an-ivor-lewis-esophagectomy-designed-to-minimize-anastomotic

An Ivor Lewis Esophagectomy Designed to Minimize Anastomotic Complications and Optimize Conduit Function

We describe a novel esophagogastric anastomotic technique (&ldquo;side-to-side: staple line-on-staple line&rdquo;, STS) for intrathoracic anastomoses ...

Indiana University Melvin and Bren Simon Cancer Center

Advanced nonsmall cell lung cancer (NSCLC) remains a therapeutic challenge. Traditional chemotherapy provides response rates of about 20-40% and median survivals of 8-10 months. The outcome of patients presenting at an advanced stage is therefore disappointing. In order to improve patients' outcomes, there has been a renewed interest in evaluating the role of maintenance or consolidation chemotherapy or both. Therefore, this review is timely and also relevant to clinical practice.

The role of maintenance chemotherapy in advanced nonsmall cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the USA. The treatment of locally advanced NSCLC (LA-NSCLC) is challenging and must be individualized. For patients with completely resected stage III NSCLC, adjuvant cisplatin-based chemotherapy for 4 cycles is recommended. For patients with inoperable or unresectable stage III NSCLC, chemoradiation is the preferred treatment. Patients with a good performance status, minimal or no weight loss, and adequate pulmonary function should be offered concurrent chemoradiation. The optimal chemotherapeutic agents to be used concurrently with radiation remain undefined. In the USA, cisplatin plus etoposide or carboplatin plus paclitaxel are the most commonly used regimens. In addition, the optimal duration of therapy remains undefined, including the role of consolidation chemotherapy. Thus far, randomized phase III trials have failed to identify a survival advantage for administering chemotherapy beyond that delivered during radiation therapy. Molecularly targeted agents, angiogenesis inhibitors, and immunotherapy have a defined role for patients with metastatic disease. The role, if any, of these new classes of agents is undergoing investigation for patients with earlier stage disease, including stage III disease.

Locally Advanced Non-Small Cell Lung Cancer: Optimal Chemotherapeutic Agents and Duration.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor of the lung with a tendency to metastasize widely early in the course of the disease. The VA staging system classifies the disease into limited stage (LS) which is confined to one hemithorax and can be included into one radiation field or extensive stage (ES) which extends beyond one hemithorax. Current standard of care is concurrent chemoradiation for LS disease and chemotherapy alone for ES disease. Only a quarter of patients with LS disease will be cured with current standard treatments and majority of the patients ultimately succumb to their disease. A very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and a high recurrence rate, however, at the same time this complexity can form the basis for effective targeted therapy for the disease. In recent years, several different therapeutic strategies and targeted agents have been under investigation for their potential role in SCLC. Several of them including EGFR TKIs, BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors have been unsuccessful in showing a survival advantage in this disease. Several others including DNA repair inhibitors, cellular developmental pathway inhibitors, antibody drug conjugates (ADCs), as well as immune therapy with vaccines, immunomodulators, and immune checkpoint inhibitors are being tested. So far, none of these agents are approved for use in SCLC and the majority are in phase I/II clinical trials, with immune checkpoint inhibitors being the most promising therapeutic strategy. In this article, we will discuss these novel therapeutic agents and currently available data in SCLC. 

Novel therapies in small cell lung cancer.

Purpose Macrophage-stimulating 1-receptor (RON) is expressed on macrophages, epithelial cells, and a variety of tumors. Narnatumab (IMC-RON8; LY3012219) is a neutralizing monoclonal antibody that blocks RON binding to its ligand, macrophage-stimulating protein (MSP). This study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of narnatumab in patients with advanced solid tumors. Methods Narnatumab was administered intravenously weekly at 5, 10, 15, or 20 mg/kg or every 2 weeks at 15, 20, 30, or 40 mg/kg in 4-week cycles. Results Thirty-nine patients were treated, and 1 dose-limiting toxicity (DLT) (grade 3 hyponatremia, 5 mg/kg) was reported. The most common narnatumab-related adverse events (AEs) were fatigue (20.5%) and decreased appetite, diarrhea, nausea, and vomiting (10.3% each). Except for 2 treatment-related grade 3 AEs (hyponatremia, hypokalemia), all treatment-related AEs were grade 1 or 2. Narnatumab had a short half-life (<7 days). After Cycle 2, no patients had concentrations above 140 μg/mL (concentration that demonstrated antitumor activity in animal models), except for 1 patient receiving 30 mg/kg biweekly. Eleven patients had a best response of stable disease, ranging from 6 weeks to 11 months. Despite only 1 DLT, due to suboptimal drug exposure, the dose was not escalated beyond 40 mg/kg biweekly. This decision was based on published data reporting that mRNA splice variants of RON are highly prevalent in tumors, accumulate in cytoplasm, and are not accessible by large-molecule monoclonal antibodies. Conclusions Narnatumab was well tolerated and showed limited antitumor activity with this dosing regimen.

Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors.

Esophageal adenocarcinoma (EAC) continues to be a disease associated with high mortality. Among the factors leading to poor outcomes are innate resistance to currently available therapies, advanced stage at diagnosis, and complex biology. Platinum and ionizing radiation form the backbone of treatment for the majority of patients with EAC. Of the multiple processes involved in response to platinum chemotherapy or ionizing radiation, deoxyribonucleic acid (DNA) repair has been a major player in cancer sensitivity to these agents. DNA repair defects have been described in various malignancies. The purpose of this study was to determine whether alterations in DNA repair are present in EAC compared with normal gastroesophageal tissues.

Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair.

The therapeutic landscape of lung cancer has expanded significantly over the past decade. Advancements in molecularly targeted therapies, strategies to discover and treat resistance mutations, and development of personalized cancer treatments in the context of tumor heterogeneity and dynamic tumor biology have made it imperative to obtain tumor samples on several different occasions through the course of patient treatment. While this approach is critical to the delivery of optimal cancer treatment, it is fraught with a number of barriers including the need for invasive procedures with associated complications, access to limited amount of tissue, logistical delays in obtaining the biopsy, high healthcare cost, and in many cases inability to obtain tissue because of technically difficult location of the tumor. Given multiple limitations of obtaining tissue samples, the use of blood-based biomarkers ("liquid biopsies") may enable earlier diagnosis of cancer, lower costs by avoiding complex invasive procedures, tailoring molecular targeted treatments, improving patient convenience, and ultimately supplement clinical oncologic decision-making. In this paper, we review various blood-based biomarkers including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), tumor derived exosomes, tumor educated platelets (TEPs), and microRNA; and highlight current evidence for their use in detection and treatment of lung cancer.

Blood-based tumor biomarkers in lung cancer for detection and treatment.

Anastomotic complications represent a significant source of morbidity and occasionally mortality after esophagectomy. Since 2009, we have used a novel "side-to-side: staple line-on-staple line" (STS) technique for intrathoracic esophagogastric anastomoses, designed to create a wide-diameter esophagogastric anastomosis while preserving stomach conduit blood supply. In this study, we describe the technique and review outcomes of our institution's initial 6-year experience.

Outcomes of a novel intrathoracic esophagogastric anastomotic technique.

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.

Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma.

The present study examined the degree to which loneliness mediated the influence of negative (social constraints) and positive (emotional support) relationship qualities on the global mental health of advanced gastrointestinal (GI) cancer patients and their family caregivers.

Article	Year
The role of maintenance chemotherapy in advanced nonsmall cell lung cancer. Current opinion in oncology\| PubMed ID: 19532011	2009
Locally Advanced Non-Small Cell Lung Cancer: Optimal Chemotherapeutic Agents and Duration. Current treatment options in oncology\| PubMed ID: 26233240	2015
Novel therapies in small cell lung cancer. Translational lung cancer research\| PubMed ID: 26629422	2015
Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors. Investigational new drugs\| PubMed ID: 28161886	2017
Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair. Lung Cancer (Auckland, N.Z.)\| PubMed ID: 28210138	2014
Blood-based tumor biomarkers in lung cancer for detection and treatment. Translational lung cancer research\| PubMed ID: 29218268	2017
Outcomes of a novel intrathoracic esophagogastric anastomotic technique. The Journal of thoracic and cardiovascular surgery\| PubMed ID: 30033105	2018
Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma. JCI insight\| PubMed ID: 30135316	2018
Social correlates of mental health in gastrointestinal cancer patients and their family caregivers: Exploring the role of loneliness. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer\| PubMed ID: 30225573	2019
Breakthroughs and challenges in the management of tropomyosin receptor kinase fusion-positive tumors. Annals of translational medicine\| PubMed ID: 31576362	2019

Shadia I. Jalal

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