Immunotherapy in the Management of Esophagogastric Cancer: A Practical Review.

Recent data support incorporation of immune checkpoint inhibitors into the treatment armamentarium for esophageal, gastroesophageal junction, and gastric (esophagogastric) cancer. This practical review focuses on clinical trials that influenced US Food and Drug Administration approvals and treatment guidelines in esophagogastric cancer, including the impact of location, stage, histology, human epidermal growth factor receptor 2 status, and PD-(L)1 expression on these guidelines. The role of immunotherapy in the locally advanced and metastatic setting is constantly expanding. Over the next few years, the many ongoing trials exploring immunotherapy are anticipated to bring new treatment regimens into the frontline setting with the potential to improve survival in patients with advanced disease.

Disparities in melanoma incidence and mortality in rural versus urban Michigan.

INTRODUCTION: We sought to identifying the possible existence of disparities between rural and urban residents of Michigan for the incidence by stage of disease and disease-specific mortality for cutaneous melanoma (CM). METHODS: Incidence rates for stage of disease and disease-specific mortality of cutaneous melanoma were calculated and controlled for gender, age, and area of residence from January 1, 2014, to December 31, 2018, from data collected form the Michigan Department of Health and Human Services and the Centers for Disease Control and Prevention. RESULTS: The incidence rates for CM were significantly higher in rural Michigan counties, from 2014-2018, for all patients, both age groups, both genders and all stages. Melanoma-specific mortality rates were also significantly higher for all patients, both age groups and both genders in rural Michigan counties. Using logistic regression analysis, while controlling for age and gender, rural Michigan counties continued to have a higher melanoma-specific morality rate during our study period (OR = 1.491; 95% CI, 1.27-1.74; p = <.001). CONCLUSION: We found significant disparities in the incidence rates and disease specific mortality for cutaneous melanoma in rural compared to urban Michigan from 2014-2018.

Treatment with Granulocyte-colony Stimulating Factor (G-CSF) is not associated with Increased Risk of Brain Metastasis in Patients with De Novo Stage IV Breast Cancer.

Background: Survival outcome after developing brain metastasis is poor and there is an unmet need to identify factors that can promote brain metastasis. Granulocyte-colony stimulating factor (G-CSF) is given to support neutrophil recovery after myelosuppressive chemotherapy to some patients. However, there is emerging evidence that neutrophils can promote metastasis, including through the formation of neutrophil extracellular traps (NETs), scaffolds of chromatin with enzymes expelled from neutrophils to the extracellular space. In animal models, G-CSFs can induce NETs to promote liver and lung metastasis. The primary objective of this study was to test the association between G-CSF use and the later incidence of brain metastasis. Methods: Patients with de novo Stage IV breast cancer, without known brain metastasis at the time of initial diagnosis, were identified from electronic medical records covering the period from 1/1/2013 to 12/31/2020 at Northwell Health. Univariate and multivariate logistic regression models were used to test the association between variables of interest, including G-CSF use, and brain metastasis. Results: A total of 78 patients were included in the final analysis. Among those 78 patients, 24 patients (30.8%) had received G-CSF along with chemotherapy at least once. In logistic regression models, G-CSF use was not a significant factor to predict brain metastasis (OR 1.89 [95%CI 1.89-5.33]; P=0.23). Interestingly, in multivariate logistic models, pulmonary embolism (PE)/deep venous thrombosis (DVT) was a significant predictive factor of brain metastasis (OR 6.74 [95%CI 1.82-25.01]; P=0.004) (38.5% vs 21.5%). Conclusions: The use of G-CSF was not associated with increased risk of brain metastasis in patients with de novo Stage IV breast cancer. Interestingly, PE/DVT, which can be associated with elevated NETs, was associated with brain metastasis. Further studies are warranted to determine whether DVT/PE with or without elevated NETs levels in the blood, is predictive of developing brain metastasis in patients with de novo Stage IV breast cancer.

The role of PARP inhibitors in BRCA mutated pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) accounts for about 3% of all cancers in the United States and about 7% of all cancer deaths. Despite the lower prevalence relative to other solid tumors, it is one of the leading causes of cancer-related death in the US. PDAC is highly resistant to chemotherapy as well as radiation therapy. Current standard-of-care chemotherapeutic regimens provide transient disease control but eventually tumors develop chemoresistance. Tumors that are deficient in DNA damage repair mechanisms such as BRCA mutants respond better to platinum-based chemotherapies. However, these tumor cells can utilize the poly adenosine diphosphate (ADP)-ribose polymerase (PARP) as a salvage DNA repair pathway to prolong survival. Hence, in the presence of BRCA mutations, the inhibition of the PARP pathway can lead to tumor cell death. This provides the rationale for using PARP inhibitors in patients with BRCA mutated PDAC. The phase III POLO trial showed a near doubling of progression-free survival (PFS) compared with placebo in advanced PDAC when a PARP inhibitor, olaparib, was used as maintenance therapy. As a result, the US Food and Drug Administration (FDA) approved olaparib as a maintenance treatment for germline BRCA mutated advanced PDAC that has not progressed on platinum-based chemotherapy. The success of olaparib in treating advanced PDAC opened the new field for utilizing PARP inhibitors in patients with DNA damage repair (DDR) gene defects. Currently, many clinical trials with various PARP inhibitors are ongoing either as monotherapy or in combination with other agents. In addition to germline/somatic BRCA mutations, some trials are enrolling patients with defects in other DDR genes such as ATM, PALB2, and CHEK2. With many ongoing PARP inhibitor trials, it is hopeful that the management of PDAC will continuously evolve and eventually lead to improved patient outcomes.

Impact of Biopsy Technique on Clinically Important Outcomes for Cutaneous Melanoma: A Systematic Review and Meta-analysis.

We performed a systematic review and meta-analysis to examine the relationship between the type of biopsy technique employed in the diagnosis of cutaneous melanoma and 4 clinically important outcomes: melanoma-specific mortality, all-cause mortality, Breslow tumor depth, or melanoma recurrence. Our database was obtained by searching PubMed, Ovid MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Library from inception until December 6, 2019. Studies were identified that compared biopsy techniques used to diagnose cutaneous melanoma with any of our study outcomes. We included 7 observational studies for our meta-analysis after screening 3231 titles and abstracts. Pooled data identified a significantly higher all-cause mortality in the punch biopsy group (risk ratio [RR], 1.520; P=.02). A higher, but nonsignificant, rate of melanoma-specific mortality (RR, 1.96; P=.22) and melanoma recurrence (RR, 1.20; P=.186) was also found for the punch biopsy group. Breslow tumor thickness was not significantly lower for punch incision (standardized mean difference, -0.42; P=.27). We found limited evidence for differences in clinically important outcomes across the spectrum of the most common methods employed in clinical practice for the initial diagnosis of cutaneous melanoma. A small, but significant, increase (P=.02) in all-cause mortality with punch biopsies was not seen for the other outcomes and was most likely due to small sample sizes and demographic differences in the included studies and unlikely represents a clinically important outcome. Our findings support the use of existing clinical practice guidelines for evaluating pigmented lesions suspicious for cutaneous melanoma.

Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats.

Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.