oxygenation is an established life-saving procedure for severe acute respiratory failure due to various causes. In general, the duration of extracorporeal membrane oxygenation ranges fr...

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Editorial introductions

No abstract available

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Targeting EZH2 in cancer therapy

Purpose of review: The present review introduces recent outstanding progress pertaining to Enhancer of zeste homolog 2 (EZH2), especially regarding its mode of action as a master regulator of chromatin, and provides molecular-based evidence for targeting EZH2 in cancer therapy. We discuss the active development of small molecules targeting the enzymatic activity of EZH2/polycomb repressive complex 2 (PRC2). Recent findings: Genetic, transcriptional, and posttranscriptional dysregulation of EZH2 is frequently observed in many cancer types. EZH2 promotes tumorigenesis by altering the expression of numerous tumor suppressor genes. Furthermore, the executive molecular processes initiated by EZH2, such as NF-κB activation, microRNA silencing, tumor immune evasion, and noncanonical transcription regulation, appear to be the fundamental characteristics of each cancer. Systematic investigations have suggested coordinated regulation of the cancer epigenome wherein antagonistic complexes of both polycomb and SWI/SNF are involved. Frequent loss-of-function mutations in epigenetic factors, such as ARID1A, SMARCA4, SMARCB1, BAP1, and KDM6A, are likely to elicit the EZH2/PRC2-addicted situation. Our comprehensive understanding encourages the development of advanced strategies for the appropriate manipulation of the cancer epigenome. Moreover, a couple of small molecules that can effectively inhibit the enzymatic activity of EZH2/PRC2 have been translated into early-phase clinical trials. Summary: The EZH2-mediated epigenome and subsequent transcriptome define cellular identity. Effective and specific strategies for the manipulation of EZH2/PRC2 may lead to the development of more precise cancer medicines.

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Elderly patients with multiple myeloma: towards a frailty approach?

Purpose of review: To describe how to better identify frail multiple myeloma patients and to treat them appropriately. Recent findings: Proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, and immunomodulatory agents (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, have significantly improved the outcome of multiple myeloma patients in the last decade. However, both in clinical trials and in daily clinical practice, elderly multiple myeloma patients have shown lesser benefit. This is mainly due to less stringent use of proteasome inhibitors and IMiDs, increased toxicity, and subsequent early discontinuation of therapy in elderly. Summary: Multiple myeloma typically affects elderly patients. Approximately one-third of patients are older than 75 years at diagnosis. Moreover, at least 30% are frail, both due to disease-related symptoms and (age-related) decline in physical capacity, presence of comorbidities, frailty, polypharmacy, nutritional status, and cognitive impairment. Treatment regimens that are investigated in clinical trials for transplant-ineligible patients have largely been investigated in fit, rather than frail patients, the latter being typically excluded or highly underrepresented therein. Data on the feasibility and efficacy of current standards of care are therefore lacking in frail patients. Preliminary data suggest a higher toxicity and discontinuation rate, loss of efficacy, and impaired quality of life in frail patients. Geriatric assessment helps to identify frail patients according to their functional and cognitive status. Both the International Myeloma Working Group (IMWG)-frailty index and Revised Myeloma Comorbidity Index constitute recently proposed algorithms that easily identify intermediate-fit and frail patients. Ongoing and future clinical trials, specifically designed for frail patients, will hopefully define frailty-directed treatment selection.

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The genetics of Hodgkin lymphoma: an overview and clinical implications

Purpose of review: The goal of this review is to give an overview of the genetics of classical Hodgkin lymphoma. Copy number changes, somatic mutations, genome-wide association studies, changes in gene expression, familial classical Hodgkin lymphoma and epigenetic changes will be reviewed. In doing so, special focus is placed on the way recent discoveries have influenced clinical research, diagnostics, treatment and remission monitoring. Furthermore, emphasis is put on how these advances can help to advance the treatment of elderly patients who have a markedly worse prognosis than younger patients. Recent findings: Frequent amplifications of the 9p24.1 locus in classical Hodgkin lymphoma could be the basis for the success of immune checkpoint inhibitors targeting PD-1 or PD-L1 in this disease. The same amplification also affects the JAK/STAT pathway, which has also been targeted in recent clinical trials. Hodgkin lymphoma-specific copy number alterations and mutations have recently been found to be detectable in cell-free DNA. This could provide the basis for advances in the detection of residual disease during treatment and while monitoring patients in remission. Summary: The advent of new technologies such as massive parallel sequencing has improved our understanding of the genetics of classical Hodgkin lymphoma. Some of these discoveries are now being translated into clinical research in the form of new diagnostics and treatments.

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Therapeutic oncolytic viruses: clinical advances and future directions

Purpose of review: The present review will highlight recent advances in the clinical application of oncolytic viral therapy. Recent findings: Until recently, oncolytic viral researchers saw the immune system as an enemy that would clear the virus from the bloodstream. However, researchers now understand that sustained responses are seen in those patients with more robust antitumor immune responses. Much of the current focus in oncolytic viral research is trained on manipulation of the immune system to affect cancer cell killing in the tumor microenvironment and to facilitate durable systemic antitumor immunity. Many investigators have demonstrated synergistic effects of checkpoint inhibition and other immune therapies with viral administration. At the same time, insertion of various markers enables noninvasive deep tissue imaging. Finally, following regulatory approval in the United States and Europe, unbridled clinical use of T-VEC for patients with metastatic melanoma is also generating large volumes of patient data that will help elucidate strengths and weaknesses of oncolytic viral therapy. Perhaps the most telling sign of the field's future is a seismic shift in clinical trials with more investigators combining virus and immunotherapies. Summary: This article reviews the current state of therapeutic oncolytic viruses in clinical use, and explores future directions of the field.

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Novel therapeutic agents in the management of brain metastases

Purpose of review: This review aims to highlight the novel therapeutic agents in the management of brain metastases which are in various stages of clinical development. We review the results from recent clinical trials, publications and presentations at recent national and international conferences. Recent findings: Several new systemic treatment options for brain metastases are in early or advanced clinical trials. These drugs have good intracranial and extracranial activities. As lung cancer, breast cancer, and melanoma are the three most common causes of brain metastases, most agents in clinical development are focused on these tumor types. Several of these therapies are small molecule tyrosine kinase inhibitors or monoclonal antibodies against the tyrosine kinase receptors. Another exciting development in brain metastases management is the use of immunotherapy agents. The anti-CTLA-4 and\or anti-PD-1 antibodies have shown promising intracranial activity in melanoma and nonsmall cell lung cancer patients with brain metastases. Summary: Contemporary clinical trials have shown encouraging intracranial activity of newer tyrosine kinase inhibitors, monoclonal antibodies against tyrosine kinase receptors and immunotherapy agents in select group of patients with brain metastases. Further studies are needed to develop therapeutic strategies, in order to improve survival in patients with brain metastases.

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Rational therapeutic choice for older patients with lymphoma

Purpose of review: The choice for an optimal treatment in older lymphoma patients is a real challenge for hemato-oncologists. They have to treat a potentially curative lymphoma, and concomitantly protect their patients from unacceptable toxicities. Some recommendations are provided for the major subtypes of lymphomas including the antitumoral treatment and primarily the optimal supportive care. Recent findings: All the recent literature data converge to say that the approach of an older patient with a malignant hemopathy is a multistep procedure. This process comprises the appraisal of life expectancy of the patient with or without the disease, the prognostic factors of the tumor, the functional, physiological and cognitive functions evaluation, the socio-economical environment and the patient's expectancy in terms of quality of life. Major progresses have been achieved in the management of diffuse large B cell lymphoma and mantle cell lymphoma in patients up to 80 and above 80 years old. Summary: With all these information in hands, the hematologist will decide if the treatment's objective is the standard treatment with optimal supportive care (fit patients), tailor-made adapted chemotherapy (unfit patients) or preservation of quality of life (frail patients).

http://ift.tt/2uOgpv1

Emerging cancer-specific therapeutic aptamers

Purpose of review: We will describe recently discovered smart aptamers with tumor specificity, with an emphasis on targeted delivery of novel therapeutic molecules, cancer-specific biomarkers, and immunotherapy. Recent findings: The development of cancer-specific aptamers has facilitated targeted delivery of potent therapeutic molecules to cancer cells without harming nontumoral cells. This specificity also makes it possible to discover novel cancer biomarkers. Furthermore, alternative immune-checkpoint blockade aptamers have been developed for combinational immunotherapy. Summary: Aptamers selected against cancer cells show cancer specificity, which has great potential for targeting. First, functionalizing targeted aptamers with therapeutic molecule payloads (e.g., small activating RNAs, antimitotic drugs, therapeutic antibodies, and peptides) facilitates successful delivery into cancer cells. This approach greatly improves the therapeutic index by minimizing side-effects in nontumoral cells. Second, cancer-specific proteins have been identified as cancer biomarkers through in-vitro and in-vivo selection, aptamer pull-down assays, and mass spectrometry. These newly discovered biomarkers improve therapeutic intervention and diagnostic specificity. In addition, the development of alternative immune-checkpoint blockade aptamers is suggested for use in combinational immunotherapeutic with current immune blockade regimens, to reduce the resistance and exhaustion of T cells in clinical trials. Video abstract: http://ift.tt/2sLQ5Bq .

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Surgery for patients with newly diagnosed advanced ovarian cancer: which patient, when and extent?

Purpose of review: Cytoreduction to no residual disease is the mainstay of primary treatment for advanced epithelial ovarian cancer (AdvEOC). This review addresses recent insights on optimal patient selection, timing, and extent of surgery, intended to optimize cytoreduction in patients with AdvEOC. Recent findings: Clinical guidelines recommend primary cytoreductive surgery (PCS) for AdvEOC patients with a high likelihood of achieving complete cytoreduction with acceptable morbidity. In line with this, preoperative prediction markers such as cancer antigen-125, histologic and genomic factors, innovative imaging modalities, and the performance of a diagnostic laparoscopy have been suggested to improve clinical decision-making with regard to optimal timing of cytoreductive surgery. To determine whether these strategies should be incorporated into clinical practice validation in randomized clinical trials is essential. Summary: The past decade has seen a paradigm shift in the number of AvdEOC patients that are being treated with upfront neoadjuvant chemotherapy instead of PCS. However, although neoadjuvant chemotherapy may reduce morbidity at the time of interval cytoreductive surgery, no favorable impact on survival has been demonstrated and it may induce resistance to chemotherapy. Therefore, optimizing patient selection for PCS is crucial. Furthermore, surgical innovations in patients diagnosed with AvdEOC should focus on improving survival outcomes.

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Cancer in pregnancy: safety and efficacy of systemic therapies

Purpose of review: Cancer in pregnancy has become increasingly frequent. It has become clear that for specific cancers under well defined circumstances, oncological treatment in pregnancy can be well tolerated and feasible for both mother and fetus. Continued critical assessment of the available literature and registration of cancer in pregnancy cases and outcomes for mother and child are necessary to work toward implementing optimal cancer treatment during pregnancy. Recent findings: Physiologic changes in pregnancy may alter distribution and efficacy of systemic therapy. Data on systemic therapy including, chemotherapy, hormonal therapy, and targeted therapy during pregnancy are available but incomplete. Outcomes of fetuses exposed to chemotherapy in utero are generally reassuring, but new targeted therapies are mostly discouraged in pregnancy. Summary: Cancer treatment during pregnancy is possible, depending on type and timing of systemic therapy and treatment modality. Available data are reassuring with a modest increase in complications such as growth restriction and preterm birth. The effect of new targeted therapies is often still unclear and therefore discouraged.

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Novel imaging techniques in gynaecological cancer

Purpose of review: To describe the added value of novel functional MRI techniques towards detection, staging, characterization, response monitoring and prognostication in gynaecological cancer. Recent findings: Functional MRI including diffusion-weighted imaging (DWI)-MRI and dynamic contrast-enhanced (DCE)-MRI adds structural, hemodynamic and physiological information to anatomical MRI. In endometrial and cervical cancer, the addition of DWI-MRI and DCE-MRI improves tumour detection as well as staging of uterine and extra-uterine pelvic spread. Quantitative assessment of DWI and DCE-MRI reflecting tissue properties of biological aggressiveness or treatment resistance may enable the prediction of risk of extra-uterine or extra-ovarian disease spread, predict risk of recurrence and assess treatment response. DWI shows high accuracy for detecting peritoneal metastases and allows for comprehensive staging of (recurrent) ovarian cancer following the clinical development of whole body DWI-MRI. Summary: The added value of DWI/DCE-MRI for characterization and staging of gynaecological malignancy is becoming increasingly established and may improve treatment stratification. Ongoing multicentre studies are expected to further consolidate its use in clinical routine. Quantitative evaluation of functional MRI may help in prognostication and risk stratification.

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Immunotherapy-based combinations: current status and perspectives

Purpose of review: Since the approval of ipilimumab, different immune checkpoint inhibitors, vaccines and costimulatory agonists have been developed with success, improving patient's survival in a number of different tumour types. However, immunotherapy results in durable responses but only in a fraction of patients. In order to improve this, combination of different immune agents is currently being attempted in the clinic with the potential of becoming one day the next wave of immune treatments available for our cancer patients. Recent findings: Combinatory regimens may have synergistic effects by acting at different points of the cancer immune cycle, from initiation and propagation of anticancer immunity, to stimulation of neoantigen presentation and priming, promotion of trafficking of immune cells to access the tumour and, finally, cancer-cell recognition and killing. Summary: In this article, the most relevant combination strategies that are currently under research are reviewed, as they are expected to become a new standard of care in the near future.

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Re-irradiation of cervical and endometrial cancer

Purpose of review: Re-irradiation historically has been associated with unacceptable toxicity and limited benefit. Recent advances in radiotherapy can change the treatment paradigm to provide new salvage treatments for recurrences of cervical and endometrial cancer. Recent findings: Image-guided brachytherapy is an effective method for salvaging central pelvic recurrence, although it has resulted in 20–25% severe late toxicity. Pelvic sidewall disease is not accessible to brachytherapy, so a combined modality approach with radical surgery and intraoperative radiotherapy is an alternative approach. Stereotactic body radiotherapy (SBRT) now provides the option of radical re-irradiation with local control rates of 50–80% and a low incidence of severe late complications. Summary: Initial outcomes using SBRT and image-guided brachytherapy for re-irradiation of gynaecological cancer are encouraging. There has been good local control and acceptable toxicity. Further, large-scale studies are required to define optimal target doses and OAR limits.

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How to emerge from the conservatism in clinical research methodology?

Purpose of review: Despite recent changes in clinical research methodology, many challenges remain in drug development methodology. Recent findings: Advances in molecular biology and cancer treatments have changed the clinical research landscape. Thus, we moved from empirical clinical oncology to molecular and immunological therapeutic approaches. Along with this move, adapted dose-limiting toxicities definitions, endpoints, and dose escalation methods have been proposed. Moreover, the classical frontier between phase I, phase II, and phase III has become unclear in particular for immunological approaches. So, investigators are facing major challenges in drug development methodology. Summary: We propose to individualize clinical research using innovative approaches to significantly improve patient outcomes and targeting what is considered unmet need. Integrating high level of translational research and performing well designed biomarker studies with great potential for clinical practice are of utmost importance. This could be performed within new models of clinical research networks and by building a strong collaboration between academic, cooperative groups, on-site investigators, and pharma.

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Optimaler Resektionsrand für die brusterhaltende Operation und Ganzbrustbestrahlung beim duktalen Carcinoma in situ

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Optimaler Resektionsrand für die brusterhaltende Operation und Ganzbrustbestrahlung beim duktalen Carcinoma in situ

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Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome with multiorgan failure

International Journal of Hematologic Oncology, Ahead of Print.


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Neurocognitive sparing of desktop microbeam irradiation

Normal tissue toxicity is the dose-limiting side effect of radiotherapy. Spatial fractionation irradiation techniques, like microbeam radiotherapy (MRT), have shown promising results in sparing the normal brai...

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Prospective Evaluation of the Relationship Between Mechanical Stability and Response to Palliative Radiotherapy for Symptomatic Spinal Metastases

AbstractBackground.A substantial number of patients with spinal metastases experience no treatment effect from palliative radiotherapy. Mechanical spinal instability, due to metastatic disease, could be associated with failed pain control following radiotherapy. This study investigates the relationship between the degree of spinal instability, as defined by the Spinal Instability Neoplastic Score (SINS), and response to radiotherapy in patients with symptomatic spinal metastases in a multi‐institutional cohort.Methods and Materials.The SINS of 155 patients with painful thoracic, lumbar, or lumbosacral metastases from two tertiary hospitals was calculated using images from radiotherapy planning CT scans. Patient‐reported pain response, available for 124 patients, was prospectively assessed. Pain response was categorized, according to international guidelines, as complete, partial, indeterminate, or progression of pain. The association between SINS and pain response was estimated by multivariable logistic regression analysis, correcting for predetermined clinical variables.Results.Of the 124 patients, 16 patients experienced a complete response and 65 patients experienced a partial response. Spinal Instability Neoplastic Score was associated with a complete pain response (adjusted odds‐radio [ORadj] 0.78; 95% confidence interval [CI] 0.62–0.98), but not with an overall pain response (ORadj 0.94; 95% CI 0.81–1.10).Conclusions.A lower SINS, indicating spinal stability, is associated with a complete pain response to radiotherapy. This supports the hypothesis that pain resulting from mechanical spinal instability responds less well to radiotherapy compared with pain from local tumor activity. No association could be determined between SINS and an overall pain response, which might indicate that this referral tool is not yet optimal for prediction of treatment outcome.Implications for Practice.Patients with stable painful spinal metastases, as indicated by a Spinal Instability Neoplastic Score (SINS) of 6 or lower, can effectively be treated with palliative external beam radiotherapy. The majority of patients with (impending) spinal instability, as indicated by a SINS score of 7 or higher, will achieve a (partial) response after palliative radiotherapy; however, some patients might require surgical intervention. Therefore, it is recommended to refer patients with a SINS score of 7 or higher to a spine surgeon to evaluate the need for surgical intervention.

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Robert L. Comis: In Memoriam

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Curative, Life‐Extending, and Palliative Chemotherapy: New Outcomes Need New Names

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Data Linkage to Improve Geriatric Oncology Research: A Feasibility Study

AbstractOlder adults (aged 65 years and older) diagnosed with cancer account for most cancer‐related morbidity and mortality in the United States but are often underrepresented on clinical trials. Recent attention from a variety of professional, research, regulatory, and patient advocacy groups has centered on data linkage and data sharing as a means to capture patient information and outcomes outside of clinical trials to accelerate progress in the fight against cancer. The development of a more robust observational research data infrastructure would help to address gaps in the evidence base regarding optimal approaches to treating cancer among the growing and complex population of older adults. To demonstrate the feasibility of building such a resource, we linked information from a sample of older adults with cancer in North Carolina using three distinct, but complementary, data sources: (a) the Carolina Senior Registry, (b) the North Carolina Central Cancer Registry, and (c) North Carolina fee‐for‐service Medicare claims data. A description of the linkage process, metrics, and characteristics of the final cohort is reported. This study highlights the potential for data linkage to improve the characterization of health status among older adults with cancer and the possibility to conduct passive follow‐up for outcomes of interest over time. Extensions of these linkage efforts in partnership with other institutions will enhance our ability to generate evidence that can inform the management of older adults with cancer.

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Prolonged Pemetrexed Infusion Plus Gemcitabine in Refractory Metastatic Colorectal Cancer: Preclinical Rationale and Phase II Study Results

AbstractLessons Learned. Difficulties in translating in vitro results into clinical practice are inevitable.Further efforts to verify the efficacy of alternative schedules of pemetrexed in solid tumors are encouraged.Background.We investigated the cytotoxic activity of pemetrexed in combination with several drugs (gemcitabine, carboplatin, vinorelbine, and mitomycin C) using different exposure schedules in three colon cancer cell lines. The best results were obtained with the following schedule: a prolonged pemetrexed exposure followed by a 48‐hour wash‐out and then gemcitabine. This combination was then advanced to a phase II clinical trial.Methods.Patients with metastatic colorectal cancer in progression after standard treatment were included in the study. Adequate bone marrow reserve, normal hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 were required. Treatment consisted of an 8‐hour intravenous infusion of pemetrexed 150 mg/m2 on day 1 and a 30‐minute intravenous infusion of gemcitabine 1,000 mg/m2 on day 3 of each cycle, repeated every 14 days.Results.Fourteen patients were enrolled onto the study (first step). No objective responses were seen, and evidence of stable disease was observed in only one of the 12 evaluable patients. The most important grade 3–4 side effects were hematological toxicity (neutropenia 64.2%, thrombocytopenia 71.4%, anemia 28.7%), fatigue (50.0%), and stomatitis (21.5%). Median overall survival and time to progression were 5.8 months (95% confidence interval [CI]: 3.9–7.1) and 2.1 months (95% CI: 1.7–2.8), respectively.Conclusion.The experimental pemetrexed‐gemcitabine combination proved to be inactive and moderately toxic.

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Health Care Resource Utilization and Associated Costs Among Metastatic Cutaneous Melanoma Patients Treated with Ipilimumab (INTUITION Study)

AbstractBackground.There are limited real‐world data on health care resource utilization (HCRU) among advanced melanoma patients. The objective of this study was to describe HCRU and health care costs associated with the management of advanced melanoma patients receiving ipilimumab.Methods.This retrospective multinational, observational study included advanced melanoma patients from Australia, Germany, Italy, and Spain who had received at least 1 dose of ipilimumab. Data extracted from medical charts included inpatient admissions, outpatient visits, surgical procedures, laboratory investigations, radiation therapy, imaging studies, and concomitant medications. Cost estimates were based on unit costs from country‐specific standard reimbursement sources. Subgroup analyses were performed for BRAF mutation status and ipilimumab refractory patients, who had disease progression within 24 weeks of their last dose of ipilimumab.Results.Mean age of 362 enrolled patients was 60.6 years (standard deviation [SD] 14.4). During a median follow‐up period of 30.2 weeks, 57% of patients were admitted to hospital and 16% underwent surgery. Health care resource utilization rates varied substantially across countries and were highest in Germany. Concomitant medications to treat adverse events were commonly used. Subgroup analyses showed higher utilization rates among ipilimumab refractory and BRAF mutant patients. Mean weekly total costs associated with HCRU were lower in the pre‐progression period (€107; 95% confidence interval (CI): 79–145) than in the post‐progression period (€216; 95% CI: 180–259).Conclusion.Health care resource utilization pattern and associated costs among patients treated with ipilimumab varied greatly among countries and between pre‐ and post‐progression periods. There is a high economic burden associated with ipilimumab refractory melanoma.Implications for Practice.Metastatic melanoma patients treated with the anti‐CTLA‐4 inhibitor ipilimumab have a high utilization of various types of health care services, such as inpatient hospital stays or doctor visits. There are differences across countries regarding patterns of health care utilization and economic burden of the disease. Health care services are used more frequently after patients experience progression of their disease. The study highlights that better therapies leading to durable response in patients with metastatic melanoma have the potential to decrease health care costs and patient burden in terms of hospitalizations and other health care services.

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A Phase II Multi‐Center Study of Bevacizumab in Combination with Ixabepilone in Subjects with Advanced Renal Cell Carcinoma

AbstractLessons Learned. Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression‐free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development.Background.Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule‐stabilizing agent approved for the treatment of breast cancer, is active in taxane‐sensitive and ‐resistant cells. In this single‐arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC.Methods.We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)‐approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m2 ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days. After 6 cycles, the treatment interval could be extended to every 28 days. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were progression‐free survival (PFS), overall survival (OS), and the toxicity of the combination.Results.The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2–54). The median follow‐up was 36.4 months (range 23.5–96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9–10.6) and the median OS was 15.0 months (95% CI, 11.3–28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%).Conclusion.The combination of ixabepilone and bevacizumab was well tolerated, with modest activity in second ‐ or later‐line mRCC, but it is not recommended as a therapy without further clinical development. Alternative combinations with these agents could be explored in future studies.

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Hepatosplenic Candidiasis Without Prior Documented Candidemia: An Underrecognized Diagnosis?

AbstractIntroduction.Patients with a history of chemotherapy or stem cell transplantation (SCT) and prolonged neutropenia are at risk for hepatic and/or splenic seeding of Candida. In our experience, hepatosplenic candidiasis (HSC) without documented candidemia often remains unrecognized.Case presentations.We describe three cases of HSC without documented candidemia and the challenges in establishing the diagnosis and adequately treating this condition. The first patient had a history of SCT for treatment of breast cancer and was scheduled for hemihepatectomy for suspected liver metastasis. A second opinion at our institute resulted in the diagnosis of hepatic candidiasis without prior documented candidemia, for which she was treated successfully with fluconazole. The second case demonstrates the limitations of (blood and tissue) cultures and the value of molecular methods to confirm the diagnosis. Case 3 illustrates treatment challenges, with ongoing dissemination and insufficient source control despite months of antifungal therapy, eventually resulting in a splenectomy.Literature review.A structured literature search was performed for articles describing any patient with HSC and documented blood culture results. Thirty articles were available for extraction of data on candidemia and HSC. Seventy percent (131/187) of patients with HSC did not have documented candidemia. The majority of HSC events were described in hematologic patients, although some cases were described in patients with solid tumors treated with SCT (n = 1) or chemotherapy and a history of leukopenia (n = 2). Current guidelines and practices for diagnosis and treatment are described.Conclusion.Clinicians should be aware that HSC most often occurs without documented candidemia. In case of persistent or unexplained fever or lesions in the liver and/or spleen, a history of neutropenia should place disseminated candidiasis in the differential diagnosis. HSC is not limited to hematological patients and may occur in patients with solid tumors treated with bone marrow‐suppressing chemotherapy or SCT. In the latter group, HSC as alternative diagnosis for hepatic metastasis should be considered when lesions are not typical for metastasis. This might prevent unnecessary surgery or inappropriate treatment.Implications for Practice.Timely diagnosis of hepatosplenic candidiasis (HSC) is challenging, but can prevent further complications and dissemination, and may even prevent unnecessary invasive procedures. Clinicians should realize that HSC often occurs without documented candidemia and that sensitivity of blood cultures for candidemia is limited. HSC is not strictly limited to hematologic patients and might also occur in patients with solid tumors treated with intensive chemotherapy or stem cell transplantation. Increased awareness for HSC in patients with any history of neutropenia is of importance to increase detection and prevent serious sequelae.

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Association Study Confirmed Three Breast Cancer‐Specific Molecular Subtype‐Associated Susceptibility Loci in Chinese Han Women

AbstractBackground.Breast cancer is a heterogeneous and polygenic disease that can be divided into different molecular subtypes based on histological and genomic features. To date, numerous susceptibility loci of breast cancer have been discovered by genome‐wide association studies and may expand the genetic features. However, few loci have been further studied according to molecular subtypes.Materials and Methods.We genotyped 23 recently discovered single nucleotide polymorphisms using the Sequenom iPLEX platform in a female Chinese cohort of 3,036 breast cancer patients (2,935 samples matched molecular subtypes) and 3,036 healthy controls.Results.Through a stratification analysis, 5q11.2/MAP3K1 (rs16886034, rs16886364, rs16886397, rs1017226, rs16886448) and 7q32.3/LINC-PINT (rs4593472) were associated with Luminal A, and 10q26.1/FGFR2 (rs35054928) was associated with Luminal B.Conclusion.In our study, breast cancer‐specific molecular subtype‐associated susceptibility loci were confirmed in Chinese Han women, which contributes to a better genetic understanding of breast cancer in different molecular subtypes.Implications for Practice.To date, genome‐wide association studies have identified more than 90 susceptibility loci associated with breast cancer. However, few loci have been further studied according to molecular subtype. The results of this study are that breast cancer‐specific molecular subtype‐associated susceptibility loci were confirmed in Chinese Han women, which contributes to a better genetic understanding of breast cancer in different molecular subtypes.

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The Best Thing I Saw at ASCO

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Male Breast Cancer as a Second Primary Cancer: Increased Risk Following Lymphoma

AbstractBackground.Male breast cancer (MBC) as a second primary cancer (SPC) has a known association with prior MBC. However, its association with non‐breast index malignancies, relative to population risk, has not been previously reported.Materials and Methods.Using Surveillance, Epidemiology, and End Results program (9 catchment area) data, we identified MBCs diagnosed from 1973–2012 as their SPC. Information regarding the index malignancy was also obtained. Standardized incidence ratios (SIR) of MBC as SPC were estimated, along with incidence rates and trends. Kaplan‐Meier curves were used to estimate survival.Results.Over a 38‐year period, 464 MBCs were identified as SPC. The most common index malignancies were breast (SIR 30.86, 95% confidence interval [CI] 21.50–42.92, p < .001), lymphoma (SIR 1.58, 95% CI 1.08–2.22, p = .014), melanoma (SIR 1.26, 95% CI 0.80–1.89), urinary (SIR 1.05, 95% CI 0.74–1.43), colorectal (SIR 0.94, 95% CI 0.69–1.24), and prostate (SIR 0.93 95% CI 0.81–1.07). Apart from the known association with prior breast cancer, the only significant association was with lymphoma as an index cancer, although not significant with a Bonferroni correction. From 1975–2012, incidence of breast cancer as a first cancer increased at an annual percentage change of 1.3% while breast cancer as a SPC increased at 4.7% (both p values < .001).Conclusion.Male breast cancer as a SPC has increased markedly over 4 decades. Men with a history of lymphoma may experience higher‐than‐expected rates of breast SPC. These observations warrant further research, and suggest possible etiologic connections with disease biology, prior therapy, or genetics.Implications for Practice.This study reports that men are presenting more frequently to the clinic with breast cancer, both as an initial cancer and as a second cancer following an earlier malignancy. We also report the novel observation that men who survive lymphoma are at increased risk of developing a subsequent breast cancer. Further work is needed to better understand possible treatment or biologic causes of this association. More immediately, these findings suggest the need for heightened vigilance for male breast cancer overall and, in particular, for male lymphoma survivors.

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Debunking the Delusion That Precision Oncology Is an Illusion

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First‐Line Palliative HER2‐Targeted Therapy in HER2‐Positive Metastatic Breast Cancer Is Less Effective After Previous Adjuvant Trastuzumab‐Based Therapy

AbstractBackground.Survival of patients with human epidermal growth receptor 2 (HER2)‐positive metastatic breast cancer (MBC) has improved dramatically since trastuzumab has become available, although the disease eventually progresses in most patients. This study investigates the outcome (overall survival [OS] and time to next treatment [TNT]) in MBC patients pretreated with trastuzumab in the adjuvant setting (TP‐group) compared with trastuzumab‐naïve patients (TN‐group) in order to investigate the possibility of trastuzumab resistance.Patients and Methods.Patients treated with first‐line HER2‐targeted‐containing chemotherapy were eligible for the study. A power analysis was performed to estimate the minimum size of the TP‐group. OS and TNT were estimated using Kaplan‐Meier curves and multivariable Cox proportional hazards models.Results.Between January 1, 2000, and June 1, 2014, 469 patients were included, of whom 82 were in the TP‐group and 387 were in the TN‐group. Median OS and TNT were significantly worse in the TP‐group compared with the TN‐group (17 vs. 30 months, adjusted hazard ratio [HR] 1.84 [1.15–2.96], p = .01 and 7 vs. 13 months, adjusted HR 1.65 [1.06–2.58], p = .03) after adjustment for age, year of diagnosis, disease‐free interval, hormone receptor status, metastatic site, and cytotoxic regimens.Conclusion.First‐line trastuzumab‐containing treatment regimens are less effective in patients with failure of adjuvant trastuzumab compared with trastuzumab‐naïve patients and might be due to trastuzumab resistance. The impact of trastuzumab resistance on the response on dual HER2 blockade with trastuzumab and pertuzumab and how resistance mechanisms can be used in the optimization of HER2‐targeted treatment lines need further investigation.Implications for Practice.Evidence on the efficacy of palliative trastuzumab‐based therapy after failure of trastuzumab in the adjuvant setting is limited because of a minority of patients treated with adjuvant trastuzumab in clinical trials. In this study, less clinical benefit of palliative trastuzumab‐based therapy was observed in patients relapsing after adjuvant trastuzumab compared with no adjuvant trastuzumab treatment. Subgroup analyses and multivariable analyses revealed that this was independent of possible confounding factors, including adjuvant taxane‐treatment. This might suggest a clinically meaningful impaired efficacy of trastuzumab after previous, in this case adjuvant, trastuzumab therapy. These results could have implications for treatment decision‐making after short progression‐free intervals on trastuzumab‐containing regimens in the palliative setting.

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Impact of Age on Outcomes with Immunotherapy for Patients with Melanoma

AbstractBackground.Monoclonal antibodies (mAb) targeting PD‐1/PD‐L1 have revolutionized melanoma treatment, yet data regarding effectiveness and tolerability across age groups is limited. We sought to determine the impact of age on overall survival (OS), progression‐free survival (PFS), and rates of immune‐mediated toxicities in patients treated with anti–PD‐1/anti‐PD‐L1 mAb at two academic medical centers.Methods.We retrospectively collected data on all patients with metastatic melanoma treated with anti‐PD‐1/PD‐L1 mAb between May 2009 and April 2015. We used Kaplan‐Meier and Cox regression analyses to assess OS and PFS and identify factors associated with these outcomes. We also compared rates of autoimmune toxicity across age groups.Results.Of 254 patients, 57 (22.4%) were <50 years old, 85 (33.5%) were age 50–64, 65 (25.6%) were age 65–74, and 47 (18.5%) were ≥75 years. Across age groups, no differences existed in median OS (age <50: 22.9 months, age 50–64: 25.3 months, age 65–74: 22.0 months, age ≥75: 24.3 months) or PFS (age <50: 4.1 months, age 50–64: 6.5 months, age 65–74: 5.4 months, age ≥75: 7.9 months). The presence of liver metastases and elevated pre‐treatment lactate dehydrogenase (LDH) were associated with reduced OS. Presence of liver metastasis, pretreatment LDH, BRAF mutation, and type of melanoma correlated with PFS. Overall, 110 patients (43.3%) experienced immune‐mediated toxicities; 25 (9.8%) had colitis and 26 (10.2%) had endocrine toxicity. Rates of colitis, hepatitis, and pneumonitis did not differ across age groups.Conclusion.We demonstrated that patients could safely tolerate anti‐PD1/PDL‐1 mAb therapy and achieve similar outcomes regardless of their age.Implications for Practice.Immunotherapy has revolutionized treatment for patients with metastatic melanoma, yet data are lacking regarding the effectiveness and tolerability of these treatments for older patients. In this study, we demonstrated that patients with melanoma safely tolerate immunotherapy and achieve similar outcomes regardless of their age. Specifically, we utilized data from two academic cancer centers and found no significant difference in overall survival, progression free survival, or immune‐related toxicities, other than arthritis, across age groups. As the population ages, studies such as this will become critical to help us understand how best to treat older adults with cancer.

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The National Cancer Institute Community Cancer Centers Program (NCCCP): Sustaining Quality and Reducing Disparities in Guideline‐Concordant Breast and Colon Cancer Care

AbstractBackground.The National Cancer Institute Community Cancer Centers Program (NCCCP) pilot was designed to improve quality of cancer care and reduce disparities at community hospitals. The NCCCP's primary intervention was the implementation of the Commission on Cancer Rapid Quality Reporting System (RQRS). The RQRS is a hospital‐based data collection and evaluation system allowing near real‐time assessment of selected breast and colon cancer quality of care measures. Building on previous NCCCP analyses, this study examined whether improvements in quality cancer care within NCCCP hospitals early in the program were sustained and whether improvements were notable for minority or underserved populations.Methods.We compared changes in concordance with three breast and two colon cancer quality measures approved by the National Quality Forum for patients diagnosed at NCCCP hospitals from 2006 to 2007 (pre‐RQRS), 2008 to 2010 (early‐RQRS), and 2011 to 2013 (later‐RQRS). Data were obtained from NCCCP sites participating in the Commission on Cancer Rapid Quality Reporting System. Logistic regression analyses were performed to identify predictors of concordance with breast and colon cancer quality measures.Results.The sample included 13,893 breast and 5,546 colon cancer patients. After RQRS initiation, all five quality measures improved significantly and improvements were sustained through 2013. Quality of care measures showed sustained improvements for both breast and colon cancer patients and for vulnerable patient subgroups including black, uninsured, and Medicaid‐covered patients.Conclusions.Quality improvements in NCCCP hospitals were sustained throughout the duration of the program, both overall and among minority and underserved patients. Because many individuals receive cancer treatment at community hospitals, facilitating high‐quality care in these environments must be a priority.Implications for Practice.Quality improvement programs often improve practice, but the methods are not maintained over time. The implementation of a real‐time quality reporting system and a network focused on improving quality of care sustained quality improvement at select community cancer centers. The NCCCP pilot increased numbers of patients receiving guideline‐concordant care for breast and colon cancer in community settings, and initial improvements noted in earlier years of RQRS were sustained into later years, both overall and among minority and underserved patients. National initiatives that improve care for diverse patient groups are important for reducing and eliminating barriers to care.

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Efficacy of Trabectedin in Patients with Advanced Translocation‐Related Sarcomas: Pooled Analysis of Two Phase II Studies

AbstractBackground.Trabectedin is reported as effective, especially against translocation‐related sarcomas (TRSs) after failure of or intolerance to standard chemotherapy. We conducted two phase II studies of TRS, confirming high efficacy of 1.2 mg/m2 trabectedin. The updated data of 66 patients in these studies was integrated to evaluate the efficacy of trabectedin against each histological subtype, and analyze final overall survival (OS).Methods.Trabectedin was administered on day one of a 21‐day cycle. Efficacy was assessed using progression‐free survival (PFS), OS, and best overall response. An analysis of OS and PFS was performed for subgroups divided by baseline lymphocyte count (<1,000/μL, ≥1,000/μL) or number of previous chemotherapy regimens (0, 1, 2, ≥3 regimens), and a Weibull parametric model was used to estimate the numerical relationship between lymphocyte count and PFS and OS.Results.Median PFS and OS in overall patients were 5.6 (95% confidence interval [CI]: 4.1–7.3) and 17.5 months (95% CI: 12.6–23.6), respectively. PFS in the myxoid and round‐cell liposarcoma (MRCL) group (7.4 months [95% CI: 5.6–11.1]) was longer than in the other subtypes. The response rate was also highest in the MRCL group. Median OS was longer in patients with baseline lymphocyte counts ≥1,000/μL than in those with counts of <1,000/μL, but median PFS was not different between the two subgroups.Conclusion.Our updated and pooled data showed that trabectedin exerted prolonged disease control and antitumor effects in patients with advanced TRS, especially in MRCL. We consider that the subgroup analyses also provide important information for trabectedin treatment in patients with TRS.Implications for Practice.The progression‐free survival (PFS) for the integrated data of 66 patients with translocation‐related sarcomas (TRSs) in two phase II studies of trabectedin 1.2 mg/m2 was 5.6 months (95% confidence interval: 4.1–7.3). PFS and response rate in myxoid/round‐cell liposarcoma was longer than that of other subtypes. The overall survival (OS) in all TRS subtypes was similar to previous data of TRS patients. In subgroup analysis, the patients with baseline lymphocyte count ≥1,000/μL exhibited better OS, although PFS was not different by baseline lymphocyte count. Our data are considered important information for trabectedin treatment in TRS patients.

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Social Network Structures of Breast Cancer Patients and the Contributing Role of Patient Navigators

AbstractBackground.Minority women in the U.S. continue to experience inferior breast cancer outcomes compared with white women, in part due to delays in care delivery. Emerging cancer care delivery models like patient navigation focus on social barriers, but evidence demonstrating how these models increase social capital is lacking. This pilot study describes the social networks of newly diagnosed breast cancer patients and explores the contributing role of patient navigators.Materials and Methods.Twenty‐five women completed a one hour interview about their social networks related to cancer care support. Network metrics identified important structural attributes and influential individuals. Bivariate associations between network metrics, type of network, and whether the network included a navigator were measured. Secondary analyses explored associations between network structures and clinical outcomes.Results.We identified three types of networks: kin‐based, role and/or affect‐based, or heterogeneous. Network metrics did not vary significantly by network type. There was a low prevalence of navigators included in the support networks (25%). Network density scores were significantly higher in those networks without a navigator. Network metrics were not predictive of clinical outcomes in multivariate models.Conclusion.Patient navigators were not frequently included in support networks, but provided distinctive types of support. If navigators can identify patients with poorly integrated (less dense) social networks, or who have unmet tangible support needs, the intensity of navigation services could be tailored. Services and systems that address gaps and variations in patient social networks should be explored for their potential to reduce cancer health disparities.Implications for Practice.This study used a new method to identify the breadth and strength of social support following a diagnosis of breast cancer, especially examining the role of patient navigators in providing support. While navigators were only included in one quarter of patient support networks, they did provide essential supports to some individuals. Health care providers and systems need to better understand the contributions of social supports both within and outside of health care to design and tailor interventions that seek to reduce health care disparities and improve cancer outcomes.

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Implementation of the Edmonton Symptom Assessment System for Symptom Distress Screening at a Community Cancer Center: A Pilot Program

AbstractBackground.Distress screening is mandated by the American College of Surgeons Commission on Cancer; however, there is limited literature on its impact in actual practice. We examined the impact of a pilot distress screening program on access to psychosocial care.Methods.Edmonton Symptom Assessment System (ESAS) screening was routinely conducted at our community‐based medical oncology program. Patients who screened positive for severe distress were sent to a social worker for triage and referred to the appropriate services if indicated. We compared the proportion of patients who had ESAS completed, the proportion of patients who screened positive, and the number of patients who had social work assessment and palliative care consultation over the preimplementation (September 2015), training (October/November 2015), and postimplementation (December 2015) periods.Results.A total of 379, 328, and 465 cancer patients were included in the preimplementation, training, and postimplementation periods, respectively. The proportion of patients who completed ESAS increased over time (83% vs. 91% vs. 96%). Among the patients who had completed ESAS, between 11% and 13% were positive for severe distress, which remained stable over the three periods. We observed a significant increase in social work referrals for psychosocial assessment (21% vs. 71% vs. 79%). There was also a trend towards an increased number of palliative care referrals (12% vs. 20% vs. 28%).Conclusion.Our community‐based cancer center implemented distress screening rapidly in a resource‐limited setting, with a notable increase in symptom documentation and psychosocial referral.Implications for Practice.The American College of Surgeons Commission on Cancer mandates distress screening; however, there is limited literature on how this process should be implemented and its impact on clinical practice. We used the Edmonton Symptom Assessment System for routine symptom distress screening in a community‐based medical oncology program that provides care for an underserved population. Comparing before and after program implementation, we found an increase in the number of documentations of symptom burden and an increase in psychosocial referrals. Findings from this study may inform the implementation of routine symptom distress screening in cancer patients.

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Patterns of Chemotherapy Use in a U.S.‐Based Cohort of Patients with Metastatic Pancreatic Cancer

AbstractPurpose.Few population studies have examined patterns of systemic therapy administration in metastatic pancreatic cancer (MPC) or the predictors associated with specific treatment choices.Patients and Methods.We assessed 4,011 consecutive MPC patients who received chemotherapy between January 2005 and December 2015 at academic, private, and community‐based oncology practices subscribing to a U.S.‐wide chemotherapy order entry system capturing disease, patient, provider, and treatment data. Multivariate analyses of these prospectively recorded characteristics identified significant predictors of specific therapeutic choices.Results.Overall, 100 different regimens were used in first‐line treatment of MPC. First‐line gemcitabine monotherapy usage fell steadily from 72% in 2006 to 16% in 2015. This steep decline mirrored increases in first‐line usage of both 5 fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine + nab‐paclitaxel. Younger male patients were more likely to receive FOLFIRINOX as first‐line treatment, whereas patients treated at community practices and by oncologists with lower MPC patient volume were more likely to receive gemcitabine plus nab‐paclitaxel (all p ≤ .05). Among all patients receiving first‐line chemotherapy for MPC, 49% went on to receive second‐line therapy and 19% received third‐line therapy; administration of second‐ and third‐line therapies increased steadily over the time course of follow‐up. Younger patients and those treated by oncologists with higher MPC patient volume were more likely to receive second‐ and third‐line therapies.Conclusion.This population‐based study provides insight into treatment patterns of MPC in the U.S. Usage patterns varied greatly according to patient and provider characteristics.Implications for Practice.This study examined real world metastatic pancreatic cancer treatment patterns in the United States with the goals of understanding changes in chemotherapy treatment frequencies over time and determining the individual predictors that underlie the chemotherapy choices oncologists make for their patients. Our data set is unique in that it captured not only patient‐level data, but also oncologist‐level data. It also captured data from private and community practices as well as academic centers. To our knowledge, this is the only data set that can give this degree of insight into oncologist decision making practices.

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What's the Harm?

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Prognostic Value of Pre- and Post-Treatment FDG PET/CT Parameters in Small Cell Lung Cancer Patients

Abstract

Purpose

To evaluate the prognostic value of PET parameters obtained from pre- and post-treatment FDG PET/CT examinations in patients with SCLC.

Methods

Fifty-nine patients with initially diagnosed SCLC from 2009 to 2014 were included and had chemotherapy and/or concurrent chemoradiotherapy. FDG PET/CT examinations were performed before (PET1) and after (PET2) treatment to evaluate treatment response. A region of interest was placed over the primary lesion and metastatic lymph nodes within the thoracic cavity. PET parameters including change from PET1 to PET2 (Δ in %) were acquired: SUVmax, SUVpeak, MTV2.5, TLG, ΔSUVmax, ΔSUVpeak, ΔMTV and ΔTLG. Patient characteristics including staging, age, sex, LDH and response evaluation by RECIST were surveyed. Statistical analysis was done using Kaplan-Meier method and Cox regression analysis with respect to OS and PFS.

Results

The median follow-up was 9.6 months (2.5–80.5 months). 27 patients were LD and 32 were ED. Forty-six patients (78.0%) had died, and median OS was 8.6 months; 51 patients (86%) showed disease progression, and median PFS was 2.5 months. On univariate analysis, patients with ED, high interval change (ΔSUVmax and ΔSUVpeak) and low PET2 parameters showed longer OS and PFS. Multivariate analyses demonstrated that ΔSUVpeak (HR 2.6, P = 0.002) was an independent prognostic factors for OS, and MTV2.5 of PET2 (HR 2.8, P = 0.001), disease stage (HR 2.7, P = 0.003) and RECIST (HR 2.0, P = 0.023) were independent prognostic factors for PFS.

Conclusions

Metabolic and volumetric PET parameters obtained from pre- and post-treatment FDG PET/CT examinations in patients with SCLC have significant prognostic information.

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Unusual Contralateral Axillary Lymph Node Metastasis in a Second Primary Breast Cancer Detected by FDG PET/CT and Lymphoscintigraphy

Abstract

Contralateral metastatic axillary lymph nodes in a patient with breast cancer is a rare condition. Here, we present a 55-year-old woman with a second primary breast cancer. The patient underwent ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) for staging work-up. Additionally, preoperative lymphoscintigraphy was performed to detect sentinel lymph nodes. FDG PET/CT demonstrated increased FDG uptake in the left nipple and right axillary lymph nodes. Lymphoscintigraphy identified the right axillary lymph nodes which was consistent with the FDG PET/CT findings. This case emphasizes the usefulness of FDG PET/CT and lymphoscintigraphy for identifying unpredictable contralateral axillary lymph node metastasis from a second primary breast cancer.

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Fibrinogen promotes malignant biological tumor behavior involving epithelial–mesenchymal transition via the p-AKT/p-mTOR pathway in esophageal squamous cell carcinoma

Abstract

Purpose

Hyperfibrinogenemia is associated with unfavorable prognosis and advanced tumor behavior in various malignancies, including esophageal squamous cell carcinoma (ESCC). However, its biological function in ESCC is unknown. The present study was designed to further validate the prognostic value of preoperative plasma hyperfibrinogenemia and evaluate the biological role of fibrinogen, as well as the underlying mechanism in ESCC.

Methods

Data from 452 cases with newly diagnosed ESCC followed by curative surgery between 2006 and 2010 were retrospectively evaluated. The Clauss method was utilized to measure the preoperative plasma fibrinogen level. Correlations between the fibrinogen level and clinicopathologic characteristics and survival analysis were performed. The effects of fibrinogen on malignant behaviors, including tumor cell viability, colony formation, migration, and invasion, were also investigated.

Results

The optimal cut-off value for plasma fibrinogen level was defined as 4.0 g/L according to recommendations. Thus, the proportion of hyperfibrinogenemia was 24.8% (112/452). Preoperative plasma hyperfibrinogenemia was significantly associated with advanced tumor length, deep tumor invasion, advanced tumor–node–metastasis stage, alcohol consumption, a higher white blood cell count, a higher platelet count, and high globulin levels. Univariate survival analysis revealed that compared to those with normal plasma fibrinogen levels, patients with hyperfibrinogenemia tended to have poorer disease-free survival (DFS) [hazard ratio (HR), 1.692; 95% confidence interval (CI), 1.304–2.196; P < 0.001] and overall survival (OS) (HR 1.864; 95% CI 1.424–2.440; P < 0.001). In the multivariate Cox regression models, these factors remained independent predictors for impaired DFS (HR 1.491; 95% CI 1.138–1.955; P = 0.004) and OS (HR 1.648; 95% CI 1.246–2.180; P < 0.001) after adjusting for other confounding variables. In addition, fibrinogen could significantly promote cell migration and invasion but not proliferation. Moreover, it could also induce epithelial–mesenchymal transition (EMT) and increase the levels of p-PTEN, p-AKT, and p-mTOR in ESCC cell lines.

Conclusions

Preoperative plasma hyperfibrinogenemia might serve as an independent predictor of unfavorable survival in ESCC. Furthermore, fibrinogen may promote cell motility by inducing EMT via the p-AKT/p-mTOR pathway.

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Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials

Abstract

Background

Elucidation of mechanisms regulating bone metastasis has progressed significantly in recent years and this has translated to many new therapeutic options for patients with bone metastatic cancers. However, the rapid rate of progress in both the basic science literature and therapies undergoing clinical trials makes staying abreast with current developments challenging. This review seeks to provide an update on the current state of the science in bone metastasis research and give a snap shot of therapies in clinical trials for bone metastatic cancer.

Main body

Bone metastasis represents a difficult to treat clinical scenario due to pain, increased fracture risk, decreased quality of life and diminished overall survival outcomes. Multiple types of cancer have the specific ability to home to the bone microenvironment and cause metastatic lesions. This osteotropism was first described by Stephen Paget nearly 100 years ago as the 'seed and soil' hypothesis. Once cancer cells arrive at the bone they encounter a variety of cells native to the bone microenvironment which contribute to the establishment of bone metastatic lesions. In the first part of this review, the 'seed and soil' hypothesis is revisited while emphasizing recent developments in understanding the impact of native bone microenvironment cells on the metastatic process. Next, approved therapies for treating bone metastasis at the systemic level as well as those that target the bone microenvironment are discussed and current National Comprehensive Cancer Network (NCCN) guidelines relating to treatment of bone metastases are summarized. Finally, all open interventional clinical trials for therapies relating to treatment of bone metastasis have been complied and categorized.

Conclusion

Understanding the recent advancements in bone metastasis research is important for continued development of novel bone targeted therapies. The plethora of ongoing clinical trials will hopefully translate into improved treatments options for patients suffering from bone metastatic cancers.

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Novel concepts of antiangiogenic therapies in metastatic renal cell cancer

Summary

The era of antiangiogenic drugs targeting the vascular endothelial growth factor (VEGF) signaling pathway has become a mainstay in the treatment of metastatic renal cell carcinoma (mRCC), showing primary responses in 65–70% of patients. Nevertheless, most of those patients progress to angiogenesis inhibitors over time due to different modes of resistance (adaptive and intrinsic). Both in vitro and in vivo analyses provided evidence that PD-L1 upregulation in hypoxia conditions is dependent on hypoxia-inducible factor (HIF)-2alpha and is associated with an overexpression of VEGF. Thus, additional blockade of PD-L1 along with inhibition of angiogenesis pathways seems to represent a novel and innovative treatment concept in mRCC. In this short review, we provide an overview on ongoing phase III trials combining antiangiogenic therapies with checkpoint inhibitors in the first-line setting. Moreover, we critically analyze the impact of recently approved therapeutic antiangiogenic agents and checkpoint inhibitors after progression to first-generation tyrosine kinase inhibitors and their mode of action. In addition, response and resistance hypotheses and biomarkers to antiangiogenic therapy in clinical practice are critically discussed.

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Unresectable squamous cell carcinoma of upper trachea with long-term survival after concurrent chemoradiotherapy

Upper tracheal malignancies are rare, and long-term survival is even rarer, especially among the unresectable malignancies. A 66-year-old chronic smoker was diagnosed as a locally advanced, non-metastatic squamous cell carcinoma of the upper trachea. Being unresectable, he was treated with six cycles of concurrent weekly cisplatin and three-dimensional conformal radiotherapy to a dose of 60 Gy in 30 fractions over 6 weeks. Follow-up imaging at 6 and 12 months revealed no disease. Our patient is presently 36 months post-treatment and is disease free without tracheal necrosis, fistula or radiation pneumonitis but developed hypothyroidism and is presently euthyroid. Concurrent chemoradiotherapy appears safe up to 3 years at least without any necrosis and is effective in controlling local disease. Meticulous planning obviates the need for higher technology like motion management techniques or intensity-modulated radiotherapy.

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Paraneoplastic mucous membrane pemphigoid with ocular and laryngeal involvement

A 73-year-old woman was treated 8 years previously for synchronous breast and uterine neoplasms. She presented with a severe sore throat, odynophagia, dysphonia, dyspnoea, ocular irritation and weight loss over the last 3 months. Physical examination revealed ulcerations in the oral cavity, posterior pharyngeal wall and supraglottic larynx, nasal crusting, bilateral conjunctivitis and three cutaneous blisters. A diagnosis of anti-laminin 5 mucous membrane pemphigoid was retained, based on skin biopsy, direct immunofluorescence and immunoprecipitation. A positron emission tomography (PET)-CT detected multiple adenopathies. Cytology revealed adenocarcinoma with an immunocytology compatible with a breast origin and this was considered as a late metastatic recurrence of her previous breast cancer. A treatment of prednisone, dapsone and hormonotherapy was introduced, but intravenous immunoglobulin and rituximab were added due to new mucosal lesions. Despite treatment, a posterior laryngeal scar and bilateral symblepharon were developed. After 3 years, the patient is still alive and reports a satisfactory quality of life.

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Isolated intraductal variant of hepatocellular carcinoma

Description

A 70-year-old male teetotaller, with a history of chronic obstructive lung disease and hypertension, presented to the emergency department with a 2-day history of right upper quadrant pain and melaena. Investigations revealed total bilirubin 6.8 mg/dL, aspartate and alanine transaminases 88 and 122 IU/L, respectively, alkaline phosphatase 338 IU/L and gamma-glutamyl transpeptidase 223 IU/L. Tests for chronic hepatitis B, hepatitis C and HIV were negative. Serum alpha-fetoprotein was 22.8 ng/mL, whereas carcino-embryonic antigen (CEA), CA 19–9, prostate specific antigen and chromogranin levels were normal. Contrast CT of the abdomen revealed fatty liver with moderate dilation of bilateral intrahepatic biliary radicles (figure 1A) and dilated common bile duct (CBD) with hyperdense contents, without identifiable mass lesions in the liver or biliary tree. Upper gastrointestinal endoscopy revealed haemobilia, and cholangiogram showed normal calibre CBD with filling defects. Endoscopic intraductal ultrasound revealed focal thickening of segment three hepatic duct, and Spyglass cholangioscopy confirmed a...

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Bilateral painful tic convulsif

'Painful tic convulsif' (PTC) describes the coexistence of hemifacial spasm and trigeminal neuralgia. In this report, we describe a unique presentation of bilateral PTC in a man with bilateral hemifacial spasm and trigeminal neuralgia secondary to neurovascular conflict of all four cranial nerves. Following failed medical and radiofrequency therapy, microvascular decompression of three of the four involved nerves was performed, where the offending vessels were mobilised and Teflon used to prevent conflict recurrence. He continues to respond to Botox for right hemifacial spasm. Since surgery, he remains pain free bilaterally and spasm free on the left.

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Lenalidomide-associated arterial thrombosis in a patient with JAK2 positive atypical myeloproliferative neoplasm

Description

A 71-year-old woman, with a recent diagnosis of JAK2 positive atypical myeloproliferative neoplasm, presented to the emergency room (ER) for bilateral foot pain and purplish discolouration of her toes (figure 1). She started her first cancer treatment 3 weeks ago using lenalidomide with prednisone 20 mg daily. Venous thromboprophylaxis was not prescribed then due to anaemia and history of intracranial haemorrhage. ER work up included simple X-rays of her feet that were normal. Lower extremity ultrasound did not show any deep vein thrombosis, so she was discharged home. The patient did not have atrial fibrillation or hyperviscosity. No history of arterial thrombosis or smoking. Two weeks later, she was re-evaluated by her haematologist, and a hospital admission was arranged given worsening symptoms. Her physical exam now showed the purplish discolouration has progressed over both feet, associated with some toes turning black (figure 2). She had strong lower extremity...

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Right hepatic artery 'caterpillar hump and dual cystic arteries: relevance of critical view of safety in a 'straightforward cholecystectomy

Description

A 60-year-old woman with unremarkable medical history, underwent elective laparoscopic cholecystectomy for symptomatic cholelithiasis. A four-port technique was performed. Initial exploration of Calot's triangle was carried out by upward traction of the fundus and lateral retraction of the Hartmann's pouch; after dissection of the peritoneum medially at the level of the infundibulum, two tubular structures entering the gallbladder were visible, as usually expected. However, to obtain a 'critical view of safety',1 dissection was continued by opening up the lateral aspect of the peritoneum; hepatobiliary triangle was dissected free of areolar tissue and the bottom of the gallbladder was dissected off the lower part of the liver bed. At this stage, an anatomical variation became evident (figure 1): the right hepatic artery made a 'caterpillar-like' loop inside Calot's triangle and two short cystic arteries reached the gallbladder. According to a recent review, among clinically...

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Therapeutic options for bleeding oesophageal varices: cyanoacrylate and balloon-occluded retrograde obliteration (BRTO)

A 56-year-old male with cirrhosis presented with acute bleeding from cardiofundal gastroesophageal varices (GOV) and was treated with endoscopic cyanoacrylate glue. Glue therapy achieved stabilisation of the patient in the emergent setting. Three months later, the patient suffered rebleeding. At that time, he underwent retreatment with balloon-occluded retrograde obliteration (BRTO), with no recurrence at a follow-up of 14 months.

Available treatments for bleeding GOV include methods to (a) directly obstruct the varices (endoscopic variceal ligation , sclerotherapy and cyanoacrylate glue, BRTO) or to (b) decrease portal pressure (surgical portacaval shunts; transportal intrahepatic portosystemic shunt). No precise guidelines are available regarding when to use which modality, and few centres have experience with all of them. This case report illustrates a setting in which both options of cyanoacrylate glue therapy and BRTO were used for acute gastric variceal bleeding.

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Ibrutinib Becomes First FDA-Approved Drug for Chronic Graft-Versus-Host Disease

A drug used to treat several blood cancers, ibrutinib, has been approved by FDA to treat chronic graft-versus-host disease, making it the first approved therapy for this potentially fatal side effect of cancer-related stem cell transplants.

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High risk human papilloma viruses (HPVs) are present in benign prostate tissues before development of HPV associated prostate cancer

Abstract

Background

Although high risk HPVs are associated with an increased risk of prostate cancer it is not known if they have a causal role. The purpose of this study is to investigate the potential role of human papilloma viruses (HPVs) in prostate cancer. The aims are (i) to investigate the presence and confirm the identity of high risk HPVs in benign prostate tissues prior to the development of HPV positive prostate cancer in the same patients, and (ii) to determine if HPVs are biologically active.

Methods

We used polymerase chain reaction (PCR) to identify HPVs in specimens from 52 Australian men with benign prostate biopsies who 1 to 10 years later developed prostate cancer. Immunohistochemistry (IHC) was used to assess the expression of HPV E7 oncoproteins, cytokeratin and prostate specific antigen (PSA).

We used RNASeq data from The Cancer Genome Atlas (TCGA) to identify possible HPV RNA sequences in prostate cancer.

Results

HPV screening using standard PCR was conducted on 28 of the 52 sets of benign and later prostate cancers. HPV L1 genes were identified in 13 (46%) benign and 8 (29%) of 28 later prostate cancers in the same patients. HPV E7 genes were identified in 23 (82%) benign and 19 (68%) of 28 subsequent prostate cancers in the same patients. The same HPV types were present in both the benign and subsequent prostate cancers in 9 sets of specimens. HPV type 16 was identified in 15% of benign and 3% of prostate cancers. HPV type 18 was identified in 26% of benign and 16% of prostate cancers. Small numbers of HPV types 45, 47, 76 and 115 were also identified.

High confidence RNA-Seq evidence for high risk HPV types 16 and 18 was identified in 12 (2%) of the 502 TCGA prostate cancer transcriptomes.

High risk HPV E7 oncoprotein was positively expressed in 23 (82%) of 28 benign prostate specimens but only in 8 (29%) of 28 of the later prostate cancer specimens. This difference is statistically significant (p = 0.001). Prostate specific antigen (PSA) was more highly expressed in 26 (50%) of 52 prostate cancer specimens as compared to prior benign prostate specimens in the same patients.

Conclusions

High risk HPVs are present in benign prostate tissues prior to the development of HPV positive prostate cancer. There is a significantly higher expression of HPV E7 oncoproteins in benign prostate tissues as compared to late prostate cancer that subsequently developed in the same patients. This observation suggests that HPV oncogenic activity is an early phenomenon in a majority of prostate oncogenesis. TCGA RNA-Seq data suggests that HPV is biologically active in some prostate tumour samples.

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