Impact of Genetic Polymorphisms in NF-ĸB2 and TRAF3 Genes on Response to Bortezomib-Based Therapy in Multiple Myeloma Patients.

BACKGROUND: Multiple myeloma (MM), being the second most common hematological malignancy, has garnered significant attention. The ubiquitin proteasomal pathway (UPP), crucial for normal cell function, plays a pivotal role in myeloma pathophysiology, especially with the advent of bortezomib (BTZ). Dysregulation of the UPP has implications ranging from developmental abnormalities to cancer. OBJECTIVES: This study aimed to delineate the clinical characteristics of newly diagnosed multiple myeloma patients and investigate the influence of single nucleotide polymorphisms (SNPs) in NF-ĸB2 and TRAF3 genes on the risk and treatment response to bortezomib-based chemotherapy. MATERIALS AND METHODS: Conducted at JIPMER, Pondicherry, this prospective study enrolled 184 participants, comprising cases and controls. DNA extraction from peripheral blood samples was followed by SNP analysis through Real-time Polymerase Chain Reaction. Patients were categorized into Good and Poor responders, and SNP associations with treatment response, response rates, and survival outcomes were assessed using chi-square and Kaplan-Meier analyses. RESULTS: The median age of participants was 55 years, with backache being the most prevalent symptom (66.3%). Hypercalcemia (22%), renal failure (8.7%), and bone fractures (45.7%) were also observed, alongside high prevalence of anemia. Notably, the frequency of the TRAF3 rs12147254 A allele was lower in cases compared to controls (31% vs. 49%, P-value=0.002). Poor responders exhibited higher frequencies of the GA+AA genotypes in TRAF3 rs12147254 (OR-3.882(1.629-9.251), P-value-0.002) and NFKB2 rs1056890 (OR-3.308(1.366-8.012), P-value-0.008) when compared to good responders. The GA+AA genotype in TRAF3 rs11160707 SNP correlated with improved progression-free survival. CONCLUSION: The study findings underscore a significant association between genetic polymorphisms and treatment response outcomes, suggesting their utility in prognostic determinations and clinical outcomes prediction in multiple myeloma patients.

Role of CYFRA 21-1 and CEA as prognostic and predictive markers in locally advanced and metastatic gastric carcinoma.

PURPOSE: Tumor-associated serum markers have demonstrated predictive and prognostic value in patients being treated for malignancies. However, the clinical importance of tumor markers in gastric cancers (GC) is poorly standardized. OBJECTIVES: The objective is to assess the clinical utility of cytokeratin-19 fragment (CYFRA 21-1) and carcinoembryonic antigen (CEA) as serum tumor markers in advanced GC. METHODS: In this prospective study, CYFRA 21-1 and CEA levels were measured at baseline and after three cycles of chemotherapy in patients with advanced GC. The association of tumor marker levels with prognosis and decline of tumor markers with radiological overall response rates (ORR) and survival were analyzed. RESULTS: In the 105 patients, the proportion of patients with elevated baseline CYFRA 21-1 and CEA levels was 55% (N = 58) and 37% (N = 39) based on predefined cutoffs. Response assessment was done for 61 patients who received a minimum of three cycles of chemotherapy. A 15% and 13% reduction of serum levels from baseline for CYFRA 21-1 and CEA were selected for defining "CYFRA 21-1 response" and "CEA-response," respectively. Both responses were significant predictors of radiological ORR. The median overall survival (OS) was 9.6 months in the entire cohort and 13 months for patients who received at least three cycles of chemotherapy. In multivariate analysis, baseline CEA levels and ECOG status were significant predictors of OS. In a subset analysis of patients receiving palliative chemotherapy, any of the tumor marker responses predicted improved 1-year OS. CONCLUSION: In advanced GC, CYFRA 21-1 and CEA decline from baseline appeared to be reliable surrogate markers of chemotherapy efficacy and improved survival.

Aggressive Histology and Extensive Metastasis Characteristic of Very Young Gastric Cancer (Less Than 30 Years): A Retrospective Clinical Audit.

Narendran KrishnamoorthiObjectives Gastric cancer (GC) is an aggressive disease and remains one of the most common causes of cancer-related mortality worldwide. Incidence of gastric cancer in young (GCY) varies between 2 and 8%. GCY faces unique challenges such as biological variation, diagnosis at an advanced stage, issues related to fertility preservation, and psychosocial considerations. This study aimed to find the differences in clinical characteristics and treatment outcomes of GCY compared to gastric cancer in older adults (GCO). Material and Methods This is a retrospective study from a tertiary care center. We screened records from 2015 to 2020, identified 33 records of GCY (less than 30 years), and compared the data with GCO (greater than 30 years) during 2015 and 2018. Results We identified 33 patients with GCY with a median age of 28 years (21-30) and a female to male ratio of 2:1. In GCY, 60% of patients presented with metastatic disease. Diffuse-type histology was more common in the GCY than in GCO (66.7% vs. 41.7%, p = 0.001). In patients with metastasis, multiple metastases were common in GCY compared to GCO (45% vs. 15%, p = 0.003). The median duration of follow-up for all patients was 27 (24-29) months. In GCY, the median OS was not reached for patients treated with curative intent, and it was 13 months for those treated with palliative intent. Conclusion The incidence of GCY in our study was like the western literature. Female patients with aggressive diffuse histology and multiple extensive metastases were characteristic of GCY. The survival outcomes were identical to GCO.

Clinicopathological features and survival outcomes for gastric adenocarcinoma: Real-world single-center data.

INTRODUCTION: Gastric cancer is the fifth most-common cancer and fourth common cause for cancer-related deaths globally. Surgery preceded or followed by chemotherapy or chemoradiotherapy is considered an optimal treatment for locally advanced gastric cancer. This study is a real-world data from a tertiary referral institute in southern India, in its experience with treating gastric adenocarcinoma over a period of four years with a minimum of two-year follow-up. METHODS: This was a retrospective analysis of data of patients with histologically proven gastric adenocarcinoma enrolled in the Department of Medical Oncology from 2015 to 2018. The demographic details, presentation, staging, treatment received and outcomes of patients with gastric adenocarcinoma were collected and analyzed in this study. RESULTS: Total 488 patients with gastric adenocarcinoma were included for the study. The stage-wise distribution of patients revealed early and locally advanced (45%) and metastatic (55%). The peritoneum and liver were the common sites of metastasis. The treatment distribution of these patients included perioperative chemotherapy followed by surgery (25 [5%]), surgery followed by adjuvant chemotherapy (65 [13%]), surgery alone (16 [3%]), perioperative chemotherapy alone (23 [4%]), palliative chemotherapy (274 [56%]) and supportive care (85 [17%]). The median overall survival for curative, palliative and supportive treatment was 23 (18-28), nine (7.6-10.4) and four (2.7-5.3) months, respectively. The two-year overall survival in the intention to treat population in the primary surgery (n = 81) and perioperative chemotherapy groups (n = 66) was 67.4% vs. 29.9% (p < 0.0001), respectively. CONCLUSION: This study highlights the advanced nature of the presentation of gastric cancer patients and the poor rate of treatment completion. The median survival rates in curative patients remain to be dismally poor. The treatment sequence in curable gastric cancer of surgery followed by adjuvant chemotherapy vs. perioperative chemotherapy followed by surgery needs to be explored in our country.

Negative impact on bone homeostasis in postmenopausal women with non-metastatic breast cancer during cytotoxic chemotherapy.

INTRODUCTION: The burden and mechanisms of endocrine therapy-related bone loss are well known, while there are limited data on chemotherapy-induced bone resorption. The study aimed to evaluate the effect of cytotoxic chemotherapy on bone homeostasis among postmenopausal women with non-metastatic breast cancer. MATERIALS AND METHODS: Early and locally advanced postmenopausal non-metastatic breast cancer patients aged 45 to 65 planned for three cycles of anthracycline and four cycles of taxane chemotherapy administered along with dexamethasone (cumulative dose-256 mg) as an antiemetic from June 2018 to December 2021 were included. Bone mineral density (BMD), bone turnover markers, calciotropic hormones, pro-inflammatory cytokines, oxidative stress, and total antioxidant levels (TAS) were measured. RESULTS: We recruited 109 patients, with early 34 (31.2%) and locally advanced breast cancer 75 (68.8%) with median age 53 (45-65) years. There was a significant decrease in the % BMD at the lumbar spine, neck of the femur, and total hip post-chemotherapy. There was a significant increase in serum C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) levels post-chemotherapy. PINP/CTX ratio significantly decreased post-chemotherapy. Serum 25-OH vitamin D was significantly reduced with a compensatory increase in plasma iPTH levels. The change in CTX, PINP/CTX ratio, 25-OH vitamin D, iPTH, and oxidative stress index was more pronounced during anthracycline as taxane chemotherapy. There were no significant changes in pro-inflammatory cytokine levels. CONCLUSION: Chemotherapy and dexamethasone as antiemetic resulted in significant bone loss, as evidenced by bone turnover markers. Further studies are required to understand the mechanism of chemotherapy-induced bone loss and the need for bone-strengthening agents during chemotherapy.

Efficacy and safety of pomalidomide, bortezomib, and dexamethasone combination chemotherapy for newly diagnosed multiple myeloma: POMACE Phase II Study.

Bortezomib, lenalidomide, and dexamethasone induction chemotherapy (VRd), followed by autologous stem cell transplantation (ASCT), are the standard of care for patients with newly diagnosed multiple myeloma (NDMM). Pomalidomide is currently approved for relapsed-refractory multiple myeloma. This single-arm, open-label, phase 2 study was the prospective evaluation of the efficacy and safety of bortezomib, pomalidomide, and dexamethasone (VPd) induction for NDMM. We used Fleming's two-stage design for sample size calculation. We included transplant-eligible and ineligible patients aged 18-75 years in the study. The patients received four cycles of VPd induction followed by response assessment. Thirty-four patients were included in the study, of which 31 completed all four cycles of induction. The median age was 52 years (32-72). Thirty (91%) patients had multiple myeloma, and three had multiple plasmacytomas with less than 10% bone marrow involvement. Nine (27%) had ISS-I, 9 (27%) had ISS-II, and 15 (46%) had ISS-III myeloma. Three patients had high-risk cytogenetic abnormalities. After four cycles of VPd induction, ten patients (32%) achieved stringent CR, nine had CR (29%), eight (26%) had VGPR, and 4 (13%) had PR. Fifteen (48%) had a complete metabolic response (CMR) on PET-CT. Two patients developed SAEs. Anemia was the most common hematological toxicity. Peripheral neuropathy and constipation were the most common non-hematological toxicities. Patients with ≥VGPR had significantly better 12-month PFS than those with PR. Patients with ≥VGPR and CMR on PET-CT had significantly better 12-month OS. Our study showed VPd induction is safe and efficacious in NDMM. Further Phase 3 studies are necessary to establish the superiority and survival benefits.

Cytotoxic chemotherapy is associated with decreased bone mineral density in postmenopausal women with early and locally advanced breast cancer.

PURPOSE: The burden and mechanisms of endocrine therapy-related bone loss have been studied in detail. However, there is limited data regarding cytotoxic chemotherapy's impact on bone health. There are no definitive guidelines for bone mineral density (BMD) monitoring and treatment with bone-modifying agents during cytotoxic chemotherapy. The study's primary objective was to evaluate the changes in BMD and fracture risk assessment tool (FRAX) scores among breast cancer women on cytotoxic chemotherapy. METHODS: One hundred and nine newly diagnosed early and locally advanced postmenopausal breast cancer patients planned for anthracycline and taxane-based chemotherapy were recruited prospectively during the study period from July 2018 to December 2021. BMD of the lumbar spine, the femoral neck, and the total hip were assessed by dual-energy X-ray absorptiometry scan. BMD and FRAX scores were evaluated at baseline, end of chemotherapy, and 6 months of follow-up. RESULTS: The median age of the study population was 53 (45-65) years. Early and locally advanced breast cancers were seen in 34 (31.2%) and 75 (68.8%) patients, respectively. The duration of follow-up between two BMD measurements was 6 months. The percentage of decrease in BMD at the lumbar spine, femoral neck, and total hip were - 2.36 ± 2.90, - 2.63 ± 3.79, and - 2.08 ± 2.80, respectively (P-value = 0.0001). The median risk of major osteoporotic fracture (MOF) at 10 years (FRAX score) increased from 1.7 (1.4) to 2.7% (2.4) (P-value = 0.0001). CONCLUSION: This prospective study in postmenopausal breast cancer women shows a significant association of cytotoxic chemotherapy with the worsening of bone health in terms of BMD and FRAX score.

Comparison of Efficacy of Aspirin Plus EOX vs. EOX Alone in Patients with Locally Advanced and Metastatic Gastric Cancer: a Randomized Clinical Trial.

PURPOSE: The role of aspirin in cancer prevention has been well defined; the last decade revealed its therapeutic role with improved efficacy when aspirin was added to capecitabine in heavily pre-treated metastatic colorectal cancer. Aspirin affects tumour growth through the PI3K pathway, which regulates apoptosis and autophagy. The objective was to compare the efficacy of aspirin plus epirubicin, oxaliplatin, capecitabine (EOX) chemotherapy versus EOX alone in locally advanced and metastatic gastric cancer. METHODS: All patients with advanced gastric cancer reporting to the Department of Medical oncology between March 2017 and May 2019 were screened for study eligibility. They were randomly assigned to standard EOX with or without aspirin at a daily dose of 150 mg. Tumour measurements were assessed at baseline and after 3-4 cycles by an independent blinded radiologist according to RECIST criteria 1.1. Toxicity profiles were recorded as per CTCAE v 4.03. Per-protocol group was identified as 70 patients. The primary endpoint was overall response rates in the per-protocol group (defined as patients who received a minimum of 3 cycles and had an evaluable response after randomization). The secondary endpoints included toxicity analysis, progression-free survival, and overall survival. RESULTS: Ninety-five patients who fulfilled the study inclusion and exclusion criteria were randomized to group 1 EOX (50) or group 2 EOX plus aspirin (45). Seventy patients were included for the per-protocol analysis. The overall response rate in group 1 was 27% compared to group 2, which was 42%, P = 0.176. The median duration of follow was 29 (18.56-39.45) months. The median overall survival (n = 95) of group 1 versus group 2 was 11 (8.58-13.42) months and 10 (6.86-13.14) months, respectively, P = 0.90. There was no statistical significance in the overall survival per-protocol analysis (n = 70) between group one 12 (8.75-15.25) months versus group two 12 (6.21-17.79) months, P = 0.50. CONCLUSIONS: There was no improvement in the response rates, progression-free survival, and overall survival on adding aspirin to EOX chemotherapy in locally advanced and metastatic gastric cancer in an unselected population. A further role of PI3K mutation as a biomarker needs to be evaluated in this setting.

Modified neoadjuvant clinicopathological risk stratification as a prognostic score in early and locally advanced triple-negative breast cancer.

Background: Triple-negative subtype is an aggressive breast cancer with inferior survival. Pathological complete remission (pCR) is a good surrogate endpoint for survival among patients receiving neoadjuvant chemotherapy (NACT). We attempted to validate the clinical pathological score (CPS) with a modified risk grouping among Triple-negative breast cancer (TNBC) patients receiving NACT at our center. Methodology: Data of patients with TNBC who underwent NACT between January 2014 to July 2017 were retrospectively analyzed. The composite CPS score included cTN stage and y pTN stage and ranged from 0 to 4. This was calculated using an available online software developed by MD Anderson Center. The score obtained from the calculator was used to develop a risk grouping into low risk (0, 1) and high risk (2, 3, 4). Invasive disease-free survival (iDFS) and locoregional recurrence-free survival (LRFS) were calculated using the Kaplan-Meier method. Results: Seventy-eight patients with TNBC (median age: 45 [24-75]) had received NACT (anthracyclines and taxanes). Early and locally advanced breast cancer constituted 17 (21.8%) and 61 (78.2%), respectively, and 22 (28.2%) achieved pCR. After a median follow-up of 25 months (5-62), 3-year iDFS and OS were 59% and 81%, respectively, for the entire population. The 3-year iDFS in low-risk (n = 18) and high-risk (n = 60) patients was 85% and 51%, respectively (P = 0.03). The 3-year LRFS in low risk and high risk was 93% versus 58% (P = 0.03). The 3-year OS in the low and high risk was 93% and 77%, respectively (P = 0.24, NS). Conclusion: Our study supports the use of the modified neoadjuvant clinicopathological score as a prognostic marker in patients with nonmetastatic triple-negative breast cancer. This needs to be validated in a larger subset of patients.

Atherogenic Risk Factors among Young Indian Adults with Epilepsy on Treatment with Phenytoin: Need for Novel Therapeutic Strategies.

BACKGROUND: Risk for the development of coronary heart disease and diabetes is found to be more among people with epilepsy especially when on treatment. Redox imbalance contributes to this risk especially in India as it is the diabetic capital of the world with higher prevalence of inflammation. OBJECTIVES: The aim of this study was to evaluate atherogenic risk factors; dyslipidemia, oxidative stress, and systemic inflammation among young Indian adults with epilepsy on treatment with Phenytoin. MATERIAL AND METHODS: Three groups of age and gender-matched young subjects were recruited. Group 1-Healthy control subjects, Group 2- Newly diagnosed epileptic young adults with recent epileptic seizures, Group 3- Epileptic adults on treatment with Phenytoin for more than 6 months were recruited. RESULTS: Dyslipidemia was found among the newly diagnosed epileptic subjects in comparison to healthy subjects. The LDL-cholesterol further increased, and HDL-cholesterol further decreased in the third group treated with Phenytoin. Body mass index of these treated epileptic subjects was more in comparison to healthy control. Low-grade inflammation as assessed by hsCRP and oxidative stress were significantly higher among the newly diagnosed epileptic subjects when compared to the healthy controls which further increased on treatment with phenytoin. We found dyslipidemia, oxidative stress, and low-grade inflammation among newly diagnosed epileptic subjects which further increased on treatment with Phenytoin for more than 6 months. CONCLUSION: From this study, we conclude that dyslipidemia, oxidative stress and low-grade inflammation are identified among the newly diagnosed young adult Indian epileptic patients. Phenytoin treatment further augmented these complications.

Effect of cytotoxic chemotherapy on bone health among breast cancer patients. Does it require intervention?

BACKGROUND: Breast cancer (BC) is one of the most common malignancies worldwide. Although the burden and mechanisms of endocrine therapy-related bone loss are known, the evidence is scanty regarding the impact of cytotoxic chemotherapy on bone health. We have attempted to summarize the effect of cytotoxic chemotherapy on bone health in BC patients. METHODS: A comprehensive literature search was performed via MEDLINE and Cochrane library databases to evaluate the effect of chemotherapy on bone health among women with BC. We included articles related to skeletal-related events, bone mineral density, bone turnover markers, osteoporosis-specific quality of life, bisphosphonate, and other bone-directed therapy. We excluded articles that included patients with metastatic breast cancer and patients receiving hormonal therapy. DISCUSSION: Bone microenvironment in cancer is directly or indirectly influenced by clinical, hormonal, nutritional, and treatment factors. Calcitonin, parathyroid hormone, calcitriol, and estrogen are the major hormonal regulators. Bone turnover markers, namely bone formation and resorption markers, have been used to predict bone loss, fracture risk, and monitoring treatment response. Chemotherapeutic drugs such as anthracyclines and taxanes synergistically affect BMD and quality of life. Calcium, vitamin D, bisphosphonates, and denosumab are supplemented to prevent excess bone resorption. Bone-targeted anti-resorptive agents have been studied as potential anticancer agents in the adjuvant treatment of breast cancer. CONCLUSION: This review summarizes the negative effect of chemotherapy on bone health of BC patients and the importance of preventing or treating bone loss.

Clinico-Pathologic Profile and Treatment Outcomes of Patients with Diffuse Large B Cell Lymphoma Based on Cell of Origin Classification.

Diffuse large B cell lymphoma (DLBCLs) constitute 40% of all non-Hodgkin lymphoma and it represent a heterogeneous group of neoplasms rather than a single clinicopathological entity. We analysed the outcomes and clinical features based on the cell of origin in a series of patients with DLBCL from our institute. Medical case records of all newly diagnosed DLBCL treated in our institute from January 2015 to July 2017 were analysed for this study. Cell of origin classification was based on immunohistochemistry using Hans algorithm. Kaplan-Meier curves were used to determine survival. Ninety-five patients were diagnosed to have DLBCL subtype. Immunophenotypic subtyping was available for 71 patients. The median age at diagnosis was 56 years with no difference between Germinal centre B cell (GCB) and non-Germinal centre B cell (non-GCB) subtypes. Approximately 44% of patients had extra-nodal disease, stomach being the commonest site. Forty percent of patients had stage III/IV disease. Bulky disease and extra-nodal presentation was predominantly seen with non-GCB subtype (46% vs 20% and 36% vs 29% respectively). Rituximab was used in 75% of the patients with DLBCL. The 2-year disease-free survival was 70% versus 53% (p = 0.38) in GCB versus non-GCB subtype. This is one of the few data on DLBCL patients reported from India which has described outcomes based on the cell of origin. The disease-free survival in our country appears to be superior in GCB subtype which needs to be confirmed in a larger subset of patients.

Late Effects of Breast Cancer Treatment and Outcome after Corrective Interventions.

Purpose: To study the late toxicities of treatment and its impact on Breast cancer survivors among Indian patients. Materials and Methods: Our study recruited 152 curatively treated non metastatic carcinoma breast patients. The baseline demographic details, disease related and treatment related information were collected. The late effects included breast cancer related lymphedema, shoulder dysfunction, treatment induced bone loss, hypothyroidism, cardiac dysfunction, and chemotherapy induced cognitive dysfunction and Quality of life. Results: The median age was 47 years (range 27 -72 years). The cumulative frequency of BCRL and shoulder dysfunction was 31.57% and 34.86% respectively. The improvement in BCRL with corrective intervention was not statistically significant. The BCRL was significantly associated with shoulder dysfunction. The frequency of loss of bone mineral density was 38.15%. There was statistically significant improvement in bone mineral density with interventions. The cumulative rate of hypothyroidism and cardiac dysfunction was 14.47 % and 2.17% respectively which improved after corrective therapy. We did not find any delayed cognitive dysfunction. There was improvement in global health, physical function, role function, fatigue, Nausea, vomiting, pain scores, insomnia, Loss of appetite, diarrhea and arm symptoms over time with intervention. Conclusion: Our study has shown that nearly half of the survivors were suffering from at least one of the late effects. The intervention helped in improving the loss of bone mineral density, hypothyroidism, cardiac dysfunction and quality of life in Breast cancer survivors.

Biochemical derangements related to metabolic syndrome in epileptic patients on treatment with valproic acid.

PURPOSE: Evaluation of biochemical derangements related to metabolic syndrome in epileptic patients on treatment with Valproic acid. METHODS: This study consisted of two groups of 42 patients. Group I - Newly diagnosed patients with epileptic seizures untreated with any Anti-epileptic drugs (AEDs). Group II - Patients on treatment with Valproic acid for more than one year. Age and gender matched patients of 18-40 years were recruited. Patients who were diabetic, hypertensive, smokers, alcoholics, with persistent infection, head injuries, pregnancy and lactation were excluded from the study. Biochemical parameters, fasting blood glucose, lipid profile, Malondialdehyde (MDA), Total Antioxidant Status (TAS), MDA/TAS ratio, leptin, adiponectin, fasting insulin, high sensitive c-reactive protein (hsCRP), Homeostatic model assessment of insulin resistance (HOMA-IR) and leptin/adiponectin ratio were estimated. RESULTS: There was a decrease in Total cholesterol and Low Density Lipoprotein- cholesterol levels among the VPA-treated epileptic patients in comparison to newly diagnosed patients. BMI did not differ between the untreated and treated patients. There were no significant difference in the levels of hsCRP, leptin and TAS between the newly diagnosed and VPA-treated patients. Increased insulin as well as HOMA-IR levels and decreased adiponectin levels were found in VPA treated subjects when compared to the newly diagnosed patients. Oxidative stress parameters (MDA, MDA/TAS ratio) were elevated in VPA treated subjects when compared to newly diagnosed patients. CONCLUSION: VPA treatment increased the risk factors for the development of metabolic syndrome such as hyperinsulinemia, insulin resistance and oxidative stress. However VPA treatment corrected the dyslipidemia of epileptic patients.