Classical cannabinoid receptors as target in cancer-induced bone pain: a systematic review, meta-analysis and bioinformatics validation.

To test the hypothesis that genetic and pharmacological modulation of the classical cannabinoid type 1 (CB1) and 2 (CB2) receptors attenuate cancer-induced bone pain, we searched Medline, Web of Science and Scopus for relevant skeletal and non-skeletal cancer studies from inception to July 28, 2022. We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] - 24.83, 95% confidence interval [95%CI] - 34.89, - 14.76, p < 0.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB1/2-non-selective) and AM1241 (CB2-selective) (MD - 28.73, 95%CI - 45.43, - 12.02, p = 0.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB2-selective) increased paw withdrawal threshold (MD 0.89, 95%CI 0.79, 0.99, p < 0.00001), and ACEA (CB1-selective), AM1241 and JWH015 (CB2-selective) reduced spontaneous flinches (MD - 4.85, 95%CI - 6.74, - 2.96, p < 0. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB1/2-non-selective), JWH015 and AM1241 (CB2-selective) in osteolysis-bearing females (MD 8.18, 95%CI 6.14, 10.21, p < 0.00001), and treatment with AM1241 (CB2-selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, 95%CI 2.13, 5.75, p < 0.0001), confirming the analgesic capabilities of CB1/2 ligands in rodents. In human, treatment of cancer patients with medical cannabis (standardized MD - 0.19, 95%CI - 0.35, - 0.02, p = 0.03) and the plant-derived delta-9-THC (20 mg) (MD 3.29, CI 2.24, 4.33, p < 0.00001) or its synthetic derivative NIB (4 mg) (MD 2.55, 95%CI 1.58, 3.51, p < 0.00001) are associated with reduction in pain intensity. Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB1 and CB2 receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB1/2 receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted.

Obesity is associated with improved progression-free survival in Microsatellite-Instability-High endometrial cancer treated with pembrolizumab.

OBJECTIVES: To determine the clinical predictors of response rate, progression-free survival (PFS), and overall survival (OS) to pembrolizumab in advanced or recurrent, mismatch repair deficient (MMRd) or Microsatellite Instability-High (MSI-H) endometrial adenocarcinomas. METHODS: A retrospective, single institution study was conducted among women with recurrent or advanced MMRd or MSI-H endometrial adenocarcinomas treated with single-agent pembrolizumab at our institution from 2017 to 2021. Logistic regression was used for univariable and multivariable analyses. PFS and OS were estimated using the methods of Kaplan and Meier and modeled via Cox proportional hazards regression. Log-rank test was used for intergroup comparisons based on body mass index (BMI). RESULTS: Among the 44 patients included in the analysis, the median BMI was 32.9 (range 18.5-51.8). Median cycles of pembrolizumab given was 11.5 (range 2-37). Median follow-up was 33 months (range 5-61) with a response rate of 63.6% and stable disease rate of 75%. When stratified by obesity status (BMI≥30), disease control rate was 59.8% in patients with a BMI < 30 and 85.2% in patients with a BMI≥30 patients (p = 0.05). On multivariable analysis, obesity was associated with increased rate of disease control (OR 4.03, 95%CI 1.09, 28) while prior smoking was associated with decreased rate of disease control (OR 0.18, 95%CI 0.03, 0.85). PFS was significantly increased among patients with a BMI≥30 (p = 0.03) but OS was similar (p = 0.5). CONCLUSION: In this retrospective study, obesity is associated with increased rates of disease control and improved PFS in patients treated with pembrolizumab for recurrent or advanced MMRd/MSI-H endometrial adenocarcinomas.

Posterior-scleritis: Case report of an uncommon immune-related adverse event in the treatment of advanced endometrial cancer.

As Immune checkpoint inhibitors are being expanded for use in gynecologic malignancies, rare immune-related adverse events are more frequently being reported. Here we describe a 63-year-old with Stage IIIB mismatch repair deficient uterine adenocarcinoma who underwent six cycles of carboplatin and paclitaxel with partial response but persistent disease. She was then started on single agent pembrolizumab. After six cycles of pembrolizumab, she developed bilateral vision changes and was diagnosed with posterior scleritis. Pembrolizumab was held and she was treated with oral prednisone, with rapid resolution of symptoms. One month after completion of prednisone, vision changes were again reported and she was restarted on a longer oral prednisone course. She then underwent definitive surgical management consisting of a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy, with final pathology of benign endometrial hyperplasia. She has completed her steroid course without any symptoms. Given her complete pathologic response, she was subsequently placed into surveillance and is currently without evidence of disease. Prompt recognition and treatment of this rare immune-related adverse event led to the prevention of potential permanent, debilitating outcomes.

Toxicity and efficacy of the combination of pembrolizumab with recommended or reduced starting doses of lenvatinib for treatment of recurrent endometrial cancer.

OBJECTIVE: We reviewed our institutional data to evaluate toxicity and efficacy outcomes of pembrolizumab/lenvatinib in recurrent endometrial cancer in a "real-world" clinical setting and to compare the impact of reduced lenvatinib starting dose on outcomes. METHODS: Retrospectively, we reviewed toxicity, treatment responses, and survival outcomes of patients with recurrent endometrial cancer who received ≥1 cycle of pembrolizumab/lenvatinib. We compared subgroups based on lenvatinib starting dose (recommended [20 mg] vs reduced [<20 mg]) and histologic type. RESULTS: We analyzed 70 patients (recommended dose cohort, n = 16; reduced dose cohort, n = 54). The most common starting dose was 14 mg daily. Compared to the reduced dose cohort, the recommended dose cohort had a significantly higher mean number of lenvatinib dose reductions due to side effects (1.1 vs. 0.4; p = 0.003) and significantly shorter median time to treatment toxicity (1.3 vs. 3.7 days; p = 0.0001). Response rates did not differ significantly between the recommended and reduced dose cohorts (28.6% vs. 38.3%, respectively; p = 0.752). Two patients, both in the reduced dose cohort, had complete responses. Patients with carcinosarcoma histology had response and clinical benefit rates of 25% (3 of 12) and 58.3% (7 of 12), respectively. There were no differences between the 2 dose cohorts with respect to progression-free (p = 0.245) or overall survival (p = 0.858). CONCLUSION: In clinical practice, a lower starting dose of lenvatinib (14 mg daily) in combination with pembrolizumab was safe and efficacious in recurrent endometrial cancer. The combination produced responses in endometrial carcinosarcomas. Larger studies are required to validate these findings.

Implementation of postdischarge follow-up telephone calls at a comprehensive cancer center.

PURPOSE: The development and implementation of a pharmacy-driven, postdischarge follow-up telephone call program to assess medication adherence, provide education, and address medication-related concerns are discussed. SUMMARY: Many readmissions are avoidable through effective discharge planning and patient follow-up after hospitalization. However, there is limited information on how to effectuate this process. To address this barrier, a team consisting of a clinical pharmacy specialist, a clinical pharmacy manager, a postgraduate year 1 pharmacy resident, and an education specialist at The University of Texas MD Anderson Cancer Center collaborated to create a postdischarge telephone call program within a transitions-of-care (TOC) pilot program. Various education and training materials were created to ensure trainees were competent. As of February 2016, 23 outpatient pharmacists and students have completed training, earning a median pretest and posttest score of 6 and 9, respectively, out of 10. There have been 206 calls completed; 150 patients (73%) were successfully reached, and 20 patients (9%) declined the telephone call. Medication adherence assessed during the telephone follow-up identified that 134 patients (89%) received their new medications within 72 hours, and 87 patients (58%) were recognized as having one or more discrepancies. CONCLUSION: Developing a TOC program similar to this pilot program requires several resources including time, collaboration, and support from the management team. Pharmacy is well positioned to complete an accurate medication review and conduct postdischarge telephone calls to address medication-related issues. By providing these services, patients will receive continuity of care and positively impact emergency room visitation rates and hospital readmission rates.

Oxaliplatin-induced immune-mediated cytopenias: a case report and literature review.

Oxaliplatin is a third-generation platinum antineoplastic agent that commonly causes diarrhea, nausea, vomiting, myelosuppression, and peripheral neuropathy. Less common adverse effects that are increasingly being reported include acute immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia. Here, we report a patient case of suspected oxaliplatin-induced immune-mediated thrombocytopenia and a thorough literature evaluation of acute oxaliplatin-induced immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia that has yet to be reported until now. There have been 39 previously published reports of these cytopenic events with a median number of 16 treatment cycles prior to presentation. Patients experiencing unusual signs and symptoms such as chills, rigors, fever, back pain, abdominal pain, ecchymosis, hematemesis, hematuria, dark urine, hematochezia, petechiae, epistaxis, or mental status changes during or shortly after an oxaliplatin infusion should have complete blood counts ordered and evaluated promptly.

Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction.

Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality and, whilst smoking remains the single most important risk factor, COPD risk is heritable. Of 26 independent genomic regions showing association with lung function in genome-wide association studies, eleven have been reported to show association with airflow obstruction. Although the main risk factor for COPD is smoking, some individuals are observed to have a high forced expired volume in 1 second (FEV1) despite many years of heavy smoking. We hypothesised that these "resistant smokers" may harbour variants which protect against lung function decline caused by smoking and provide insight into the genetic determinants of lung health. We undertook whole exome re-sequencing of 100 heavy smokers who had healthy lung function given their age, sex, height and smoking history and applied three complementary approaches to explore the genetic architecture of smoking resistance. Firstly, we identified novel functional variants in the "resistant smokers" and looked for enrichment of these novel variants within biological pathways. Secondly, we undertook association testing of all exonic variants individually with two independent control sets. Thirdly, we undertook gene-based association testing of all exonic variants. Our strongest signal of association with smoking resistance for a non-synonymous SNP was for rs10859974 (P = 2.34 × 10(-4)) in CCDC38, a gene which has previously been reported to show association with FEV1/FVC, and we demonstrate moderate expression of CCDC38 in bronchial epithelial cells. We identified an enrichment of novel putatively functional variants in genes related to cilia structure and function in resistant smokers. Ciliary function abnormalities are known to be associated with both smoking and reduced mucociliary clearance in patients with COPD. We suggest that genetic influences on the development or function of cilia in the bronchial epithelium may affect growth of cilia or the extent of damage caused by tobacco smoke.