Gastric Cancer Survivorship: Multidisciplinary Management, Best Practices and Opportunities.

PURPOSE: Gastric cancer is the 5th most common malignancy worldwide. As early detection increases and treatments for gastric cancer improve, the number of gastric cancer survivors grows. METHODS: Here, we review the diagnosis and management of gastric cancer and discuss important considerations for gastric cancer survivorship including cancer surveillance, weight loss, malnutrition, fatigue, specific complications related to surgery and radiation, quality of life in gastric cancer survivorship, health behavior, and models of survivorship. RESULTS: Multimodality therapy with chemotherapy and surgery can result in chronic toxicities in multiple organ systems. This emphasizes the need for a multidisciplinary survivorship care model including cancer surveillance, management of chronic toxicities, and optimization of modifiable risk factors with long-term involvement of appropriate providers. CONCLUSION: Adequately caring for gastric cancer survivors requires a coordinated, multidisciplinary approach.

Hepatocellular Carcinoma: Surveillance, Diagnosis, Evaluation and Management.

Hepatocellular carcinoma (HCC) ranks fourth in cancer-related deaths worldwide. Semiannual surveillance of the disease for patients with cirrhosis or hepatitis B virus allows for early detection with more favorable outcomes. The current underuse of surveillance programs demonstrates the need for intervention at both the patient and provider level. Mail outreach along with navigation provision has proven to increase surveillance follow-up in patients, while provider-targeted electronic medical record reminders and compliance reports have increased provider awareness of HCC surveillance. Imaging is the primary mode of diagnosis in HCC with The Liver Imaging Reporting and Data System (LI-RADS) being a widely accepted comprehensive system that standardizes the reporting and data collection for HCC. The management of HCC is complex and requires multidisciplinary team evaluation of each patient based on their preference, the state of the disease, and the available medical and surgical interventions. Staging systems are useful in determining the appropriate intervention for HCC. Early-stage HCC is best managed by curative treatment modalities, such as liver resection, transplant, or ablation. For intermediate stages of the disease, transarterial local regional therapies can be applied. Advanced stages of the disease are treated with systemic therapies, for which there have been recent advances with new drug combinations. Previously sorafenib was the mainstay systemic treatment, but the recent introduction of atezolizumab plus bevacizumab proves to have a greater impact on overall survival. Although there is a current lack of improved outcomes in Phase III trials, neoadjuvant therapies are a potential avenue for HCC management in the future.

Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers.

KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C-mutant tumors. However, patients receiving these agents as monotherapy often develop drug resistance. To address this issue, we evaluated the combination of the PAK4 inhibitor KPT9274 and KRASG12C inhibitors in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We found that cancer cells resistant to KRASG12C inhibitor were sensitive to KPT9274-induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRASG12C-mutant cancer cells and reduce their clonogenic potential. Mechanistically, this combination suppressed cell growth signaling and downregulated cell-cycle markers. In a PDAC cell line-derived xenograft (CDX) model, the combination of a suboptimal dose of KPT9274 with sotorasib significantly reduced the tumor burden (P= 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model, in which KPT9274, given as maintenance therapy, prevented tumor relapse following the discontinuation of sotorasib treatment (P= 0.0001). Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for patients with cancer who do not respond or develop resistance to KRASG12C inhibitor treatment.

Anticancer efficacy of KRASG12C inhibitors is potentiated by PAK4 inhibitor KPT9274 in preclinical models of KRASG12C mutant pancreatic and lung cancers.

KRASG12C inhibitors have revolutionized the treatment landscape for cancer patients harboring the G12C mutant isoform of KRAS. With the recent FDA approval of sotorasib and adagrasib, patients now have access to more promising treatment options. However, patients who receive these agents as a monotherapy usually develop drug resistance. Thus, there is a need to develop logical combination strategies that can delay or prevent the onset of resistance and simultaneously enhance the antitumor effectiveness of the treatment regimen. In this study, we aimed at pharmacologically targeting PAK4 by KPT9274 in combination with KRASG12C inhibitors in KRASG12C mutant pancreatic ductal adenocarcinoma (PDAC) and nonâ€"small cell lung cancer (NSCLC) preclinical models. PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We assessed the cytotoxicity of PAK4 and KRASG12C inhibitors combination in KRASG12C mutant 2D and 3D cellular models. KPT9274 synergized with both sotorasib and adagrasib in inhibiting the growth of KRASG12C mutant cancer cells. The combination was able to reduce the clonogenic potential of KRASG12C mutant PDAC cells. We also evaluated the antitumor activity of the combination in a KRASG12C mutant PDAC cell line-derived xenograft (CDX) model. Oral administration of a sub-optimal dose of KPT9274 in combination with sotorasib (at one-fourth of MTD) demonstrated significant inhibition of the tumor burden ( p = 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model where KPT9274, acting as an adjuvant, prevented tumor relapse following the discontinuation of sotorasib treatment ( p = 0.0001). KPT9274 and sotorasib combination also resulted in enhanced survival. This is the first study showing that KRASG12C inhibitors can synergize with PAK4 inhibitor KPT9274 both in vitro and in vivo resulting in remarkably enhanced antitumor activity and survival outcomes. Significance: KRASG12C inhibitors demonstrate limited durable response in patients with KRASG12C mutations. In this study, combining PAK4 inhibitor KPT9274 with KRASG12C inhibitors has resulted in potent antitumor effects in preclinical cancer models of PDAC and NSCLC. Our results bring forward a novel combination therapy for cancer patients that do not respond or develop resistance to KRASG12C inhibitor treatment.

The urban injury severity score (UISS) better predicts mortality following penetrating gunshot wounds (GSW).

BACKGROUND: The Injury Severity Score (ISS) and the New ISS (NISS) underscore injury severity after GSW. This study assesses the Urban ISS (UISS), which incorporates all injuries. METHODS: Complete trauma program registry (TPR) data and chart analyses were performed on 585 patients (pts) over 28 months. Factors analyzed included age, gender, ISS, NISS, UISS, time of admission, intent of injury, race, number GSW, weapon, and outcome. RESULTS: The 585 patients could be categorized within three groups. The first group included 98 pts with low ISS (1-2), no organ injuries, and early discharge; the second group included 47 patients with severe shock who died during operation; the third group of 442 pts were admitted after operation. All injury scores correlated (p < 0.001) with assault, number GSW, death, and length-of-stay (LOS). Death and LOS correlated closely with assault and the resultant number of GSW, best seen with UISS compared to ISS or NISS. Race and admission time did not correlate with death or LOS. CONCLUSIONS: UISS correlates better than ISS and NISS in victims of inner-city firearm injuries.

A case of tricuspid atresia with normally related great vessels and coarctation of the aorta.

Tricuspid atresia is a congenital cardiac anomaly that is most commonly associated with normally related great vessels and less commonly with transposition of the great vessels. When tricuspid atresia is associated with dextro-transposition of the great vessels, there is a high incidence of coarctation of the aorta. This report documents the rare case of a newborn male with tricuspid atresia and normally related great arteries with both pulmonary stenosis and coarctation of the aorta.