Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers.

The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.

Slowdown of interpenetration of two counterpropagating plasma slabs due to collective effects.

The nonlinear evolution of electromagnetic instabilities driven by the interpenetration of two e^{-},e^{+} plasma clouds is explored using ab initio kinetic plasma simulations. We show that the plasma clouds slow down due to both oblique and Weibel generated electromagnetic fields, which deflect the particle trajectories, transferring bulk forward momentum into transverse momentum and thermal velocity spread. This process causes the flow velocity v_{inst} to decrease approximately by a factor of sqrt[1/3] in a time interval Δt_{αB}ω_{p}∼c/(v_{fl}sqrt[α_{B}]), where α_{B} is the magnetic equipartition parameter determined by the nonlinear saturation of the instabilities, v_{fl} is the initial flow speed, and ω_{p} is the plasma frequency. For the α_{B} measured in our simulations, Δt_{αB} is close to 10 times the instability growth time. We show that as long as the plasma slab length L>v_{fl}Δt_{αB}, the plasma flow is expected to slow down by a factor close to sqrt[1/3].

FOXO3 gene hypermethylation and its marked downregulation in breast cancer cases: A study on female patients.

Background: FOXO3, a member of the FOX transcription factor family, is frequently described as being deregulated in cancer. Additionally, notable role of FOXO3 can be easily recognized in the process of ageing and survival. Even though various studies have been done to acknowledge the tumour-suppressive or oncogenic role of FOXO3 in cancer, still there exist a lack of understanding in terms of cancer prognosis and treatment. Therefore, to provide better insight, our study aims to evaluate the role and function of FOXO3 in breast cancer in Indian female patients. We examined the FOXO3 expression levels in breast cancer samples by analyzing mRNA and protein expression along with its clinicopathological parameters. Results: A total of 127 cases of breast cancer with equal normal cases (n=127) were assessed with methylation (MS-PCR), Immunohistochemistry (IHC), mRNA expression using Real-time PCR was analysed and 66.14% cases at mRNA level were found to be downregulated, while 81.10% of cases had little or very little protein expression. Our data state, the promoter hypermethylation of the FOXO3 gene and the downregulated protein expression are significantly correlated (p=0.0004). Additionally, we found a significant correlation between the level of FOXO3 mRNA with ER (p=0.04) and status of lymph node (p=0.01) along with this. Conclusion: Data suggests the prognostic significance and the tumour-suppressive role of FOXO3 in breast cancer cases studied in India. However, there is a need for the extended research targeting FOXO3 to measure its clinical potential and develop well-defined therapeutic strategies.

Long-Term Survivors of Metastatic Colorectal Cancer: A Tertiary Care Centre Experience.

Background Prognosis of metastatic colorectal cancer (mCRC) is poor and goal of treatment is mainly palliative unless there is limited metastatic disease which is surgically resectable. Here, we report a case series of long-term survivors treated predominantly with chemotherapy. Methods This is a single-center retrospective analysis of patients of mCRC. Records of metastatic colorectal cancer patients registered at Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, between the year 2005 and 2015 were retrieved and reviewed. Inclusion criteria were patients who survived 5 years or more, treated mainly by chemotherapy, with either initial presentation as metastatic disease or those who progressed after initial surgery with or without adjuvant therapy. The details about the patient characteristics, treatment, and outcome were collected. The data were censored on September 30, 2020. Results Records of 370 mCRC patients were reviewed. Thirty-one patients with all the available details fulfilled the criteria for inclusion in the study. Median age was 53 years (range, 22-74 years). Sixteen were women (51.6%). Twenty-four (77%) were newly diagnosed cases with initial presentation as metastatic disease. Commonest site of primary was on the left (21, 67.6%) followed by right side and transverse colon in 5 patients each. Liver was the most common site of metastasis ( n = 18, 58.06%). In metastatic setting, the most common chemotherapy regimen used in the first line was CAPOX ( n = 11, 35.48%). Only three patients could undergo metastatectomy. Monoclonal antibodies could be used only in 14 patients. Median overall survival (OS) of this cohort is 81.6 months (95% confidence interval [CI], 69.73-117.9). Conclusion A small but significant proportion of mCRC patients may achieve and maintain durable responses and long term survival with use of combination of chemotherapy with or without biologics.

Colorectal Cancers in Low- and Middle-Income Countries-Demographic Pattern and Clinical Profile of 970 Patients Treated at a Tertiary Care Cancer Center in India.

PURPOSE: Globally, colorectal cancer (CRC) ranks third in terms of incidence and second in terms of mortality. A relatively low burden of CRC has been reported from low- and middle-income countries (LMIC), and there is a paucity of publications related to CRC from LMIC. PATIENTS AND METHODS: A computerized comprehensive structured CRC clinical database was developed. All the patients with histopathologically proven CRC undergoing either curative and palliative multimodality management or surgical interventions between 2000 and 2019 were included in the study. A descriptive analysis of the demographic profile and clinical spectrum was performed. RESULTS: A total of 970 patients of CRC were treated between 2000 and 2019. Of these, 401 patients (41.3%) had colon cancer and 569 (58.7%) had rectal cancer. The male-to-female ratio was 1.79:1. The mean age at presentation was 47.7 years. A total of 337 (34.7%) patients qualified as young CRC (≤ 40 years of age at diagnosis). The commonest symptom among patients with colon cancer was abdominal pain; 55.6% of patients had a right-sided primary tumor as compared with 42.2% with left-sided tumors. The commonest symptom among patients with rectal cancer was bleeding per rectum. The predominant location of the tumor was in the lower rectum (58%). Majority of patients with CRC presented with locally advanced stage II and III disease. The most common histologic subtype encountered for both colon and rectal cancers was adenocarcinoma (84.8% and 81.2%, respectively). CONCLUSION: This study has revealed certain important findings related to CRC in LMIC including a higher burden of young colorectal cancer, a relatively higher proportion of rectal cancers in comparison with colon cancer, a high percentage of patients with low-rectal cancer, and advanced stage at presentation.

Metastatic colo-rectal cancer: real life experience from an Indian tertiary care center.

BACKGROUND: No data exist for the long-term outcome of metastatic colorectal cancer (mCRC) from the Southern part of Asia. The primary objective of the study is to evaluate the survival outcome of mCRC from an Indian tertiary care center. The study also aims to highlight the treatment pattern practiced and the unique clinico-pathologic characteristics. METHODS: This is a single-center retrospective observational study done at a large referral tertiary care center in North India. All patients with synchronous or metachronous mCRC who received at least one dose of chemotherapy for metastatic disease, registered between 2003 to 2017 were included. Primary outcome measures were overall survival and progression-free survival and prognostic factors of overall survival. Descriptive analysis was done for the clinicopathological characteristics and treatment patterns. Kaplan Meier method for overall survival and progression-free survival. Cox regression analysis was performed for the determination of the prognostic factors for overall survival. RESULT: Out of 377 eligible patients, 256 patients (68%) had de novo metastatic disease and the remaining 121 (32%) progressed to metastatic disease after initial treatment. The cohort was young (median age, 46 years) with the most common primary site being the rectum. A higher proportion of signet (9%) and mucinous histology (24%). The three common sites of metastasis were the liver, peritoneum, and lung. In the first line, most patients received oxaliplatin-based chemotherapy (70%). Only 12.5% of patients received biologicals in the first-line setting. The median follow-up and median overall survival of study cohort were 17 months and 18.5 months. The factors associated with poor outcome for overall survival on multivariate analysis were ECOG performance status of > 1, high CEA, low albumin, and the number of lines of chemotherapy received (< 2). CONCLUSION: The outcome of mCRC is inferior to the published literature. We found a relatively higher proportion of patients with the following characteristics; younger, rectum as primary tumor location, the signet, and mucinous histology, higher incidence of peritoneum involvement. The routine use of targeted therapies is limited. Government schemes (inclusion of targeted therapies in the Ayushman scheme), NGO assistance, and availability of generic low-cost targeted drugs may increase the availability.

Low Cost, Low Dose, Oral, Neoadjuvant Chemotherapy Protocol in Locally Advanced Borderline Oral Cancers-Feasibility Study.

A vast majority of oral cancer patients in developing countries present in an advanced stage with borderline resectable/inoperable stage to busy resource-constrained tertiary cancer centers. Conventional chemotherapy protocols are associated with issues like toxicity, tolerance, cost, and compliance. The present study was conducted to assess the feasibility of low-cost home-based chemotherapy options. Single-arm feasibility study was done in borderline resectable/inoperable oral cancer patients. Home-based oral neoadjuvant chemotherapy consisting of oral methotrexate 15 mg/m2 once a week and oral celecoxib 200 mg twice daily for 8 weeks was used. RECIST Criteria 1.1 was used to assess response to therapy. The study included 60 patients. The mean age was 51.98 years with male predominance (80%). Fifty-five patients adhered to the treatment; the compliance rate is 91.60%. Affordability (Rs 700 per month) and tolerance to therapy was 100%, and no grade III or IV toxicity was seen. Overall, 18 patients had stable disease (32.73%), partial response was seen in 15 patients (27.27%), and the disease progressed in 22 patients (40%). At the end of 8 weeks, 26 (43.3%) patients were deemed resectable. Neoadjuvant low cost, home-based metronomic chemotherapy using oral methotrexate and celecoxib seems to be a viable option in managing advanced oral cancer in resource-constrained setups.

Collisionless shock acceleration in the corona of an inertial confinement fusion pellet with possible application to ion fast ignition.

Two-dimensional particle-in-cell simulations are used to explore collisionless shock acceleration in the corona plasma surrounding the compressed core of an inertial confinement fusion pellet. We show that an intense laser pulse interacting with the long scale-length plasma corona is able to launch a collisionless shock around the critical density. The nonlinear wave travels up-ramp through the plasma reflecting and accelerating the background ions. Our results suggest that protons with characteristics suitable for ion fast ignition may be achieved in this way. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

Microarray based gene expression profiling of advanced gall bladder cancer.

BACKGROUND: Gall bladder cancer (GBC) is an aggressive cancer with specific predilection like female gender and specific geographical areas, however the molecular mechanisms and factors contributing to the clinical or biological behavior are not understood. AIM: The aim of this study was to perform a comprehensive analysis of differentially expressed genes in advanced GBC and chronic cholecystitis (CC) cases. MATERIALS AND METHODS: Microarray was planned on fresh specimens of advanced GBC and CC cases using single color cRNA based microarray technique (8X60K format; Agilent Technologies, USA). Twelve advanced GBC and four CC patients were included in the study. RESULTS: Of the total of 1307 differentially expressed genes, 535 genes were significantly upregulated, while 772 genes were significantly downregulated in advanced GBC vs CC samples. Differentially expressed genes were associated with biological processes (55.03%), cellular components (31.48%), and molecular functions (13.49%) respectively. The important pathways or key processes affected were cell cycle, DNA replication, oxidative stress, gastric cancer pathway. Using in silico analysis tools, three differentially expressed genes i.e. TPX2, Cdc45 and MCM4 were selected (for their significant role in DNA replication and microtubule function) and were further validated in 20 advanced GBC cohort by immunohistochemistry. Significant positive association of Cdc45 and MCM4 proteins was found in advanced GBC cases (p = 0.043), suggesting the probable oncogenic role of Cdc45 and MCM4 proteins in advanced GBC. CONCLUSION: Our data demonstrate the potential regulation of Cdc45-MCM4 axis in advanced GBC tumors. Additionally, our study also revealed a range of differentially expressed genes (e.g. TPX2, AKURA etc.) between GBC and CC, and further validation of these genes might provide a potential diagnostic or therapeutic target in future.

Characterization of on-target adverse events caused by TRK inhibitor therapy.

BACKGROUND: The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial. PATIENTS AND METHODS: Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized. RESULTS: Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% [95% confidence interval (CI), 43%-62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%-51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%-46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain. CONCLUSIONS: TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.

Association of mutation and low expression of the CTCF gene with breast cancer progression.

BACKGROUND: CTCF encodes 11-zinc finger protein which is implicated in multiple tumors including the carcinoma of the breast. The Present study investigates the association of CTCF mutations and their expression in breast cancer cases. METHODS: A total of 155 breast cancer and an equal number of adjacent normal tissue samples from 155 breast cancer patients were examined for CTCF mutation(s) by PCR-SSCP and automated DNA sequencing. Immunohistochemistry (IHC) method was used to analyze CTCF expression. Molecular findings were statistically analyzed with various clinicopathological features to identify associations of clinical relevance. RESULTS: Of the total, 16.1% (25/155) cases exhibited mutation in the CTCF gene. Missense mutations Gln > His (G > T) in exon 1 and silent mutations Ser > Ser (C > T) in exon 4 of CTCF gene were analyzed. A significant association was observed between CTCF mutations and some clinicopathological parameters namely menopausal status (p = 0.02) tumor stage (p = 0.03) nodal status (p = 0.03) and ER expression (p = 0.04). Protein expression analysis showed 42.58% samples having low or no expression (+), 38.0% with moderate (++) expression and 19.35% having high (+++) expression for CTCF. A significant association was found between CTCF protein expression and clinicopathological parameters include histological grade (p = 0.04), tumor stage (p = 0.04), nodal status (p = 0.03) and ER status (p = 0.04). CONCLUSIONS: The data suggest that CTCF mutations leading to its inactivation significantly contribute to the progression of breast cancer.

Thoracoabdominal Flap: a Simple Flap for Covering Large Post-mastectomy Soft Tissue Defects in Locally Advanced Breast Cancer.

Locally advanced breast cancer (LABC) constitutes 40-50% of breast cancer in developing countries. Large soft tissue defects after mastectomy often require some additional cover. The primary aim of reconstruction in this group should be an expeditious and simple closure with good-quality skin cover, early recovery, and short hospital stay so that the patients can receive early post-operative radio-chemotherapy. Thoracoabdominal (TA) flap is a type-c fasciocutaneous flap and the skin and fat of the upper abdomen are used, based on medial or lateral perforating vessels. We present our experience of TA flap cover for large post-mastectomy defects. A retrospective analysis of prospectively maintained breast cancer database in the Department of Surgical Oncology from January 1994 to December 2017 at All India Institute of Medical Sciences, New Delhi, was performed. The medical records of patients undergoing TA flap cover were analyzed to assess operative duration, blood loss, post-operative morbidity, hospital stay, adjuvant treatment, recurrence patterns, and survival outcome. A total of 3142 breast cancer patients underwent surgery, of which 1840 were LABC and 88 patients (4.13%) of LABC required flap cover for the closure of mastectomy defect. TA flap was used in majority of these patients 72/83 (86.7%) for cover. Majority was stage IIIB (54 out of 72) and we could achieveR0 resection in all patients. TA flap was done following MRM in 60 patients and RM in 12 patients. Upfront primary surgery was performed in 27 patients and 45 underwent surgery after neoadjuvant chemotherapy. Most commonly laterally based flaps were done, except 4 medially based flaps. The mean operating time was 30 min and blood loss was 45 ml. Mean hospital stay was 4.45 days. Superficial flap necrosis occurred in 6 and wound infection in 4 patients, all managed conservatively. Only 2 patients had major flap loss and required debridement and skin grafting. Planned post-operative radiation could be delivered in most of the patients in time. At a mean follow-up of 24 months, only 9 out of 72 (12.5%) patients had a loco-regional recurrence. Results of our experience show that TA flap is a simple, cost-effective procedure for managing large post-mastectomy soft tissue defects in LABC. It has huge potential in developing countries dealing with a large number of LABC because of simplicity and short learning curve.

Impact of p53 arg72pro SNP on Breast Cancer Risk in North Indian Population.

BACKGROUND: Genetic changes in p53 gene contribute to breast cancer susceptibility. OBJECTIVE AND METHODS: A case-control study and a meta-analysis were performed to investigate the role of p53 codon72 SNP with breast cancer susceptibility in Indian women. RESULTS: p53 heterozygous arginine variant was associated with decreased risk of breast cancer in total cohort. In meta-analysis, Allelic and GG vs. CC genetic comparison model were found to be associated with breast cancer risk. Moreover, recessive comparison model indicated a protective correlation with breast cancer occurrence. CONCLUSION: The findings of our case-control study and meta-analysis suggest a significant association between p53 Arg72Pro polymorphism and an increased risk of breast cancer in Indian population.

Hypermethylated LATS2 gene with decreased expression in female breast cancer: A case control study from North India.

BACKGROUND: LATS2, a presumed tumor suppressor gene located on chromosome 13q11-12 is involved in cell growth related activity like regulation of cell cycle at G1/S. The reduced expression of LATS2 has been reported in many tumors; including tumors of Breast, which is to the best of our knowledge has not been studied in north Indian female breast cancer population. OBJECTIVE: Here, we looked upon the expression pattern and methylation status of the LATS2 gene in north Indian female breast cancer cases to further strengthen its role as a tumor suppressor gene and more importantly as a cancer biomarker. METHODS: mRNA expression level was determined by real time PCR in 140 Breast cancer patients, Protein expression was studied by Immunohistochemistry and Promoter methylation was studied by Methylation specific PCR. All findings were correlated with clinicopathological features. RESULTS: LATS2 mRNA expression was remarkably downregulated in 67.85% (95/140) cases. The expression of Large Associated Tumor Suppressor 2 at protein level was also absent in 67.85% (95/140) cases. The absence of LATS2 protein strongly correlated with promoter hypermethylation where 91 out of a total of 107 hyper methylated cases showed absence of protein (91/107, 85%). The absence of LATS2 protein was strongly significant with HER2 neu status (0.01), TNM staging (0.009) and Molecular subtype (0.024). CONCLUSION: The decreased expression in breast cancer seems to be associated with hypermethylation of LATS2 promoter regions. Further LATS2 as a tumor suppressor can be recognized as a promising Biomarker in Breast cancer pathogenesis. Though, further studies, targeting larger sets of breast cancer population are required to establish LATS2 as a promising biomarker.

Clinicopathological profile of breast cancer: An institutional experience.

INTRODUCTION: This study was undertaken to evaluate the clinicopathological characteristics of patients with breast cancer at our institute, a tertiary-care cancer center in northern India. MATERIALS AND METHODS: This retrospective study included all patients with breast cancer registered at our institute from January 1st, 2014 to December 31st, 2016. We retrieved data (demographic, baseline clinical characteristics, pathology, and treatment details) from prospectively maintained clinical case records. Patients with incomplete case records or missing baseline information were excluded. RESULTS: We included 550 patients with breast cancer. The median age was 48 years (23-85). The median clinical tumor size was 5.0 cm. The TNM (AJCC-7th edition) stage distribution was stage I, 22 (4%); stage II, 182 (33%); stage III, 247 (44.9%); and stage IV, 99 (18%). Locally advanced breast cancer constituted 40% of the cases. Bone (48 [48.5%]) was the most common site for metastasis followed by lung. Infiltrating ductal carcinoma (528 [96%]) was the most common histologic subtype. Majority of patients, 325 (59%), were positive for estrogen receptor/progesterone receptor whereas 160 (29%) patients were HER2/neu positive. Triple negative breast cancer (TNBC) constituted 28% (154) of patients. In the nonmetastatic subgroup, 343 (76%) patients underwent modified radical mastectomy. Neoadjuvant chemotherapy (NACT) was given in 120 (26.6%) patients, of these 23 (19%) achieved pathological complete remission. Sequential anthracyline and taxane were used as NACT/adjuvant chemotherapy in most cases. Of the eligible patients, 48 (30%) received anti-HER2/neu therapy. CONCLUSION: This is one of the largest comprehensive data from a single center in India. Majority of our patients are younger in age and have advanced disease. TNBC and HER2/neu positive breast cancer are more common in our population.

Retrospective study of efficacy and safety of neoadjuvant docetaxel, carboplatin, and trastuzumab in HER2-positive locally advanced and oligometastatic breast cancer: An Indian experience.

BACKGROUND: The neoadjuvant chemotherapy in HER2-positive breast cancer consists of a chemotherapy backbone and HER2-directed therapy. The increase in cardiotoxicity by the use of trastuzumab with an anthracycline-based regimen has led to the use of nonanthracycline-based alternative regimens. The docetaxel, carboplatin, and trastuzumab (TCH) are one such regimen. The efficacy and toxicity of this regimen have not been widely studied in Indian patients. AIMS: This retrospective study aims to evaluate the efficacy and toxicity of neoadjuvant TCH regimen in locally advanced and oligometastatic HER2-positive breast cancer in Indian patients. METHODOLOGY: The hospital records between January 2014 and December 2016 were reviewed to identify patients with locally advanced and oligometastatic HER2-positive breast cancer treated with uniform 3-weekly neoadjuvant chemotherapy protocol-containing docetaxel (75 mg/m2), carboplatin (AUC = 6), and trastuzumab (8 mg/kg loading followed by 6 mg/kg) (TCH). The primary outcome was the pathologic complete response (pCR), which was defined as an absence of invasive and noninvasive cancer in breast or lymphnode. RESULTS: Thirty-two patients with mean age 46 years met our inclusion criteria, of these 24 patients had locally advanced breast cancer, and eight patients had oligometastatic breast cancer. 13 (40.6%) patients had hormone-positive breast cancer. The objective response rate as assessed clinically was 100%, and pCR rate was 36.3%. The patients with oligometastatic breast cancer also showed a good response to chemotherapy with three patients showing pCR and four patients showing resolution disease at metastatic sites. The patients experienced very few Grade III/IV toxicities, and no patient had clinical congestive heart failure. CONCLUSION: The TCH protocol is an efficacious neoadjuvant chemotherapy regimen for locally advanced and oligometastatic breast cancer and is safe and well tolerated in this population.