A Cohort Study of the Antitumor Efficacy and Toxicity Profile of Alpelisib for Metastatic or Locally Advanced HR+, HER2- Breast Cancer: A Single-Institution Experience.

INTRODUCTION: Alpelisib is approved in combination with endocrine therapy (ET) to treat patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) progressive metastatic breast cancer (MBC). The SOLAR-1 trial demonstrated the efficacy of this oral agent and showed that, while alpelisib improves outcomes compared to placebo, it is also associated with clinically relevant adverse events (AEs). There is a pressing need for improved knowledge on the effectiveness and tolerability of this agent in real-world patient populations. METHODS: We conducted a retrospective cohort study of patients with HR+, HER2- MBC treated with alpelisib and ET. We assessed the safety, tolerability, and effectiveness of alpelisib in a real-world population. Deidentified patient-, tumor-, and outcome-related data, including AEs, were collected and summarized. Kaplan-Meier methods were applied for survival analyses, and stratified analyses of interest were conducted. A p value <0.05 was considered statistically significant. RESULTS: A total of 76 women treated with alpelisib + ET were included in our cohort. Most had been previously treated with cyclin-dependent kinase (CDK) 4/6 inhibitors and chemotherapy for MBC. The estimated median progression-free survival was 5.2 months (95% CI, 4.1-8.0). The median overall survival was longer among patients without prior everolimus therapy (hazard ratio, 4.28 [95% CI, 1.64-11.16]; p = 0.0012), and no significant outcome differences were observed between patients treated with different starting doses of alpelisib. Approximately 31.6% of patients permanently discontinued alpelisib due to AEs, and 32.9% had at least one dose reduction. The most common grade 3/4 AEs were hyperglycemia (21%), fatigue (13.2%), and diarrhea (10.5%). CONCLUSIONS: For progressive HR+, HER2- MBC, alpelisib + ET showed effectiveness in a real-world patient population that was comparable to published clinical trial data, regardless of starting dose. However, the effectiveness of alpelisib following previous everolimus exposure may be limited and, hence, should be a consideration to decide sequencing of therapy in these patients. Patients treated with alpelisib are at risk for clinically relevant AEs and require close monitoring.

Tisagenlecleucel: CAR-T cell therapy for adult patients with relapsed or refractory follicular lymphoma.

INTRODUCTION: Tisagenlecleucel (tisa-cel) is an anti CD19 CAR-T therapy that has demonstrated clinical activity in R/R large B-cell lymphoma and R/R B-cell acute lymphoblastic leukemia. It showed particularly high efficacy in R/R follicular lymphoma (FL) with a manageable toxicity profile. The pivotal ELARA study in R/R FL confirmed these findings and led to the FDA approval of tisa-cel in R/R FL after two lines of systemic therapies. AREAS COVERED: We start with an introduction of FL and the current treatment landscape with emphasis on the R/R setting. We review the role of CAR-T in R/R FL with focus on currently available products. We describe the ELARA study at a high level to give a perspective of the patient population that was treated. Finally, we discuss aspects related to product selection and whether bispecific antibodies will challenge the role of CAR-T in FL given their similar efficacy. EXPERT OPINION: Tisa-cel is a highly effective therapy for heavily pretreated R/R FL with a toxicity profile that is low grade and manageable. Durable remissions (including high-risk patients) are seen in the pivotal ELARA study. Clinicians should consider early referral of R/R FL patients for assessment and discussion.

Review of Current Systemic Therapy and Novel Systemic Therapy for Pancreatic Ductal Adenocarcinoma.

BACKGROUND: This review aims to describe the systemic treatment options for pancreatic ductal adenocarcinoma and includes a summary of the current treatments as well as the ongoing clinical trials which may be efficacious in the treatment of this aggressive malignancy. METHODS: A literature review was performed using MEDLINE/PubMed between August 1996 and February 2023. The reviewed studies are categorized into these categories: current standard of care treatments, targeted therapies, immunotherapy and clinical trials. The current treatment modality for the treatment of advanced pancreatic cancer is mainly systemic chemotherapy. RESULTS: The introduction of polychemotherapy regimens including gemcitabine/nab-paclitaxel and FOLFIRINOX (oxaliplatin, irinotecan, folinic acid and fluorouracil) has improved the clinical outcome of advanced pancreatic cancer. For further improvement in clinical outcomes, several novel approaches have been extensively studied in pancreatic cancer. The review discusses the current standard chemotherapy regimen and the novel treatment options in the field. CONCLUSIONS: While there are novel treatments being explored for metastatic pancreatic, it remains a debilitating and aggressive disease with high mortality that warrants continued efforts to advance therapeutic options.

Long term outcomes in older patients with primary central nervous system lymphoma: an analysis of the Texas Cancer Registry.

Primary central nervous system lymphoma (PCNSL) is an aggressive subtype of non-Hodgkin lymphoma that carries a poor prognosis in the elderly. The aim of this study is to investigate treatment patterns and survival trends in patients ≥ 65 years with PCNSL through data provided by the Texas Cancer Registry. Adults ≥ 65 years diagnosed with PCNSL and followed between 1995-2017 were identified and separated into three eras: 1995-2003, 2004-2012, and 2013-2017. Baseline covariates compared included patient demographics and treatments administered. Pearson's chi-squared test and Cox proportional hazard models compared covariates; overall survival (OS) and disease-specific survival (DSS) were assessed via Kaplan-Meier methodology. There were 375 patients; 104 (27.7%) in 1995-2003, 146 (38.9%) in 2004-2012, and 125 (33.3%) in 2013-2017. There were 50 (48.1%), 55 (37.7%), and 31 (24.8%) in 1995-2003, 2004-2012, and 2013-2017, respectively, that did not receive treatment. At last follow up, 101 (97.1%), 130 (89.0%), and 94 (75.2%) in each era died, of which 89 (85.6%), 112 (76.7%), and 70 (56.0%) were attributed to PCNSL. Median OS per era was eight (95% confidence interval [CI] 5.06-10.93), six (95% CI, 2.30-9.69), and five months (95% CI, 2.26-7.73) (p = 0.638). DSS per era was nine (95% CI: 0.00, 26.53), 10 (95% CI: 5.14, 14.86), and 19 (95% CI, 0.00-45.49) (p = 0.931) months. Spinal cord as primary disease site (HR: 0.668 [95% CI, 0.45-0.99], p = 0.049), and chemotherapy (HR 0.532 [95% CI, 0.42-0.673], p = < 0.001) or chemotherapy + radiation (HR, 0.233 [95% CI, 0.11-0.48] p < 0.001) had better outcomes compared to no therapy or radiation therapy alone. Survival in older patients ≥ 65 with PCNSL has not improved per our analysis of the TCR from 1995-2017 despite increasing trends of treatment utilization. Strategies to augment recruitment of older individuals in trials are needed in order to determine who would derive treatment benefit and minimize treatment toxicities.

Human Epidermal Growth Factor Receptor 2-Targeting Approaches for Colorectal Cancer: Clinical Implications of Novel Treatments and Future Therapeutic Avenues.

The treatment paradigm for colorectal cancer (CRC) has changed significantly over the past decade with targeted therapeutics. Human epidermal growth factor receptor 2 (HER2) amplification is seen among 3%-4% of patients with metastatic CRC (mCRC). The biological discovery of HER2 amplification in cancer cells has led to practice-changing drug development for several solid tumors, including breast, gastric, and esophageal cancers. HER2 amplification is now highly actionable in CRC with distinct therapeutic combinations, including the combination of monoclonal antibodies and HER2 receptor-specific tyrosine kinase inhibitors, as well as antibody-drug conjugates, that delivers targeted cytotoxic agents. However, it is essential to define the therapeutic role and sequence of these different combinations, some of which are already part of standard clinical practice. In this review article, we discuss recent clinical studies demonstrating the clinical benefits of each distinct therapeutic approach and their impacts on the current management of HER2-amplified mCRC. We also review ongoing clinical trials targeting the HER2 pathway in mCRC and elaborate on novel therapeutic opportunities in this space that may further define the changing paradigm of HER2-targeted therapy for CRC.

Use of ifosfamide, carboplatin and etoposide in combination with brentuximab vedotin or romidepsin based on CD30 positivity in relapsed/refractory peripheral T-cell lymphoma.

BACKGROUND: Relapsed/refractory peripheral T-cell lymphoma (R/R PTCL) has a poor prognosis. Romidepsin (Ro) and brentuximab vedotin (Bv), combined with ifosfamide, carboplatin, and etoposide (ICE) has not been significantly studied in PTCL. AIM: We report outcomes of Bv-ICE in CD30 (+) and Ro-ICE in CD30 (-) R/R PTCL treated in "Blinded for peer review" Cancer Center. METHODS AND RESULTS: We retrospectively identified R/R PTCL patients treated with BV-ICE or romidepsin-ICE from May 2016 to September 2019. Out of 13 R/R PTCL patients, 6 were treated with Bv-ICE and 7 with Ro-ICE. Bv-ICE had an overall response rate (ORR) of 66.7%, with all the patients achieving a complete response. ORR was 71.4% for Ro-ICE with 57.1% of patients achieving a complete response. Two patients treated with Bv-ICE and three treated with Ro-ICE received transplantation. CONCLUSION: In our experience, treatment with Bv-ICE and Ro-ICE based on CD30 positivity is feasible and effective to treat patients with R/R PTCL.

Dietary Considerations for Inflammatory Bowel Disease Are Useful for Treatment of Checkpoint Inhibitor-Induced Colitis.

Checkpoint molecules are cell surface receptors on immune cells that mitigate excessive immune responses, but they have increased expression levels in cancer to facilitate immune escape. Checkpoint blockade therapies (e.g., anti-PD-1, anti-CTLA-4, and anti-LAG-3 therapy, among others) have been developed for multiple cancers. Colitis associated with checkpoint blockade therapy has pathophysiological similarities to inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. Current therapeutic guidelines for checkpoint blockade-induced colitis include corticosteroids and, if the patient is refractory to steroids, immunomodulating antibodies, such as anti-TNF and anti-integrin agents. Interestingly, immunomodulatory molecules, such as TNFα, are upregulated in both IBD and checkpoint-mediated colitis. The inflammatory colitis toxicity symptoms from checkpoint blockade are similar to clinical symptoms experienced by patients with IBD. The pathophysiologic, dietary, and genetic factors associated with IBD will be reviewed. We will then explain how the principles developed for the treatment of IBD can be applied to patients experiencing inflammatory bowel toxicity secondary to checkpoint blockade.

Metastatic colorectal carcinoma to the right atrium: a case report and review of the literature.

BACKGROUND: Cardiac metastasis due to colon cancer is extraordinarily uncommon. Given the rarity of diagnosis, there is paucity of evidence and hence, no established guidelines for evaluation or clinical management strategy. CLINICAL PRESENTATION: We present the case of a 59 year old male with a previously treated colonic carcinoma who presented with new onset exertional dyspnea. He was noted to be having a right atrial mass on an echocardiogram performed at his cardiologist's office. Further workup with CT angiogram of the chest confirmed a right atrial mass measuring 4.0 cm. Serum CEA was normal. Biopsies of the right atrial mass demonstrated metastatic moderately differentiated colonic adenocarcinoma. Mismatch repair protein expression analysis by immunohistochemistry showed no loss of MLH1, MSH2, MSH6 or PMS2 expression. Next generation sequencing for RAS and BRAF mutations was negative. Patient received treatment with FOLFIRINOX/ bevacizumab with noted reduction in size of mass. CONCLUSION: To the best of our knowledge, this is the first report of next generation sequencing results available on a biopsy of metastatic colorectal cancer to the heart with the largest literature review of 31 reported cases of metastatic colorectal cancer to the heart. It will help direct clinical management and also adds evidence to the potential efficacy of treatment of this rare aggressive disease with chemotherapy in combination with VEGF inhibitors.

Post-Marketing Analysis of Peripheral Neuropathy Burden with New-Generation Proteasome Inhibitors Using the FDA Adverse Event Reporting System

Proteasome inhibitors (PIs) are an integral component of multiple myeloma therapies. Peripheral neuropathy (PN) is a well-knownconsequence of PIs, most frequently reported with earlier generations such as bortezomib (BTZ). There is a paucity of data highlighting the risk of developing PN with the new-generation PIs carfilzomib (CFZ) and ixazomib (IZB). This study evaluated reports of PN encountered with all three PIs using the Food and Drug Administration Adverse Event (AE) Reporting System (FAERS). Signal disproportionality analysis was reported using the reporting odds ratio (ROR) with 95% confidence interval (CI). PN was reported in a total of 2.1%, 5.0%, and 10.9% of AEs with CFZ, IZB, and BTZ, respectively. The ROR (95% CI) for PN secondary to BTZ, CFZ, and IZB was 34.10 (32.76-35.49), 6.37 (5.50-7.37), and 14.97 (13.63-16.44), respectively. Compared to BTZ, CFZ and IZB have lower rates of reported PN, with RORs of 0.19 (0.16-0.22) and 0.48 (0.43-0.54), respectively.

Breast Cancer Metastasis Masquerading as a Primary Gynecological / Colonic Malignancy: A Rare Diagnostic Conundrum.

Breast cancer is the most common malignancy affecting women. Metastatic involvement of the gastrointestinal (GI) tract secondary to a primary breast malignancy is rare. Here, we describe the case of a 60-year-old woman with a history of right lobular breast cancer (diagnosed and treated five years prior to presentation) who presented with fatigue, generalized abdominal pain, distension, weight loss, and vomiting. Her initial imaging was suspicious for a primary gynecological malignancy; however, subsequent workup showed a colonic mass. Total colonoscopy revealed colon metastases, and an immunohistochemical profile favored invasive lobular carcinoma of breast. Most cases of gastrointestinal metastases from breast cancer have lobular histology; however, colonic involvement is rare.

Multiple myeloma with concurrent immune thrombocytopenic purpura.

Multiple myeloma (MM) is the second most common haematological malignancy in the USA. MM has been linked to various autoimmune disorders in many studies; one systemic review even suggested an increased risk of MM among patients with autoimmune disorders. MM is associated with many haematological, rheumatologic and neurological conditions. A few case reports suggest that MM can be associated with immune thrombocytopenic purpura (ITP), although this is rare. We present a case of MM with concurrent ITP which was refractory of steroids and intravenous immunoglobulin but had a response with anti-neoplastic therapy for MM. We also review all the cases of ITP with MM described in the literature. If conventional treatment for ITP associated with MM fails to improve platelet count, anti-neoplastic therapy for MM should be considered.

Large Cell Neuroendocrine Cervical Carcinoma: A Case Report.

We herein report a unique case of a large cell neuroendocrine tumor in a female presenting with right upper quadrant pain. She was found to have multiple metastatic lesions in the liver noted on imaging and underwent workup for malignancy of unknown origin. The initial differential diagnoses included gastrointestinal, urothelial, genital, or breast primary sites. The cervical biopsy results were consistent with large cell neuroendocrine tumor, and the patient was subsequently started on chemotherapy.

Amla fruit powder addition influences objective color and instrumental texture of pan bread.

The effect of sun-dried (SD), oven-dried (OD) and freeze-dried (FD) amla fruit powders on the mixing characteristic, objective color (ICI tristimulus L* a* b* values) and instrumental texture was investigated. The addition of differently dried amla powders did not affect the mixograms significantly. The color characteristics were affected by both the levels of addition as well as by the type of powder (SD, OD and FD) incorporated into the pan bread. The L*, a*, b* values were not significantly different for the crusts of all types of the breads at varying levels. However, incorporation of SD, OD and FD powder lowered L*and b* values significantly for the crumb, making it look lesser white but browner in color. The specific loaf volume of bread made with SD and OD amla fruit powders at lower levels of addition gave compression force values and specific loaf volumes very close to the bread made with 20 ppm of potassium bromate. But higher amounts (1-3%) of amla fruit powder resulted in harder bread texture, lower specific loaf volume and also a coarser crumb grain. Therefore, amla fruit being rich in ascorbic acid seems a good choice an alternative natural dough improver in place of potassium bromate which has been regarded as a potential carcinogen and now banned in many countries of the world.

Development of a functional food (pan bread) using amla fruit powder.

The amla fruit powders were analyzed for ascorbic acid, sugars, pectin, total phenolics (TPC), and total antioxidant activities (TEAC). Fresh amla was found to have 6644.305 mg/100 g ascorbic acid with sun-dried, oven-dried and freeze-dried having 748.427 mg/100 g, 641.364 mg/100 g, 791.233 mg/100 g, respectively. There were no significant differences for the TPC values which ranged from 113.1 for oven-dried (OD), 128.7 for sun-dried (SD), 161.2 mg for freeze-dried (FD) and 1410.5 GAE/g for fresh amla pulp (FA). The TEAC values ranged from 6.6 for OD, 6.8 for FD, 7.6 for SD and 116.4 mM/g for FA. The FD amla fruit powder had the highest total sugars (36.94%, db). The specific loaf volume of bread improved significantly (from 3.54 to 3.79 cc/g) as the level of SD or OD amla powder addition was raised to 0.25% but then decreased at higher level of addition (3.41 cc/g). However, in case of FD amla powder, the bread volume increased up to the addition level of 0.50% (4.09) then decreased slightly (3.95 cc/g) but was still significantly higher the SD and OD amla powders. Similarly, the TPC (from 0.32 to 1.16 mg GAE/g, db), TEAC (0.06-0.14 mM/g, db) and vitamin C (3.80-31.98 mg/100 g, db) contents also improved significantly as the level of amla powders were increased to 1%. The supplemented breads were well-accepted by the consumers. It can be concluded that amla supplemented pan bread with its superior nutritional and sensory qualities can be a possibility to improve consumer nutrition.