Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review.

Colorectal cancer (CRC) is a heterogeneous disease with a myriad of alterations at the cellular and molecular levels. Kristen rat sarcoma (KRAS) mutations occur in up to 40% of CRCs and serve as both a prognostic and predictive biomarker. Oncogenic mutations in the KRAS protein affect cellular proliferation and survival, leading to tumorigenesis through RAS/MAPK pathways. Until recently, only indirect targeting of the pathway had been investigated. There are now several KRAS allele-specific inhibitors in late-phase clinical trials, and many newer agents and targeting strategies undergoing preclinical and early-phase clinical testing. The adequate treatment of KRAS-mutated CRC will inevitably involve combination therapies due to the existence of robust adaptive resistance mechanisms in these tumors. In this article, we review the most recent understanding and findings related to targeting KRAS mutations in CRC, mechanisms of resistance to KRAS inhibitors, as well as evolving treatment strategies for KRAS-mutated CRC patients.

Safety and efficacy of liposomal irinotecan as the second-line treatment for advanced pancreatic cancer: A systematic review and meta-analysis.

INTRODUCTION: Nanoliposomal irinotecan (nal-IRI) is a novel regimen for pancreatic cancer, featuring a longer half-life and an increased area under the concentration-time curve. This study aims to assess the safety and efficacy of nal-IRI as a second-line treatment for advanced pancreatic cancer. METHODS: A systemic literature search was conducted based on articles published before September 26th, 2023 in databases, including PubMed, Cochrane Library, EMBASE and Web of Science. The fixed effects model was used to calculate the pooled mean difference for overall survival (OS) and progression-free survival (PFS), as well as the pooled odds ratio for the overall response rate (ORR) and the risk of adverse events. RESULTS: A total of 21 studies, including 3044 patients with locally advanced unresectable or metastatic pancreatic cancers, were considered eligible. The use of nal-IRI, combined with 5-fluorouracil and leucovorin, resulted in significantly improved PFS (pooled mean difference=1.01 months, 95 % confidence interval [CI]=0.97-1.05, p<0.01) and OS (pooled mean difference=0.29 months, 95 %CI=0.18-0.39, p<0.01), as well as significantly better ORR (pooled odds ratio=2.06, 95 %CI=1.30-3.27, p=0.002) compared to other second-line regimens. Nonetheless, an increased risk of grade 3 or greater neutropenia, anemia, hypokalemia, diarrhea, and vomiting was also noted. CONCLUSION: Second-line treatments based on nal-IRI exhibited significantly improved PFS, OS, and ORR compared to other available treatments in advanced pancreatic cancer. Further research is necessary to corroborate these findings and define the role of nal-IRI in both first and later lines of therapy.

Neoadjuvant T-DM1 for HER2-positive breast cancer used as a bridging strategy during COVID-19 pandemic: lessons learned-a case series.

Background: Coronavirus disease 19 (COVID-19) has played a pivotal role in changing medical care around the world. During the pandemic, the operating rooms (ORs) were closed to elective surgery. Since breast cancer surgery is not regarded as an emergent procedure, there was an adoption of treatment regimen modification due to delays in treatment. Therefore, a decision was made to bridge early-stage HER2-positive breast cancer patients with neoadjuvant treatment to postpone surgery. Consequently, to reduce the frequency of dosing and the number of visits, as well as avoid steroid premedication, these patients were treated with ado-trastuzumab emtansine (T-DM1) every three weeks as opposed to weekly taxol and herceptin (TH). Case Description: Five patients with early-stage HER2-positive cancer were treated with neoadjuvant T-DM1 3.6 mg/kg IV every three weeks. Three of the five patients developed cancer progression identified by their physical exam and/or imaging. T-DM1 was discontinued, and all three patients underwent immediate surgery. The remaining two patients, 4 and 5, had a complete and partial pathological response, respectively. All five patients received adjuvant therapy after surgery, and currently, none of these patients show evidence of disease on follow-up. Conclusions: Our findings underscore the obstacles and treatment challenges encountered during the COVID-19 pandemic while preventing the spread of the virus and cancer progression. Furthermore, the use of T-DM1 for neoadjuvant treatment remains controversial, particularly when T-DM1 is used as a bridge to surgery during critical times. Perhaps better patient selection or a different drug regimen could have resulted in a better outcome in our study.

Immunotherapy Efficacy in Advanced Hepatocellular Carcinoma in a Diverse and Underserved Population in the United States.

Background :   Incidence of hepatocellular cancer (HCC) in the Bronx is 61% higher than the rest of New York State. Underserved populations are not well represented in clinical trials of immune checkpoint inhibitors (ICI). Methods: Demographics were tabulated for 194 patients treated with ICI at the Montefiore-Einstein Comprehensive Cancer Center (MECCC) between 2017 and 2022. Categorical variables were analyzed by Chi-squared test, and survival was analyzed using Kaplan-Meier (KM) curves. Results: MECCC patients were 40.7% Hispanic and 20.6% Black, compared with 3% and 2%, respectively, in the landmark IMbrave 150 study. Median overall survival (mOS) on ICI was 9.0 months, 25.0 months for the 100 (51.5%) favorable-prognosis Child Pugh A (CPA) patients included in HCC clinical trials. Disease control rate (DCR) was 58.5% among 123 evaluable patients per mRECIST 1.1. Baseline liver function, as defined by CP and the Model for End-Stage Liver Disease-Sodium (MELD-Na), correlated with survival (p < 0.001). Hepatitis C Virus (HCV) and alcoholism were over-represented relative to National Cancer Institute (NCI) data (56.2% vs 4.7% and 38.7% vs 8.2%, respectively). HCV treatment correlated with prolonged survival in infected patients (p = 0.0017). AFP decline correlated with response (p = 0.001). Hispanic patients lived longer when clinical variables were controlled for (mOS 52 vs 23 months; p = 0.011). Conclusion: In an underserved HCC population, ICI yielded a DCR of 58.5% and low rates of severe toxicity. This work highlights ICI efficacy in minority groups, a need for earlier HCC diagnosis and for studies of genetic and environmental factors in Hispanics with HCC.

Long-term outcomes of sinus node modification in patients with severely symptomatic drug-refractory inappropriate sinus tachycardia: a single-center experience.

BACKGROUND: The purpose of the study was to evaluate the long-term outcomes of sinus node modification (SNM) in treating patients with severely symptomatic drug-refractory inappropriate sinus tachycardia (IST). METHODS: The study included 39 patients with symptomatic drug-refractory IST who have undergone SNM at Saint Louis University Hospital. Data was reviewed retrospectively. Recurrence of symptoms was assessed at 3-6-month follow-up intervals. RESULTS: The mean age of our cohort was 31.5 ± 11. The mean HR at diagnosis was 135 ± 25.4 beats per minute (BPM). Thirty-seven of 39 (94.8%) patients had complete resolution of symptoms. Of these 37 patients, 16 required 1 SNM, 17 patients required 2 SNM, and 4 patients required 3 SNM in order to achieve complete symptom resolution. Mean HR post-procedure was 78.6 ± 12.3 BPM. Thirteen of 39 patients required rate control medication post-procedure, all of whom were prescribed beta-blockers. Patients were followed every 3 to 6 months with a mean follow-up duration of 62.3 ± 42.9 months from the patient's last SNM procedure. Thirteen of those 37 patients (35.1%) developed intermittent symptomatic bradycardia requiring permanent pacemaker implantation. Two of the 39 patients had phrenic nerve injury, and 6 patients had post-procedure pericarditis. CONCLUSIONS: This study provides additional information to the limited dataset available in the literature and shows that SNM might provide patients with long-term symptomatic relief bearing in mind the potential increased risk for the need for permanent pacing.

The Role of Cost-Effectiveness Analysis in Patient-Centered Cancer Care in the Era of Precision Medicine.

Over the last few decades, changes in diagnostic and treatment paradigms have greatly advanced cancer care and improved outcomes [...].

Current and Future Systemic Therapies for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common cancer with unmet needs and limited effective therapeutic options. The management strategy for diagnosed HCC is based on Barcelona Clinic Liver Cancer (BCLC) staging. Advanced HCC is treated with systemic therapy comprising oral tyrosine kinase inhibitors (TKIs) and intravenous immune checkpoint inhibitors, provided that liver function is reasonable. Five new agents have been approved by the US Food and Drug Administration (FDA) in the past 2 years for the treatment of HCC: lenvatinib in the first-line setting, and regorafenib, nivolumab, pembrolizumab, and cabozantinib as second-line therapies. The FDA is considering a label expansion of ramucirumab to include its use in HCC. These therapies have all been shown to extend overall patient survival and appear to have a reasonable safety profile. Multiple ongoing trials are studying immune checkpoint inhibition alone or in combination with TKIs. The results of these trials will help determine the optimal choice, timing, and sequence of agents. This article reviews the role of currently approved systemic therapies for HCC and highlights potential future combination therapeutic strategies. The article also brings forward the concept of a developing shift to the left for therapy, as mapped out in the BCLC staging and treatment algorithm, marking earlier use of systemic therapy prior to advanced progression of the disease.

Post-surgical Euglycemic Diabetic Ketoacidosis in a Patient on Empagliflozin in the Intensive Care Unit.

Euglycemic diabetic ketoacidosis (EDKA) is a rare variant of diabetic ketoacidosis which has been recently reported in association with sodium-glucose cotransporter 2 (SGLT-2) inhibitors. Empagliflozin, an agent belonging to this therapeutic class, was approved by the U.S. Food and Drug Administration (FDA) in 2014 for management of type 2 diabetes. Since then, sparse reports of its association with EDKA are emerging, similarly to its predecessors in the class. We report the case of a 58-year-old female who developed EDKA in the intensive care unit (ICU) 48 hours after her last intake of empagliflozin and a day after neurosurgery. Though expected to improve in the post-operative period, she developed a rapidly worsening and unexplained anion gap metabolic acidosis. She was eventually diagnosed with EDKA which was successfully treated with intravenous insulin infusion, dextrose-containing fluids and discontinuation of the offending drug. Metabolic abnormalities improved in less than 24 hours and patient recovered without complications. This report highlights the importance of recognizing EDKA as a complication of oral anti-diabetics and discontinuing SGLT-2 inhibitors days prior to surgery and ICU admission. Care should be applied to providing patient with low-dose ketogenesis-inhibiting basal insulin and close observation of laboratory values in order to minimize delays in diagnosis, prolonged hospital stays and complications of EDKA.

Prevalence, awareness, treatment, and control of hypertension in Lebanon.

The prevalence and factors related to hypertension (HTN) treatment and control are well investigated in the Western world but remain poorly understood in the Middle East and in middle-income countries such as Lebanon. In order to measure the prevalence, awareness, treatment, and control rates of HTN in Lebanon, the authors measured blood pressure (BP) in 1697 adults. The prevalence of optimal BP (<120/80 mm Hg) was 33% and that of pre-HTN (BP ≥120/80 mm Hg but <140/90 mm Hg) was 30%. The prevalence, awareness, treatment, and control (among treated hypertensive) rates of HTN were 36.9%, 53%, 48.9%, and 54.2%, respectively. Overall, only 27% of patients with HTN had their BP under control. Awareness was the most important predictor of treatment. No predictor of control could be identified. The authors concluded that HTN is prevalent in Lebanon and its overall control is low. Improving awareness is the most important target for intervention.