Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.

Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.

Prescription Pattern of Anamorelin; a Therapeutic Agent for Cancer Cachexia.

Background: The commercial availability of anamorelin, Japan's first therapeutic agent for cancer cachexia in 2021, led to an investigation into its prescription patterns at Toyama University Hospital. Objective: We aimed to analyze anamorelin prescription trends and outcomes among cancer cachexia patients. Methods: A retrospective study from July 2021 to December 2022 examined 88 cases, assessing demographics, cancer types, prescription locations, and meal intake changes. Results: Anamorelin usage was predominant during chemotherapy, especially for pancreatic cancer in outpatient settings. Approximately 30% experienced increased meal intake. Chemotherapy-initiated cases had a longer median duration (55 days) compared with best supportive care only cases (12 days). Conclusion: Anamorelin demonstrated significant prescription patterns, particularly during chemotherapy for pancreatic cancer in outpatient settings, suggesting potential efficacy enhancements when administered with chemotherapy in cancer cachexia management. The study underscores the importance of tailored approaches to optimize anamorelin's therapeutic benefits.

Comparison of the efficacy of first­/second­generation EGFR­tyrosine kinase inhibitors and osimertinib for EGFR­mutant lung cancer with negative or low PD­L1 expression.

In epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) with negative or low programmed death ligand-1 (PD-L1) expression, the acquisition rate of the T790M mutation is higher after treatment with first-/second-generation EGFR-tyrosine kinase inhibitors (TKIs) and the progression-free survival (PFS) is longer in patients treated with osimertinib. The present study compared the clinical course after the initiation of each EGFR-TKI monotherapy in patients with EGFR-mutant NSCLC with negative or low PD-L1 expression. Data of patients with EGFR-mutant NSCLC with negative or low PD-L1 expression who were treated with EGFR-TKI monotherapy were retrieved and retrospectively analyzed. Between June 2013 and November 2023, 26 and 29 patients were treated with first-/second-generation EGFR-TKIs and osimertinib, respectively. The PFS time was longer in patients treated with osimertinib (median, 22.5 months) than in those treated with first-/second-generation EGFR-TKIs (median, 12.9 months). However, the EGFR-TKI treatment duration, defined as the PFS for osimertinib, or the sum of the PFS for first-/second-generation EGFR-TKIs and sequential osimertinib therapy after the acquisition of the T790M mutation, was similar between patients treated with first-/second-generation EGFR-TKIs (median, 23.0 months) and osimertinib (median, 22.5 months). The Cox proportional hazard model suggested that there was no significant difference in the EGFR-TKI treatment duration between patients treated with first-/second-generation EGFR-TKIs and patients treated with osimertinib (hazard ratio, 1.31, 95% CI, 0.55-3.13). In conclusion, first-/second-generation EGFR-TKIs and osimertinib were associated with a similar EGFR-TKI treatment duration in patients with EGFR-mutant NSCLC with negative or low PD-L1 expression. The findings suggested that both treatments are promising for this population.

Pure Red Cell Aplasia and Chromosomal Abnormality in a Patient With Lung Adenocarcinoma Receiving Immune Checkpoint Inhibitors: A Case Report.

BACKGROUND/AIM: Immune checkpoint inhibitors can induce immune-related adverse events in various organs, thus careful observation is required. CASE REPORT: A 69-year-old man was diagnosed with advanced lung adenocarcinoma and treated with combined therapy of carboplatin plus pemetrexed plus pembrolizumab. After two cycles of treatment, anemia was noted. Myelosuppression due to cytotoxic anticancer agents was suspected and the cytotoxic agents were discontinued, followed by three courses of pembrolizumab monotherapy. However, the anemia persisted, requiring red blood cell transfusions. A bone marrow biopsy revealed erythroblast hypoplasia and chromosomal abnormalities, resulting in a diagnosis of pure red cell aplasia. These adverse events were considered immune-related because of the treatment history with an immune checkpoint inhibitor, and 60 mg/day (1 mg/kg/day) of prednisolone was initiated. Anemia improved, and it did not recur during the tapering of prednisolone. CONCLUSION: Immune-related pure red cell aplasia should be considered for patients presenting anemia during treatment with immune checkpoint inhibitors.

Immune Checkpoint Inhibitor Therapy for Patients With Non-small Cell Lung Cancer Ineligible for Platinum Doublet Chemotherapy.

BACKGROUND/AIM: Combined therapy with immune checkpoint inhibitors plus platinum doublet chemotherapy has a survival advantage over platinum doublet chemotherapy in patients with non-small cell lung cancer. However, a variety of factors make it difficult to administer treatment with platinum doublet chemotherapy in many patients in clinical practice and there are few reports on the efficacy and safety of first-line treatments with immune checkpoint inhibitors for patients who are ineligible for platinum doublet chemotherapy. This observational study aimed to evaluate the efficacy and safety of first-line immune checkpoint inhibitor therapy for this population. PATIENTS AND METHODS: We retrospectively assessed the survival and adverse events from the initiation of first-line immune checkpoint inhibitor therapy, including pembrolizumab or nivolumab plus ipilimumab in patients with non-small cell lung cancer who were ineligible for platinum doublet chemotherapy. RESULTS: Data from 48 patients were analyzed. Seventeen patients showed a performance status (PS) of ≥2 while 16 and 15 patients were considered ineligible for platinum doublet chemotherapy because of age and comorbidities, respectively. The median (95% confidential interval, CI) progression-free survival (PFS) and overall survival (OS) of the 48 patients were 7.1 (1.7-13.7) and 31.7 (8.8-not estimated) months, respectively. The two-year PFS and OS rates (95% CI) were 30.8% (18.2%-47.2%) and 50.7% (33.7%-67.7%), respectively. In patients with a PS of ≥2, the median (95% CI) PFS and OS were 1.6 (1.2-not estimated) and 5.5 (2.3-not estimated) months, respectively. The two-year PFS and OS rates (95% CI) were 34.3% (15.8%-59.2%) and 45.3% (22.2%-70.7%), respectively. CONCLUSION: Patients with non-small cell lung cancer and a PS of 0-1 who were ineligible for platinum doublet chemotherapy had favorable outcome after the initiation of ICI therapy, and even in patients with a PS of ≥2, they achieved high two-year PFS and OS rates.

Multifocal fatty liver nodules mimicking a metastatic disease: A case report.

Multifocal fatty liver nodules can present a diagnostic challenge due to their resemblance to metastatic liver disease. This case report illustrates the complexity of such scenarios through the presentation of a middle-aged male patient. Despite the common nature of fatty liver disease, characterized by hepatocyte fat accumulation leading to diffuse and uniform liver lesions, rare instances exhibit heterogeneous appearances. The case underlines the potential confusion arising from imaging modalities when multiple small nodules disperse throughout the liver, mimicking multifocal tumors or metastases. The report emphasizes the critical role of comprehensive diagnostic procedures in preventing misdiagnosis and unwarranted interventions. Effective management hinges on multidisciplinary collaboration among specialists, ensuring accurate differentiation and appropriate treatment. This study serves as a reminder of the intricacies involved in interpreting multifocal fatty liver nodules that may masquerade as metastatic disease, highlighting the need for precision in clinical practice.

Pituitary apoplexy in endocrinologically silent adenoma during somatostatin analog administration for pancreatic neuroendocrine tumor: A case report.

A dopamine agonist administered for prolactinoma treatment and pituitary stimulation tests are reported as risk factors for pituitary apoplexy. We report a case of an 82-year-old patient who suffered from pituitary apoplexy in an endocrinologically silent adenoma during lanreotide administration. The patient was diagnosed with a pancreatic neuroendocrine tumor with lymph node metastasis and treated with lanreotide for two years. An endoscopic endonasal transsphenoidal approach was used for tumor and hematoma removal. The specimen showed growth hormone and prolactin positivity and was diagnosed as pit1-lineage plurihormonal adenoma. The tumor also showed positivity for somatostatin receptor 2. Thus, lanreotide treatment is a risk factor for pituitary apoplexy even in silent adenoma.