A Phase 3 Randomized Clinical Trial of Chemotherapy With or Without Algenpantucel-L (HyperAcute-Pancreas) Immunotherapy in Subjects With Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer.

OBJECTIVES: To compare the efficacy and safety of algenpantucel-L [HyperAcute-Pancreas algenpantucel-L (HAPa); IND# 12311] immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene. METHODS: A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival. RESULTS: Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (interquartile range) overall survival was 14.9 (12.2-17.8) months in the standard group (N = 158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) [hazard ratio (HR) 1.02, 95% confidence intervals 0.66-1.58; P = 0.98]. Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% confidence intervals 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05). CONCLUSIONS: Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01836432.

Serotonin Pathway in Cancer.

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine produced from the essential amino acid tryptophan. Serotonin's role as a neurotransmitter in the central nervous system and a motility mediator in the gastrointestinal tract has been well defined, and its function in tumorigenesis in various cancers (gliomas, carcinoids, and carcinomas) is being studied. Many studies have shown a potential stimulatory effect of serotonin on cancer cell proliferation, invasion, dissemination, and tumor angiogenesis. Although the underlying mechanism is complex, it is proposed that serotonin levels in the tumor and its interaction with specific receptor subtypes are associated with disease progression. This review article describes serotonin's role in cancer pathogenesis and the utility of the serotonin pathway as a potential therapeutic target in cancer treatment. Octreotide, an inhibitor of serotonin release, is used in well-differentiated neuroendocrine cancers, and the tryptophan hydroxylase (TPH) inhibitor, telotristat, is currently being investigated in clinical trials to treat patients with metastatic neuroendocrine tumors and advanced cholangiocarcinoma. Several in vitro studies have shown the anticancer effect of 5-HT receptor antagonists in various cancers such as prostate cancer, breast cancer, urinary bladder, colorectal cancer, carcinoid, and small-cell lung cancer. More in vivo studies are needed to assess serotonin's role in cancer and its potential use as an anticancer therapeutic target. Serotonin is also being evaluated for its immunoregulatory properties, and studies have shown its potential anti-inflammatory effect. Therefore, it would be of interest to explore the combination of serotonin antagonists with immunotherapy in the future.

Surgery Versus Surveillance for Well-Differentiated, Nonfunctional Pancreatic Neuroendocrine Tumors: An 11-Year Analysis of the National Cancer Database.

BACKGROUND: Pancreatic neuroendocrine tumors (panNETs) are a rare group of tumors that make up 2%-3% of pancreatic tumors. Recommended treatment for panNETs generally consists of resection for symptomatic or large asymptomatic tumors; however, optimal management for localized disease is still controversial, with conflicting recommendations in established guidelines. Our study aim is to compare surgical intervention versus active surveillance in nonmetastatic panNETs by size of primary tumor. MATERIALS AND METHODS: Using the National Cancer Database, we identified 2,004 patients diagnosed with localized well-differentiated, nonfunctional panNETs (NF-panNETs) between 2004 and 2015. Patients' clinicopathologic characteristics, treatment modalities, and overall survival (OS) were analyzed using frequency statistics, chi-square, and Kaplan-Meier curves. The objective of the study is to assess the outcome of surgical resection versus nonoperative management in patients with panNETs with different tumor sizes. RESULTS: Tumor sizes were divided into three categories: <1 cm, 1-2 cm, and >2 cm. The number of patients with tumor size <1 cm, 1-2 cm, and >2 cm was 220 (11%), 794 (39.6%), and 990 (49.4%), respectively. Overall, 1,781 underwent surgical resection, whereas 223 patients did not. Median follow-up was 25.9 months. After adjusting for covariates, surgical resection was associated with improved OS in patients with tumor size 1-2 cm (hazard ratio [HR] = 0.37) and >2c m (HR = 0.30) but not <1 cm (HR = 2.81). Independent prognostic factors were age at diagnosis, Charlson-Deyo comorbidity score, stage, tumor location, and surgical resection. Higher tumor grade was not associated with worse OS. CONCLUSION: Our findings suggest that active surveillance is potentially a safe approach for NF-panNETs <1 cm. Larger tumors likely need active intervention. Intermediate-grade tumors did not result in worse survival outcome compared with low-grade tumors. Future studies might consider prospective randomized clinical trials to validate our findings. IMPLICATIONS FOR PRACTICE: The present study seeks to address the discrepancy in treatment recommendations in the management of nonfunctional pancreatic neuroendocrine tumors (NF-panNETs) by evaluating whether surgical resection is associated with improved overall survival in different tumor size groups as well as elucidating independent prognostic factors in patients with NF-panNETs. Data from the National Cancer Database were reviewed. This study's findings suggest that active surveillance is potentially a safe approach for NF-panNETs <1 cm. Larger tumors likely need active intervention. Independent prognostic factors include age at diagnosis, Charlson-Deyo comorbidity score, stage, tumor location, and surgical resection. These findings will help guide medical and surgical oncologists when formulating treatment plans for patients with small NF-panNETs.

The evolving role of radiation in pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer mortality in the United States. Chemotherapy in resectable pancreatic cancer has improved survival by 10-20%. It only converted 10-30% of the borderline resectable and locally advanced pancreatic cancers to be surgically resectable. Radiation therapy has a documented role in managing localized pancreatic cancer, more so for borderline and locally advanced pancreatic cancer, where it can potentially improve the resectability rate of a given neoadjuvant treatment. The role of radiation therapy in resected pancreatic cancer is controversial, but it is used routinely to treat positive margins after pancreatic cancer surgery. Radiation therapy paradigms continue to evolve with advancements in treatment modalities, delivery techniques, and combination approaches. Despite the advances, there continues to be a controversy on the role of radiation therapy in managing this disease. In this review article, we discuss the recent updates, delivery techniques, and motion management in radiation therapy and dissect the applicability of this therapy in pancreatic cancer.

Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL).

Adult T-cell leukemia/lymphoma (ATL) is resistant to chemotherapy and carries a dismal prognosis particularly for the acute and lymphoma subtypes. Promising results were obtained with the combination of zidovudine and interferon-alpha. Chronic ATL has a relatively better outcome, but poor long-term survival is noted when patients are managed with a watchful-waiting policy or with chemotherapy. In ATL cell lines, arsenic trioxide shuts off constitutive NF-kappaB activation and potentiates interferon-alpha apoptotic effects through proteasomal degradation of Tax. Clinically, arsenic/interferon therapy exhibits some efficacy in refractory aggressive ATL patients. These results prompted us to investigate the efficacy and safety of the combination of arsenic, interferon-alpha, and zidovudine in 10 newly diagnosed chronic ATL patients. An impressive 100% response rate was observed including 7 complete remissions, 2 complete remissions but with more than 5% circulating atypical lymphocytes, and 1 partial response. Responses were rapid and no relapse was noted. Side effects were moderate and mostly hematologic. In conclusion, treatment of chronic ATL with arsenic, interferon-alpha, and zidovudine is feasible and exhibits an impressive response rate with moderate toxicity. Long-term follow up will clarify whether this will translate to disease cure. Overall, these clinical results strengthen the concept of oncogene-targeted cancer therapy.

Usefulness of red cell distribution width in predicting all-cause long-term mortality after non-ST-elevation myocardial infarction.

BACKGROUND: Red blood cell distribution width (RDW) is a strong predictor of adverse outcomes in patients with heart failure, stable coronary artery disease, stroke and acute myocardial infarction. The aim of our study was to explore the predictive value of RDW on all-cause mortality in patients with non-ST-segment elevation myocardial infarction (NSTEMI). METHOD: This observational study includes 619 NSTEMI patients, discharged from Staten Island University Hospital between September 2004 and December 2006. Patients were divided into equal RDW tertiles and survival was evaluated in each tertile. RESULT: Patients in the highest RDW tertile (RDW >14) had higher in-patient (7 vs. 1%) and 4-year (30 vs. 7%) mortality rates compared to those in the lowest tertile (RDW <13) (Wilcoxon χ(2) = 34.64, p < 0.0001). After controlling for Global Registry of Acute Coronary Events risk profile scores and other confounding variables, the RDW adjusted hazard ratio for 4-year all-cause mortality increased by 1.10 for each one unit increase in RDW (confidence interval 1.004-1.213, p = 0.042). CONCLUSION: RDW is an independent predictor of all-cause long-term mortality in NSTEMI patients. Further studies are needed to clarify the mechanisms of this association between RDW and adverse outcomes in patients with coronary artery disease.

Metastasis of colorectal carcinoma to the testes: clinical presentation and possible pathways.

Distant metastasis from colorectal carcinoma most often occurs in the liver and lungs. Metastasis to bones, adrenals, lymph nodes, brain, and skin has also been reported. Metastatic colorectal carcinoma to the testes is very uncommon. Even more uncommon is testicular metastasis from rectal carcinoma. Researchers throughout the last few decades have not acquired a clear understanding of the lymphatic pathways involved in reported cases of testicular metastasis from primary colorectal carcinoma. These cases may present with testicular complaints after or even before the diagnosis of colorectal cancer; this is why it is crucial to differentiate between primary testicular tumor and a secondary one from a colorectal primary. We searched the English medical literature using the MEDLINE/PUBMED database from 1950 through January 2010. Our search yielded 33 cases of testicular metastasis from rectal or colonic carcinoma. These cases are reviewed and summarized. This paper reviews the literature for all cases of testicular metastasis from colonic and rectal adenocarcinomas shedding light on the possible pathways of metastasis. We recommend that physicians be aware of the risk of metastasis from the colorectal region to the testis in their evaluation of patients with testicular symptoms in the setting of colorectal carcinoma.

Predictors of Outcome in Patients With Fibrolamellar Carcinoma: Analysis of the National Cancer Database.

BACKGROUND: Fibrolamellar carcinoma (FLC) is a very rare liver tumor. We aimed to retrospectively analyze the clinicopathological factors and treatment modalities affecting overall survival (OS) in FLC. The objective of the study was to identify predictors of survival in FLC. PATIENTS AND METHODS: Using the National Cancer Database, we identified 496 patients diagnosed with FLC between 2004 and 2015. Clinicopathological, treatment, and survival data were collected. RESULTS: Hepatic resection was performed on 254 (51.2%) patients, liver-directed therapy on 13 (2.6%) patients, and liver transplantation on 15 (3.0%) patients. Median OS by stage were 142.1, 87.2, 32.3, and 14.1 months for stages 1, 2, 3, and 4, respectively. Metastatectomy was not associated with superior median OS (23.4 vs. 10.5 months, p=0.163). Age ≤40, low Charlson-Deyo comorbidity score, early stage and hepatic resection were independently associated with longer OS. CONCLUSION: Our study reports current trends in FLC management, and identifies independent predictors of OS.

Nivolumab Is Effective in Mismatch Repair-Deficient Noncolorectal Cancers: Results From Arm Z1D-A Subprotocol of the NCI-MATCH (EAY131) Study.

PURPOSE: The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, the largest national precision oncology study to date (> 1,100 sites) of patients with relapsed or refractory malignancies, assigned patients to targeted therapy in parallel phase II studies based on tumor molecular alterations. The anti-programmed death receptor 1 inhibitor nivolumab previously showed activity in mismatch repair (MMR)-deficient colon cancer. We hypothesized that nivolumab would have activity in patients with MMR-deficient, noncolorectal tumors. PATIENTS AND METHODS: Eligible patients with relapsed or refractory tumors, good end-organ function, and Eastern Cooperative Oncology Group performance status of ≤ 1 underwent tumor biopsy for centralized screening of molecular alterations. MMR deficiency was defined by complete loss of nuclear expression of MLH1 or MSH2 MMR gene products by immunohistochemistry (IHC). Patients with MMR-deficient colorectal cancer were excluded. Nivolumab, 3 mg/kg every 2 weeks (28-day cycles) and 480 mg every 4 weeks after cycle 4, was administered intravenously. Disease reassessment was performed every 2 cycles. The primary end point was RECIST 1.1 objective response rate (ORR). RESULTS: Two percent of 4,902 screened patients had an MMR-deficient cancer by IHC. Forty-two evaluable patients were enrolled, with a median age of 60 years and a median of 3 prior therapies. The most common histologies were endometrioid endometrial adenocarcinoma (n = 13), prostate adenocarcinoma (n = 5), and uterine carcinosarcoma (n = 4). ORR was 36% (15 of 42 patients). An additional 21% of patients had stable disease. The estimated 6-, 12-, and 18-month progression-free survival rates were 51.3% (90% CI, 38.2% to 64.5%), 46.2% (90% CI, 33.1% to 59.3%), and 31.4% (90% CI, 18.7% to 44.2%), respectively. Median overall survival was 17.3 months. Toxicity was predominantly low grade. CONCLUSION: A variety of refractory cancers (2.0% of those screened) had MMR deficiency as defined in NCI-MATCH. Nivolumab has promising activity in MMR-deficient noncolorectal cancers of a wide variety of histopathologic types.

Ratio between positive lymph nodes and total excised axillary lymph nodes as an independent prognostic factor for overall survival in patients with nonmetastatic lymph node-positive breast cancer.

BACKGROUND: The status of the axillary lymph nodes in nonmetastatic lymph node-positive breast cancer (BC) patients remains the single most important determinant of overall survival (OS). Although the absolute number of nodes involved with cancer is important for prognosis, the role of the total number of excised nodes has received less emphasis. Thus, several studies have focused on the utility of the axillary lymph node ratio (ALNR) as an independent prognostic indicator of OS. However, most studies suffered from shortcomings, such as including patients who received neoadjuvant therapy or failing to consider the use of adjuvant therapy and tumor receptor status in their analysis. METHODS: We conducted a single-center retrospective review of 669 patients with nonmetastatic lymph node-positive BC. Data collected included patient demographics; breast cancer risk factors; tumor size, histopathological, receptor, and lymph node status; and treatment modalities used. Patients were subdivided into four groups according to ALNR value (< .25, .25-.49, .50-.74, .75-1.00). Study parameters were compared at the univariate and multivariate levels for their effect on OS. RESULTS: On univariate analysis, both the absolute number of positive lymph nodes and the ALNR were significant predictors of OS. On multivariate analysis, only the ALNR remained an independent predictor of OS, with a 2.5-fold increased risk of dying at an ALNR of >or= .25. CONCLUSIONS: Our study demonstrates that ALNR is a stronger factor in predicting OS than the absolute number of positive axillary lymph nodes.

A randomized phase II trial of nab-paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer.

PURPOSE: Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab is a fully human IgG2 antibody that inhibits Notch2/3 receptors. PATIENTS AND METHODS: Aphase 2, randomized, placebo-controlled, multicenter trial evaluated the activity of tarextumab in combination with nab-paclitaxel and gemcitabine in patients with metastatic PDAC. Patients were stratified based on ECOG performance score and Ca 19-9 level and randomized 1:1 to nab-paclitaxel, gemcitabine with either tarextumab or placebo. Based on preclinical and phase Ib results suggesting a positive correlation between Notch3 gene expression and tarextumab anti-tumor activity, patients were also divided into subgroups of low, intermediate, and high Notch3 gene expression. Primary endpoint was overall survival (OS) in all and in patients with the three Notch3 gene expression subgroups (≥25th, ≥50% and ≥75% percentiles); secondary end points included progression-free survival (PFS), 12-month OS, overall response rate (ORR), and safety and biomarker investigation. RESULTS: Median OS was 6.4 months in the tarextumab group vs 7.9 months in the placebo group (HR = 1.34 [95% CI = 0.95, 1.89], P = .0985). No difference observed in OS in the Notch3 gene expression subgroups. PFS in the tarextumab-treated group (3.7 months) was significantly shorter compared with the placebo group (5.5 months) (hazard ratio was 1.43 [95% CI = 1.01, 2.01]; P = .04). Grade 3 diarrhea and thrombocytopenia were more common in the tarextumab group. CONCLUSIONS: The addition of tarextumab to nab-paclitaxel and gemcitabine did not improve OS, PFS, or ORR in first-line metastatic PDAC, and PFS was specifically statistically worse in the tarextumab-treated patients. CLINICAL TRIAL REGISTRY NO: NCT01647828.

Effect of mucin production on survival in colorectal cancer: a case-control study.

AIM: To investigate the impact of mucin production on prognosis in colorectal cancer, in terms of overall survival (OS) and time to disease progression (TTP) in patients with mucinous compared to those with non-mucinous colorectal cancer (NMCRC), matched for age, gender, and tumor stage. METHODS: Thirty five patients with mucinous colorectal cancer (MCRC) were matched for age, gender, and tumor stage with 35 controls having NMCRC. OS and TTP were compared among 4 groups divided according to mucin content: group A (50%-75% mucin), group B (75%-100% mucin), group C or controls (<50% mucin). Group D consisted of all patients with tumors having <75% mucin (controls and groups A together). RESULTS: Median survival in MCRC and NMCRC groups was 46.2 and 112.9 mo, respectively (P=0.26). OS in groups A and B was 70.1 and 32.8 mo (P=0.46), and in groups B and D was 32.8 and 70.1 mo, respectively (P=0.143). TTP in MCRC and NMCRC was 50.17 and 44.77 mo, respectively (P=0.795). TTP in groups A, B, and D was 70.1, 24.8, and 65.5 mo, respectively. Twenty-eight percent of patients with MCRC had poorly differentiated adenocarcinoma versus 8.6% in NMCRC patients (P=0.028). CONCLUSION: MCRC is associated with a non-significant decrease in median survival and TTP, particularly when mucin content is >75% of tumor volume. However, it tends to be more poorly differentiated. A larger study matching for stage and grade is needed.

First line treatment of advanced non-small-cell lung cancer - specific focus on albumin bound paclitaxel.

Lung cancer is the leading cause of cancer mortality worldwide in both men and women. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for more than 80% of cases. Paclitaxel has a broad spectrum of activity against various malignancies, including NSCLC. Paclitaxel is poorly soluble in water and thus, until recently, its commercially available preparations contained a non-ionic solvent Cremophor EL®. Cremophor EL® improves the solubility of paclitaxel and allows its intravenous administration. However, certain side-effects associated with paclitaxel, such as hypersensitivity reactions, myelosuppression, and peripheral neuropathy, are known to be worsened by Cremophor®. Nanoparticle albumin-bound paclitaxel ([nab-paclitaxel] ABRAXANE® ABI-007) is a new generation formulation of paclitaxel that obviates the need for Cremophor®, resulting in a safer and faster infusion without requiring the use of premedications to avoid hypersensitivity. Albumin-binding receptor-mediated delivery and lack of sequestering Cremophor® micelles allow higher intratumoral concentration of pharmacologically active paclitaxel. Multiple clinical trials have demonstrated a superior tolerability profile of nab-paclitaxel in comparison to solvent-bound paclitaxel (sb-paclitaxel). A recent Phase III trial compared the effects of weekly nab-paclitaxel in combination with carboplatin versus sb-paclitaxel in combination with carboplatin given every 3 weeks for first line treatment of NSCLC. This trial highlights the weekly nab-paclitaxel combination as an alternate treatment option for NSCLC, with higher response rate in squamous cell NSCLC and longer survival in elderly patients. This review will focus on the properties of nab-paclitaxel and its use in the first line treatment of NSCLC.

Small cell lung cancer doubling time and its effect on clinical presentation: a concise review.

Small cell lung cancer (SCLC) is one of many types rapidly growing malignant diseases, such as Burkitt's lymphoma and testicular germ cell cancers. At present, there is no reliable way to screen for SCLC, and imaging modalities tend to be delayed in detecting this type of cancer. The clinical presentation of acutely and rapidly growing SCLC can mimic those of pulmonary inflammatory or infectious disorders, and in some instances, this delays appropriate management and negatively affects patient outcome.

Treatment of metastatic breast cancer: state-of-the-art, subtypes and perspectives.

Current treatment of metastatic breast cancer (MBC) aims at achieving meaningful clinical responses, improved quality of life, long-term remissions, prolonged survival, and dares to hope for a cure in a small percentage of cases. This article will discuss both consensus and controversies in the management of MBC in the context of the new evolving breast cancer molecular classification. Hormonal therapy remains the mainstay of management of MBC Luminal A and B. Data is emerging on management of ErbB2-positive HR-positive MBC by combining hormonal manipulation and targeted anti-ErbB2 therapy and has recently received regulatory approval in Europe and USA. The optimal use and duration of single agent or combination chemotherapy is discussed. Data and controversies surrounding the use of newer agents such as nab-paclitaxel, ixabepilone, eribulin, and PARP inhibitors as well as trastuzumab is reviewed. Better understanding of pathophysiology has paved the way for the introduction of newer anti-ErbB2 agents such as lapatinib, pertuzumab, T-DM1 and neratinib. Controversies regarding bevacizumab and anti-angiogenesis are discussed. Bisphosphonates have significantly reduced skeletal related events and made significant improvements in the quality of life of patients with MBC. Newer anti-RANK Ligand antibodies show promising results. Significant advances in the understanding of molecular biology of breast cancer have been made and should lead to an improvement in the outcome of MBC. More possibilities of cure can become an attainable goal in the near future.

Is VEGF a predictive biomarker to anti-angiogenic therapy?

Tumor growth and metastasis are dependent on angiogenesis. Inhibiting angiogenesis has therapeutic potentials for treating cancer. Researchers have identified many of the pathways involved in angiogenesis and proposed selective targeted strategies. A high probability of benefit is desirable to justify the choice of anti-angiogenic therapy from an ever-expanding list of expensive new anticancer agents. However, biomarkers of response to anti-angiogenic agents are inconclusive for predicting benefit from these drugs. This paper reviews the most important biomarker of angiogenesis, namely VEGF, in relation to its expression in cancer and the treatment of these cancers through targeting VEGF and its pathways.