Spectrum of metastatic neoplasms of the brain: A clinicopathological study in a tertiary care cancer centre.

BACKGROUND: While brain metastases (BM) are the most common causes of neurologic disorders in patients with known systemic malignancies, they can often be the initial manifestations of an undetected primary elsewhere. BM are major causes of morbidity and mortality in cancer patients. AIMS: We describe a mixed population (data from both retrospective and prospective collection) having a BM from a solid tumor. We report the percentage distribution of the most frequent types of BM, confirming the data published in the literature. This paper may play a role in presenting the Southeast Asian reality compared with the Western countries. SETTING: A tertiary-care cancer centre. MATERIALS AND METHODS: Data for 4 years were retrieved from the records of the Department of Pathology of our institute. Hematolymphoid and meningeal tumors were excluded. Hematoxylin and eosin (H and E) stained slides were reviewed, and in cases with an unknown primary, immunohistochemistry (IHC) was advised. The panel of markers was chosen based on the histomorphology on H and E sections. IHC was done in cases with an unknown primary where paraffin blocks were available. RESULTS: Lung cancer was found to be the most common primary malignancy (n = 30; 48.4%) followed by breast cancer (n = 13; 21%), colorectal cancer (n = 6; 9.6%), and skin cancer (melanoma) [n = 3; 4.8%]. CONCLUSION: The incidence of BM from lung and breast cancer was similar to that seen in the Western studies. However, BM from colorectal cancer and melanoma show a higher and lower incidence, respectively, in comparison with the Western literature.

Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study.

BACKGROUND: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway promotes tumour growth and metastasis. Rilotumumab is a fully human, monoclonal antibody that neutralises HGF. We aimed to assess the safety, efficacy, biomarkers, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine (ECX) in patients with advanced gastric or oesophagogastric junction cancer. METHODS: We recruited patients (≥18 years old) with unresectable locally advanced or metastatic gastric or oesophagogastric junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who had not received previous systemic therapy, from 43 sites worldwide. Phase 1b was an open-label, dose de-escalation study to identify a safe dose of rilotumumab (initial dose 15 mg/kg intravenously on day 1) plus ECX (epirubicin 50 mg/m(2) intravenously on day 1, cisplatin 60 mg/m(2) intravenously on day 1, capecitabine 625 mg/m(2) twice a day orally on days 1-21, respectively), administered every 3 weeks. The phase 1b primary endpoint was the incidence of dose-limiting toxicities in all phase 1b patients who received at least one dose of rilotumumab and completed the dose-limiting toxicity assessment window (first cycle of therapy). Phase 2 was a double-blind study that randomly assigned patients (1:1:1) using an interactive voice response system to receive rilotumumab 15 mg/kg, rilotumumab 7·5 mg/kg, or placebo, plus ECX (doses as above), stratified by ECOG performance status and disease extent. The phase 2 primary endpoint was progression-free survival (PFS), analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00719550. FINDINGS: Seven of the nine patients enrolled in the phase 1b study received at least one dose of rilotumumab 15 mg/kg, only two of whom had three dose-limiting toxicities: palmar-plantar erythrodysesthesia, cerebral ischaemia, and deep-vein thrombosis. In phase 2, 121 patients were randomly assigned (40 to rilotumumab 15 mg/kg; 42 to rilotumumab 7·5 mg/kg; 39 to placebo). Median PFS was 5·1 months (95% CI 2·9-7·0) in the rilotumumab 15 mg/kg group, 6·8 months (4·5-7·5) in the rilotumumab 7·5 mg/kg group, 5·7 months (4·5-7·0) in both rilotumumab groups combined, and 4·2 months (2·9-4·9) in the placebo group. The hazard ratio for PFS events compared with placebo was 0·69 (80% CI 0·49-0·97; p=0·164) for rilotumumab 15 mg/kg, 0·53 (80% CI 0·38-0·73; p=0·009) for rilotumumab 7·5 mg/kg, and 0·60 (80% CI 0·45-0·79; p=0·016) for combined rilotumumab. Any grade adverse events more common in the combined rilotumumab group than in the placebo group included haematological adverse events (neutropenia in 44 [54%] of 81 patients vs 13 [33%] of 39 patients; anaemia in 32 [40%] vs 11 [28%]; and thrombocytopenia in nine [11%] vs none), peripheral oedema (22 [27%] vs three [8%]), and venous thromboembolism (16 [20%] vs five [13%]). Grade 3-4 adverse events more common with rilotumumab included neutropenia (36 [44%] vs 11 [28%]) and venous thromboembolism (16 [20%] vs four [10%]). Serious adverse events were balanced between groups except for anaemia, which occurred more frequently in the combined rilotumumab group (ten [12%] vs none). INTERPRETATION: Rilotumumab plus ECX had no unexpected safety signals and showed greater activity than placebo plus ECX. A phase 3 study of the combination in MET-positive gastric and oesophagogastric junction cancer is in progress. FUNDING: Amgen Inc.

Delays in diagnosis and treatment of breast cancer: a multinational analysis.

BACKGROUND: Reducing treatment delay improves outcomes in breast cancer. The aim of this study was to determine factors influencing patient- and system-related delays in commencing breast cancer treatment in different countries. METHODS: A total of 6588 female breast cancer patients from 12 countries were surveyed. Total delay time was determined as the sum of the patient-related delay time (time between onset of the first symptoms and the first medical visit) and system-related delay time (time between the first medical visit and the start of therapy). RESULTS: The average patient-related delay time and total delay time were 4.7 (range: 3.4-6.2) weeks and 14.4 (range: 11.5-29.4) weeks, respectively. Longer patient-related delay times were associated with distrust and disregard, and shorter patient-related delay times were associated with fear of breast cancer, practicing self-examination, higher education level, being employed, having support from friends and family and living in big cities. The average system-related delay time was 11.1 (range: 8.3-24.7) weeks. Cancer diagnosis made by an oncologist versus another physician, higher education level, older age, family history of female cancers and having a breast lump as the first cancer sign were associated with shorter system-related delay times. Longer patient-related delay times and higher levels of distrust and disregard were predictors of longer system-related delay times. CONCLUSIONS: The delay in diagnosis and treatment of breast cancer remains a serious problem. Several psychological and behavioural patient attributes strongly determine both patient-related delay time and system-related delay time, but their strength is different in particular countries.

Neurofibromatosis type I with breast cancer: not only for women!

The association of neurofibromatosis type I with invasive male breast cancer is a rare clinical entity with only one case in literature reported in 1953. Women with NF1 are at risk of developing breast cancer and men also may be at risk but there is scarce data on the risk and association of NF1 with male breast cancer due to its rarity. Established clinical trials in male breast cancer patients are lacking and the results are extrapolated from female breast cancer patients. The treatment of male breast cancer is followed as per the guidelines of premenopausal female breast cancer and tamoxifen is the hormone treatment in them. Mendes et al suggests that silencing of NF1 gene confers resistance to tamoxifen. Our conclusions are that since NF1 is mutated or deleted in one third of sporadic breast cancers, its role as a molecular driver for treatment has to be further explored.

A Real-World Study of Safety, Immunogenicity and Efficacy of Bevacizumab in Patients With Solid Malignancies: A Phase IV, Post-Marketing Study in India.

Objective: The aim of this study was to evaluate the post-marketing safety, tolerability, immunogenicity and efficacy of Bevacizumab (manufactured by Hetero Biopharma) in a broader population of patients with solid tumors. Patients And Methods: This phase IV, prospective, multi-centric clinical study was carried out in Indian patients with solid malignancies (metastatic colorectal cancer, non-squamous non-small-cell lung cancer, metastatic renal cell carcinoma) treated with Bevacizumab between April 2018 and July 2019. This study included 203 patients from 16 tertiary care oncology centers across India for safety assessment, of which a subset of 115 patients who have consented were also evaluated for efficacy and immunogenicity. This study was prospectively registered in the Clinical Trial Registry of India (CTRI), and was commenced only after receiving approval from the competent authority (Central Drugs Standard Control Organization, CDSCO). Results: Out of the 203 enrolled patients, 121 (59.6%) patients reported 338 adverse events (AEs) during this study. Of 338 reported AEs, 14 serious adverse events (SAEs) were reported by 13 patients including 6 fatal SAEs, assessed as unrelated to the study medication and 7 non-fatal SAEs, 5 assessed as related, and 3 unrelated to Bevacizumab. Most AEs reported in this study (33.9%) were general disorders and administration site conditions, followed by gastrointestinal disorders (29.1%). The most frequently reported AEs were diarrhea (11.3%), asthenia (10.3%), headache (8.9%), pain (7.4%), vomiting (7.9%), and neutropenia (5.9%). At the end of the study, 2 (1.75%) of 69 patients reported antibodies to Bevacizumab without affecting safety and efficacy. However, at the end of 12 months, no patient had reported antibodies to Bevacizumab. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were reported in 18.3%, 22.6%, 9.6%, and 8.7% of patients, respectively. The overall response rate (CR + PR) was reported in 40.9% of patients at the end of the study. Disease control rate (DCR), also known as the clinical benefit rate (CBR) was reported in 50.4% of patients. Conclusions: Bevacizumab (Cizumab, Hetero Biopharma) was observed to be safe, well tolerated, lacking immunogenicity, and efficacious in the treatment of solid tumors. The findings of this phase IV study of Bevacizumab, primarily as a combination therapy regimen suggest its suitability and rationality for usage in multiple solid malignancies. Clinical Trial Registry Number: CTRI/2018/4/13371 [Registered on CTRI http://ctri.nic.in/Clinicaltrials/advsearch.php : 19/04/2018]; Trial Registered Prospectively.

T-Cell Prolymphocytic Leukemia: An Experience from a Tertiary Cancer Centre in South India.

Background: T-cell prolymphocytic leukemia (T-PLL) is a rare lymphoid malignancy with dismal prognosis. Most patients have increased lymphocyte count (>1,00,000/dL) and widespread disease at presentation. Despite high response rate seen with alemtuzumab, the disease relapse is inevitable. Materials andMethods: This was a retrospective observational study done at a tertiary cancer center in South India. All patients diagnosed with T-PLL from August 2010 to July 2015 were studied for the clinical characteristics, pathological findings and treatment outcomes. Results: Seven patients were diagnosed as T-PLL over a period of 5 years. The median age at diagnosis was 51 years. In the present series, 6 patients (86%) had splenomegaly and 3 had hepatomegaly (43%). Generalized lymphadenopathy was seen in 4 (57%) patients at presentation. Skin lesions were seen in 5 (71%) patients, whereas pleural effusion was seen in only one patient (14%). All had elevated total leukocyte count, with more than 1, 00,000/dL in 4 patients. The median survival was 5 months with different chemotherapy (CT) regimens (5 patients treated with CT and 2 received best supportive care). Conclusion: T-PLL is a rare disease with no definite treatment guidelines. At present, the best outcomes are achieved if treatment with alemtuzumab is followed by stem cell transplant, but the disease invariably relapses. Countries where affordability remains a big challenge, the best approach needs to be defined beyond the monoclonal antibodies and transplant.

Correlation of BMI with breast cancer subtype and tumour size.

BACKGROUND: Breast cancer is a heterogeneous disease which is divided broadly into luminal, HER2 and basal type based on molecular profiling. Increased body mass index (BMI) has been associated with the risk of developing breast cancer but the association based on molecular subtype remains conflicting. METHODS: This was an observational study carried out over a period of 2 years. Nonmetastatic breast cancer patients were evaluated for the tumour subtype based on surrogate markers (ER, PR and HER2). The BMI of these patients was correlated with the tumour subtype and size. RESULTS: We studied 476 patients with breast cancer with the median age of 46 years (range, 25-86) and 58% were premenopausal. The mean BMI of the cohort was 24.1, which was significantly higher in postmenopausal women (24.9 versus 23.6, p < 0.05). Overall, only 10% of patients were obese. The mean BMI in the luminal, HER2 and TNBC subtypes was 24.7, 22.4 and 23.9, respectively (p < 0.01). Also, the mean tumour size in luminal, HER2 and TNBC subtype was 4.02, 3.80 and 4.27 cm, respectively (p = 0.158). CONCLUSION: The average BMI was higher in patients with luminal subtype followed by TNBC and lowest for HER2 at the time of diagnosis. The mean tumour size was numerically higher for TNBC and lowest for HER2 subtype although the difference was not statistically significant. Larger studies may provide clarity of association between the BMI and tumour subtype.

Primary central nervous system lymphoma in immunocompetent patients: A regional cancer center experience.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare form of aggressive extranodal non-Hodgkin's lymphoma which occurs in both immunocompromised and immunocompetent patients. It has an overall poor prognosis in spite of a multimodality treatment approach including chemotherapy and radiotherapy. This study attempts to further delineate the clinicopathological, immunohistochemical, and radiological profile of PCNSL at Kidwai Memorial Institute of Oncology, Karnataka, India. MATERIALS AND METHODS: All the pathologically confirmed PCNSL cases between January 2010 and June 2016, at our center, were analyzed retrospectively. The influence of potential prognostic parameters on overall survival (OS) was investigated by log-rank test and Cox regression analysis. RESULTS: Of the 26 PCNSL patients, 17 (65.3%) were males. Median age at diagnosis was 42.5 years. None of the patients had HIV or Epstein-Barr virus positivity and only four patients (15.4%) had B-symptoms. The most common location in the brain was cerebral hemispheres in 15 patients (57%) and 10 patients (38.5%) had multiple intracranial lesions. Histologically, all were diffuse large B-cell lymphomas, except one case of anaplastic large cell lymphoma. Immunohistochemically, 18 patients (69%) had MUM 1 positivity and 20 cases (77%) belonged to nongerminal center subtype. DeAngelis protocol was followed in 24 patients (92%), and among this cohort, Memorial Sloan Kettering Cancer Center Class 1 (n = 17) and Class 2 (n = 7) patients had a median OS of 25 months and 11 months, respectively. CONCLUSION: None of the potential prognostic factors had a statistically significant influence on OS in our patients. High-dose methotrexate combined with radiation is an effective therapeutic approach. However, further prospective studies with a large number of patients are needed to identify more effective primary chemotherapy regimens to further improve the treatment outcome.

Plasma Epstein Barr viral load in adult-onset Hodgkin lymphoma in South India.

OBJECTIVE/BACKGROUND: Epstein Barr Virus (EBV) DNA load is increasingly being used as a noninvasive biomarker for detecting EBV association in lymphomas. Since there is a need of data from India, we undertook to prospectively evaluate plasma EBV DNA load as a marker of EBV association in newly diagnosed adult-onset Hodgkin lymphoma (HL). METHODS: EBV DNA was quantified using real-time polymerase chain reaction. In a subset of patients, an assay was validated qualitatively with EBV latent membrane protein-1 (LMP1) immunohistochemistry (IHC). Wherever possible, follow-up plasma samples post three cycles of chemotherapy were obtained. RESULTS: Over a period of 10 months, 33 newly diagnosed adult-onset HL were enrolled in the study. Pretherapy plasma EBV DNA was detectable in ∼49% (16/33) patients (viral loads range, 1.0-51.2×10(3)copies/mL) and undetectable in 30 voluntary blood donors. LMP1 IHC was positive in 56% of cases tested (14/25). Sensitivity and specificity of plasma EBV DNA with respect to LMP1 IHC were 86% and 100%, respectively. Of the eight patients in whom follow-up plasma was available, in five EBV baseline-positive patients EBV load reverted to negative postchemotherapy and corroborated with clinical remission. CONCLUSION: Plasma EBV DNA load estimation may be useful in detecting EBV-association and possibly monitoring the response to therapy in EBV-related HL especially in our country where EBV association of HL is higher than in developed nations.

Clinicopathological Profile of Pure Neuroendocrine Neoplasms of the Esophagus: A South Indian Center Experience.

Purpose. Neuroendocrine neoplasms (NENs) of the esophagus are very uncommon with only a few studies published worldwide. Studies on clinical profile, management, and outcomes are very uncommon. Methods. We report the largest single institution retrospective review of 43 patients of pure esophageal NENs out of our registry of gastrointestinal neuroendocrine tumors treated between 2005 and 2014. Data on the incidence, tumor location, clinical symptoms, stage at presentation, grading, treatment protocol, and treatment outcomes was collected and analyzed. Results. Among 1293 cases of esophageal cancers, pure esophageal NENs were diagnosed in 43 cases. The mean patient age was 55.8 years. The male : female ratio was 1.5 : 1. 81.4% of the tumors were located in the lower third of the esophagus and gastroesophageal junction. Neuroendocrine carcinomas (NEC; G3) accounted for the vast majority of NENs (83.7%). 53.5% patients were Stage IV and 32.5% were Stage III at presentation. The combined median survival of stages II and III patients was 18.25 months, with treatment. The median survival of treated patients with metastatic disease was 6.5 months. Conclusion. Esophageal NENs most commonly were neuroendocrine carcinomas, presented in metastatic stage and were associated with poor prognosis. Grade 2 (G2) tumors had better outcomes than NEC (G3). In nonmetastatic disease, presence of lymph node metastasis and unresectable disease had poorer outcomes.

Febrile Neutropenia in Hematological Malignancies: Clinical and Microbiological Profile and Outcome in High Risk Patients.

BACKGROUND AND OBJECTIVES: Febrile neutropenia (FN) is considered a medical emergency. Patients with hematological malignancies (HM) commonly experience FN. Broad spectrum antibiotics have to be started empirically to prevent complications. This study depicts the clinical profile, microbiological profile, antibiotic sensitivity pattern, and outcome in high risk HM. MATERIALS AND METHODS: In this prospective study, 72 patients with hematologic malignancies, diagnosed and treated for 108 high risk febrile neutropenic episodes from August 2011 to January 2013 at a Regional Cancer Center, in South India were analyzed. Cefoperazone-sulbactum was used as a first-line empiric antibiotic. RESULTS: Majority of the patients with FN episodes had acute myeloid leukemia. Overall culture positivity was 29.62%. The most common organisms isolated were Gram-negative bacilli (63.64%), with Escherichia coli being the most frequent pathogen. All Gram-negative organisms were sensitive to imipenem, whereas sensitivity pattern to other antibiotics were as follows: 85.71%, 78.26%, 69.52%, 63.64%, 41.66% and 47.05% for pipercillin-tazoactum, meropenem, cefoperazone-sulbactum, amikacin, ceftazidime, ciprofloxacin respectively. Overall mortality was 13.5%. Most of the patients responded to empiric antibiotic cefoperazone-sulbactum. CONCLUSIONS: In the hematologic malignancies particularly in acute leukemia, there is high risk of developing FN. Empiric therapy with cefoperazone-sulbactum as a first line leads to satisfactory outcome in high risk FN and therapy should be tailored to the most appropriate antibiotics according to the bacterial culture results.

Management of febrile neutropenia in solid organ malignancies following chemotherapy.

BACKGROUND: Febrile neutropenia is a medical emergency and it requires immediate hospitalization for evaluation and administration of empiric broad-spectrum antibiotics. The present study was undertaken to analyze the infectious agents, choice of empiric antibiotics, and outcome in high-risk febrile neutropenia in the solid organ malignancies. MATERIALS AND METHODS: In this study, 92 high risk febrile neutropenic episodes were analyzed in 72 patients with solid organ malignancies. We used cefoperazone-sulbactum as an initial empiric antibiotic. Piperacillin/tazobactum or carbapenems were added to the patients who did not respond to initial antibiotic. RESULTS: Among the 92 episodes treated, most patients received first-line chemotherapy for locally advanced disease. Microbes were isolated in 25% of febrile neutropenic episodes. Gram-negative organism (61.70%) constituted the most common isolates. The most common microbes identified were E. coli and Staphylococcus aureus in blood, Klebsiella pneumonia in sputum and E. coli in urine culture. Patients who had been treated with cefoperazone-sulbactum improved clinically in 70.6% of febrile neutropenic episodes. Second- line antibiotics (piperacillin-tazobactum with amikacin) were required in 24% episodes, while another 5.4% episodes required third-line antibiotics (carbapenems). In this study, mortality was seen in 12% of febrile neutropenic episodes. Staphylococcus aureus was 100% sensitive to linezolid, teicoplanin, and vancomycin, whereas Gram-negative organisms were 100% sensitive to imepenem and meropenem. CONCLUSION: Cephaperazone-sulbactum is a reasonable initial choice for empirical therapy in high risk febrile neutropenic patients in solid organ malignancies.