Comparative study of survival among small cell lung cancer patients in the U.S. military health system and those in the surveillance, epidemiology, and end results (SEER) program.

Purpose: The U.S. military health system provides universal health care access to beneficiaries.

RRx-001, a first-in-class small molecule inhibitor of MYC and a downregulator of CD47, is an "erythrophagoimmunotherapeutic".

The main mechanism of action of RRx-001, a pharmaceutically unprecedented Phase 3 small molecule that is derived from the aerospace industry, is clarified. RRx-001 has demonstrated anticancer activity through antiangiogenic, immune, epigenetic, antioxidant, apoptotic and nitric oxide (NO) pathways, resulting in its pleiomorphic description as an antiangiogenic/vascular normalizer.

TGF-beta: a master immune regulator.

: Transforming Growth Factor-Beta (TGF-β) is a master regulator of numerous cellular functions including cellular immunity. In cancer, TGF-β can function as a tumor promoter via several mechanisms including immunosuppression. Since the immune checkpoint pathways are co-opted in cancer to induce T cell tolerance, this review posits that TGF-β is a master checkpoint in cancer, whose negative regulatory influence overrides and controls that of other immune checkpoints.

REPLATINUM Phase III randomized study: RRx-001 + platinum doublet versus platinum doublet in third-line small cell lung cancer.

RRx-001 is a cysteine-directed anticancer alkylating agent with activity in a Phase II study in platinum refractory small cell lung cancer. Here, we describe the design of REPLATINUM, an open-label, Phase III trial. 120 patients with previously platinum-treated small cell lung cancer in third line will be randomized 1:1 to receive RRx-001 followed by four cycles of a platinum doublet, and then alternating cycles of RRx-001 and single agent platinum until progression versus four cycles of a platinum doublet.

Cardioprotective Effect of Phase 3 Clinical Anticancer Agent, RRx-001, in Doxorubicin-Induced Acute Cardiotoxicity in Mice.

Anthracycline chemotherapy (e.g., doxorubicin or DOX) is associated with a cumulative dose-dependent cardiac dysfunction that may lead to congestive heart failure, which limits both its use and usefulness in the clinic.

APOBEC Mutagenesis and Copy-Number Alterations Are Drivers of Proteogenomic Tumor Evolution and Heterogeneity in Metastatic Thoracic Tumors.

Intratumor mutational heterogeneity has been documented in primary non-small-cell lung cancer. Here, we elucidate mechanisms of tumor evolution and heterogeneity in metastatic thoracic tumors (lung adenocarcinoma and thymic carcinoma) using whole-exome and transcriptome sequencing, SNP array for copy-number alterations (CNAs), and mass-spectrometry-based quantitative proteomics of metastases obtained by rapid autopsy. APOBEC mutagenesis, promoted by increased expression of APOBEC3 region transcripts and associated with a high-risk APOBEC3 germline variant, correlated with mutational tumor heterogeneity.

A practical guide to the handling and administration of personalized transcriptionally attenuated oncolytic adenoviruses (PTAVs).

The aim of this review is to provide practical information on the handling, storage, and administration procedures for personalized oncolytic adenoviruses (PTAVs), which have recently entered clinical trials. As described herein, personalized oncolytic viruses refer to transcriptionally attenuated (TA) type 5 adenoviruses that are engineered to carry one or more neoantigenic transgenes derived from patient tumors. Vials of personalized viruses should be stored at -60°C without refreezing after thawing to maintain infectivity.

Case Series: Abscopal Benefit of Surgery in 3 Immunotherapy-Treated Patients With Unresectable Cancer.

For all of the optimism that immunotherapy has engendered, the flip side is that 7/10 patients with susceptible tumor types do not respond, while in nonsusceptible tumor types the response rates are significantly lower. In contradiction of the current orthodoxy against surgery in the setting of unresectable disease, we present 3 examples of immunotherapy-treated patients with widespread recurrence who experienced dramatic clinical improvement following debulking/metastasectomy. Taken together with examples from the literature that correlate longer survival with surgical intervention during treatment with immunotherapy, these 3 cases suggest that a new paradigm involving a wider role for surgery in the management of these patients should be explored.

Brief report: RRx-001 is a c-Myc inhibitor that targets cancer stem cells.

The goal of anticancer therapy is to selectively eradicate all malignant cells. Unfortunately for the majority of patients with metastatic disease, this goal is consistently thwarted by the nearly inevitable development of therapeutic resistance; the main driver of therapeutic resistance is a minority subpopulation of cancer cells called cancer stem cells (CSCs) whose mitotic quiescence essentially renders them non-eradicable. The Wnt signaling pathway has been widely implicated as a regulator of CSCs and, therefore, its inhibition is thought to result in a reversal of therapeutic resistance via loss of stem cell properties.

Survival among Lung Cancer Patients in the U.S. Military Health System: A Comparison with the SEER Population.

The U.S. military health system (MHS) provides universal health care access to its beneficiaries.

Navigating the "No Man's Land" of TKI-Failed EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC): A Review.

As the leading cause of cancer-related mortality, lung cancer is a worldwide health issue that is overwhelmingly caused by smoking. However, a substantial minority (~25%) of patients with non-small cell lung cancer (NSCLC) has never smoked. In these patients, activating mutations of the epidermal growth factor receptor (EGFR) are more likely, which render their tumors susceptible for a finite period to treatment with EGFR tyrosine kinase inhibitors (TKIs) and confer a better prognosis than EGFR wild-type NSCLC.

No patient left behind: The promise of immune priming with epigenetic agents.

Checkpoint inhibitors, monoclonal antibodies that inhibit PD-1 or CTLA-4, have revolutionized the treatment of multiple cancers. Despite the enthusiasm for the clinical successes of checkpoint inhibitors, and immunotherapy, in general, only a minority of patients with specific tumor types actually benefit from treatment. Emerging evidence implicates epigenetic alterations as a mechanism of clinical resistance to immunotherapy.

Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas.

This review covers the diverse topic of neuroendocrine neoplasms (NENs), a relatively rare and heterogeneous tumor type, comprising ~2% of all malignancies, with a prevalence of <200,000 in the United States, which makes it an orphan disease (Basu et al., 2010). For functional purposes, NENs are divided into two groups on the basis of clinical behavior, histology, and proliferation rate: well differentiated (low grade to intermediate grade) neuroendocrine tumors and poorly differentiated (high grade) neuroendocrine carcinoma (Bosman et al.

What's New in SCLC? A Review.

A few years ago the answer to the question in the title of this review would have been, "unfortunately not much" or even "nothing", likely eliciting knowing nods of agreement from oncologists. For the last 3 decades, SCLC has been notorious for its lack of progress, as drug after drug, over 60 of them, in fact, including inhibitors of VEGF, IGFR, mTOR, EGFR and HGF has failed and fallen by the wayside due to little or no impact on PFS or OS, while SCLC's cousin, NSCLC, has notched success after success with a spate of targeted treatment and immunotherapy regulatory approvals. However, a paradigm shift or, more appropriately, a 'paradigm nudge' is quietly underway in extensive stage SCLC with a series of agents that in early clinical trials have shown the potential to 'lift the curse' in SCLC, heretofore referred to as "a graveyard for drug development".

Electrolyte disorders with platinum-based chemotherapy: mechanisms, manifestations and management.

Platinum chemotherapy, particularly cisplatin, is commonly associated with electrolyte imbalances, including hypomagnesemia, hypokalemia, hypophosphatemia, hypocalcemia and hyponatremia. The corpus of literature on these dyselectrolytemias is large; the objective of this review is to synthesize the literature and summarize the mechanisms responsible for these particular electrolyte disturbances in the context of platinum-based treatment as well as to present the clinical manifestations and current management strategies for oncologists and primary care physicians, since the latter are increasingly called on to provide care for cancer patients with medical comorbidities. Correct diagnosis and effective treatment are essential to improved patient outcomes.

Superior Vena Cava Syndrome in a Patient with Small-Cell Lung Cancer: A Case Report.

Superior vena cava (SVC) syndrome, a potential oncologic emergency, is closely associated with malignancy and right-sided lung cancer in particular. A case of SVC syndrome presenting with facial swelling, neck distension, and enlarged veins of the upper chest, which developed over a period of 5 weeks in a 46-year-old patient on a clinical trial with small-cell lung cancer, is reported. Computed tomography scan of the chest revealed slight enlargement of a superior conglomerate mediastinal lymphadenopathy and intramural thrombus of the SVC.

A Case of Paraneoplastic Cushing Syndrome Presenting as Hyperglycemic Hyperosmolar Nonketotic Syndrome.

Carcinoid tumors are neuroendocrine tumors that mainly arise in the gastrointestinal tract, lungs, and bronchi. Bronchopulmonary carcinoids have been associated with Cushing syndrome, which results from ectopic adrenocorticotrophic hormone (ACTH) secretion. We report the case of a 65-year-old man, a colonel in the US Air Force, with metastatic bronchopulmonary carcinoid tumors treated on a clinical trial who was hospitalized for complaints of increasing thirst, polydipsia, polyuria, weakness, and visual changes.

RRx-001 Priming of PD-1 Inhibition in the Treatment of Small Cell Carcinoma of the Vagina: A Rare Gynecological Tumor.

Small cell carcinoma of the vagina is rare, so rare in fact that the total number reported in English-language journals is less than 30. Due to this extremely low incidence, no specific treatment guidelines have been established, and most of what is clinically known is derived from a handful of single case reports. However, as befitting its highly aggressive histologic features, which are reminiscent of small cell lung cancer (SCLC), first-line treatment is modeled after SCLC.

A brief review of the management of platinum-resistant-platinum-refractory ovarian cancer.

Ovarian cancer, which ranks fifth in cancer deaths among women, is the most lethal gynecologic malignancy. Epithelial ovarian cancer (EOC) is the most common histologic type, with the 5-year survival for all stages estimated at 45.6%.

RRx-001 protects against cisplatin-induced toxicities.

Purpose: RRx-001, a minimally toxic tumor-associated macrophage and neutrophil-repolarizing agent, is under investigation in Phase II clinical trials as a sensitizer/resensitizer to cisplatin and carboplatin. On the basis of anecdotal clinical observations of improved platinum tolerability following a priming period with RRx-001 as well as preclinical studies that have previously demonstrated radioprotection of intestinal stem cells and cardioprotection from doxorubicin, the in vivo cytoprotective potential of RRx-001 pretreatment against cisplatin-induced bone marrow suppression and renal toxicity was investigated.

Methods: BALB/c mice were divided into three groups: (1) no treatment, (2) vehicle and cisplatin only, and (3) RRx-001 and cisplatin.

Metformin use and survival after non-small cell lung cancer: A cohort study in the US Military health system.

Research suggests that metformin may be associated with improved survival in cancer patients with type II diabetes. This study assessed whether metformin use after non-small cell lung cancer (NSCLC) diagnosis is associated with overall survival among type II diabetic patients with NSCLC in the U.S.

RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials.

According to Hanahan and Weinberg, cancer manifests as six essential physiologic hallmarks: (1) self-sufficiency in growth signals, (2) insensitivity to growth-inhibitory signals, (3) evasion of programmed cell death, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) invasion and metastasis. As a facilitator of these traits as well as immunosuppression and chemoresistance, the presence of tumor-associated macrophages (TAMs) may serve as the seventh hallmark of cancer. Anticancer agents that successfully reprogram TAMs to target rather than support tumor cells may hold the key to better therapeutic outcomes.

Genomic profiling of multiple sequentially acquired tumor metastatic sites from an "exceptional responder" lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response.

We used next-generation sequencing to identify somatic alterations in multiple metastatic sites from an "exceptional responder" lung adenocarcinoma patient during his 7-yr course of ERBB2-directed therapies. The degree of heterogeneity was unprecedented, with ∼1% similarity between somatic alterations of the lung and lymph nodes. One novel translocation, , present in both sites, up-regulated ACTA2 expression.

Conversion of Platinum-Etoposide-Resistant to Sensitive SCLC after Treatment with the Epi-Immunotherapeutic RRx-001: A Case Report.

Background: The response to first-line platinum doublets (cisplatin/etoposide) in small-cell lung cancer (SCLC) predicts the probability of subsequent response to second-line therapy. In general, the longer-lived the responses in first line, the better the outcome in second line, with the opposite prognosis for shorter-lived responses. Resistant SCLC is defined as relapse within 90 days of platinum-doublet treatment, and predictably correlates with shortened survival compared with sensitive disease, defined as relapse after 90 days.