Publications by authors named "Subramanian Sundaram"

38 Publications

Diffuse Large B-Cell Lymphoma: Clinical Presentation and Treatment Outcomes From the Lymphoma Registry.

Front Oncol 2021 2;11:796962. Epub 2022 Feb 2.

Department of Medical Oncology, Apollo Cancer Institute, Chennai, India.

Background: Diffuse large B-cell lymphoma (DLBCL) is the commonest subtype of lymphoma, standard CHOP was the treatment of choice, 42% of patients received rituximab, and 29% of patients were lost to follow-up during therapy, were reported in a study that collected retrospective data at 13 public and private hospitals for patients diagnosed with lymphoma between January 2005 and December 2009. The OncoCollect Registry was set up in 2017 to address the challenges in the collection of retrospective data through chart review, recording access to anthracycline and rituximab-based treatment, and to study outcomes and any improvement in the patient follow-up.

Methodology: The OncoCollect Lymphoma group registry was set up at a national level with 9 participating centers. Lymphoma patients registered at these centers between 2011 and 2017 were included. The clinical features, prognostic stratification, associated comorbidities, response to first-line treatment, and 3-year outcomes of adult patients with DLBCL were analyzed.

Results: Of the 5,886 lymphoma patients registered in the OncoCollect registry, 2,581 (44%) had DLBCL. A total of 1,961 were evaluable for frontline therapy. The median age at presentation was 57 years. Gender ratio was 1.6:1. At presentation, 43% were early stage, 70% had low and low intermediate IPI, 53% had extranodal disease, and 30.9% had one or more comorbidities (data available for 1,136 patients). The commonest extra nodal site was gastro-intestinal (23.98%) followed by head and neck (19.24%). The overall response rate was 79.29%. Complete remission was seen in 61.75%, partial response in 17.5%, stable disease in 4.3%, and progression in 7.9%. Patients who received anthracycline-based therapy (86.7%) and rituximab-based therapy (83.7%) had a 3-year event-free survival (EFS) of 69.67% and 68.48%, respectively. With a median follow-up of 33 months, the 3-year overall Survival (OS) and EFS were 75.37% and 66.58%, respectively.

Conclusions: DLBCL remains the commonest (44%) lymphoma subtype and is curable with standard anthracycline- and rituximab-based therapies. The availability of rituximab has increased the proportion of patients receiving standard chemoimmunotherapy.
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http://dx.doi.org/10.3389/fonc.2021.796962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847307PMC
February 2022

Next-generation engineered microsystems for cell biology: a systems-level roadmap.

Trends Cell Biol 2022 Jun 31;32(6):490-500. Epub 2022 Jan 31.

Biological Design Center, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA. Electronic address:

Engineered microsystems for in vitro studies of cultured cells are evolving from simple 2D platforms to 3D architectures and organoid cultures. Despite advances in reproducing ever more sophisticated biology in these systems, there remain foundational challenges in re-creating key aspects of tissue composition, architecture, and mechanics that are critical to recapitulating in vivo processes. Against the backdrop of current progress in 3D fabrication methods, we evaluate the key requirements for the next generation of cellular platforms. We postulate that these future platforms - apart from building tissue-like structures - will need to have the ability to readily sense and autonomously modulate tissue responses over time, as occurs in natural microenvironments. Such interactive robotic platforms that report and guide cellular events will enable us to probe a previously inaccessible class of questions in cell biology.
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http://dx.doi.org/10.1016/j.tcb.2022.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106832PMC
June 2022

Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization.

Sci Adv 2021 Oct 15;7(42):eabh3995. Epub 2021 Oct 15.

Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.

Progressive loss of cardiac systolic function in arrhythmogenic cardiomyopathy (ACM) has recently gained attention as an important clinical consideration in managing the disease. However, the mechanisms leading to reduction in cardiac contractility are poorly defined. Here, we use CRISPR gene editing to generate human induced pluripotent stem cells (iPSCs) that harbor plakophilin-2 truncating variants (tv), the most prevalent ACM-linked mutations. The tv iPSC–derived cardiomyocytes are shown to have aberrant action potentials and reduced systolic function in cardiac microtissues, recapitulating both the electrical and mechanical pathologies reported in ACM. By combining cell micropatterning with traction force microscopy and live imaging, we found that tvs impair cardiac tissue contractility by destabilizing cell-cell junctions and in turn disrupting sarcomere stability and organization. These findings highlight the interplay between cell-cell adhesions and sarcomeres required for stabilizing cardiomyocyte structure and function and suggest fundamental pathogenic mechanisms that may be shared among different types of cardiomyopathies.
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http://dx.doi.org/10.1126/sciadv.abh3995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519574PMC
October 2021

Efficacy and safety of nanosomal docetaxel lipid suspension based chemotherapy in metastatic ovarian carcinoma: A retrospective study.

Mol Clin Oncol 2021 Aug 16;15(2):162. Epub 2021 Jun 16.

Jina Pharmaceuticals Inc., Libertyville, IL 60048, USA.

The aim of the current study was to assess the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS) based chemotherapy in patients with metastatic epithelial ovarian carcinoma. In the present multicenter study, the medical records of patients who received NDLS (60-75 mg/m; 3-weekly cycles) based chemotherapy for metastatic epithelial ovarian cancer in routine clinical care were retrospectively evaluated. Patients were followed-up from September 2014 until September 2018. The efficacy endpoints were the overall response rate (ORR) and disease control rate measured in accordance with the Response Evaluation Criteria in Solid Tumours 1.1. Overall survival (OS) and safety were also evaluated. Of the 13 patients evaluated, 46.2% (6/13) received NDLS-based first-line chemotherapy and 53.8% (7/13) patients received second-line chemotherapy [platinum-sensitive, 57.1% (4/7); platinum-resistant, 42.9% (3/7)]. The ORRs were 60.0% (3/5) and 57.1% (4/7) for patients receiving first- and second-line chemotherapy, respectively. The estimated median OS for patients receiving NDLS-based first-line chemotherapy was 17.4 months (follow-up duration, 4.3-49.4 months). The estimated median OS was 26.1 months (follow-up duration, 5.1-37.5 months) in patients with platinum-sensitive disease, whereas the OS was 14.8 months (follow-up duration, 3.5-14.8 months) in patients with platinum-resistant disease. No grade III/IV adverse events (AEs) were observed; ≥1 AE in grade I-II was reported in 84.6% (11/13) of patients. Overall, NDLS-based chemotherapy was efficacious and well-tolerated in the management of metastatic epithelial ovarian carcinoma.
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http://dx.doi.org/10.3892/mco.2021.2324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237200PMC
August 2021

Coupled oscillation and spinning of photothermal particles in Marangoni optical traps.

Proc Natl Acad Sci U S A 2021 05;118(18)

Department of Polymer Science and Engineering, University of Massachusetts, Amherst, MA 01003;

Cyclic actuation is critical for driving motion and transport in living systems, ranging from oscillatory motion of bacterial flagella to the rhythmic gait of terrestrial animals. These processes often rely on dynamic and responsive networks of oscillators-a regulatory control system that is challenging to replicate in synthetic active matter. Here, we describe a versatile platform of light-driven active particles with interaction geometries that can be reconfigured on demand, enabling the construction of oscillator and spinner networks. We employ optically induced Marangoni trapping of particles confined to an air-water interface and subjected to patterned illumination. Thermal interactions among multiple particles give rise to complex coupled oscillatory and rotational motions, thus opening frontiers in the design of reconfigurable, multiparticle networks exhibiting collective behavior.
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http://dx.doi.org/10.1073/pnas.2024581118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106307PMC
May 2021

Transient Support from Fibroblasts is Sufficient to Drive Functional Vascularization in Engineered Tissues.

Adv Funct Mater 2020 Nov 25;30(48). Epub 2020 Jun 25.

Biological Design Center, Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.

Formation of capillary blood vasculature is a critical requirement for native as well as engineered organs and can be induced in vitro by co-culturing endothelial cells with fibroblasts. However, whether these fibroblasts are required only in the initial morphogenesis of endothelial cells or needed throughout is unknown, and the ability to remove these stromal cells after assembly could be useful for clinical translation. In this study, we introduce a technique termed CAMEO (Controlled Apoptosis in Multicellular Tissues for Engineered Organogenesis), whereby fibroblasts are selectively ablated on demand, and utilize it to probe the dispensability of fibroblasts in vascular morphogenesis. The presence of fibroblasts is shown to be necessary only during the first few days of endothelial cell morphogenesis, after which they can be ablated without significantly affecting the structural and functional features of the developed vasculature. Furthermore, we demonstrate the use of CAMEO to vascularize a construct containing primary human hepatocytes that improved tissue function. In conclusion, this study suggests that transient, initial support from fibroblasts is sufficient to drive vascular morphogenesis in engineered tissues, and this strategy of engineering-via-elimination may provide a new general approach for achieving desired functions and cell compositions in engineered organs.
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http://dx.doi.org/10.1002/adfm.202003777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891457PMC
November 2020

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

Lancet 2021 02;397(10274):581-591

Division of Cancer and Genetics, Cardiff University Medical School, Cardiff, UK.

Background: Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

Methods: PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 μg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive.

Findings: Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001).

Interpretation: Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer.

Funding: Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.
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http://dx.doi.org/10.1016/S0140-6736(21)00100-8DOI Listing
February 2021

A Multicentric, Retrospective Efficacy and Safety Study of Nanosomal Docetaxel Lipid Suspension in Metastatic Castration-Resistant Prostate Cancer.

Prostate Cancer 2020 24;2020:4242989. Epub 2020 Nov 24.

Jina Pharmaceuticals Inc., Libertyville, Illinois 60048, USA.

Purpose: To evaluate the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS, DoceAqualip) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Materials And Methods: In this multicenter, retrospective study, we analyzed the medical charts of mCRPC patients, who were treated with NDLS administered as 2-weekly (50 mg/m) or 3-weekly regimens (75 mg/m). The study endpoints were prostate-specific antigen (PSA) response (>50% PSA decline from baseline), PSA progression (PSA increase from baseline beyond 12 weeks: ≥25% and ≥2 ng/mL), median PSA decline, and time-to-treatment failure (TTF). Overall survival (OS) and safety were also evaluated.

Results: Data of 24 patients with mCRPC were analyzed in this study. NDLS was administered as a 2-weekly regimen in 37.5% (9/24; all first-line) patients and as a 3-weekly regimen in 62.5% patients (15/24; first-line: 20% (3/15), second-line: 80% (12/15)). Overall, PSA response was reported in 66.7% (16/24) patients. The PSA response was 77.8% (7/9 patients) in the 2-weekly group and 60% (9/15 patients) in the 3-weekly group. The median decline in PSA was 96.31% in the 2-weekly group and 83.29% in the 3-weekly group; the median TTF was 6.7 and 6.5 months in the 2 weekly group and 3-weekly group, respectively. The median OS was 14.6 months (follow-up: 5.5-25.8 months) in the 2-weekly group whereas it was not reached in the 3-weekly group (follow-up: 7.9-15.6 months). The most common hematological AEs were anemia, lymphopenia, thrombocytopenia, and neutropenia whereas nausea, weakness, constipation, vomiting, and diarrhea were the most common (≥10%) nonhematological AEs. Overall, NDLS treatment was well tolerated without any new safety concerns.

Conclusions: Nanosomal docetaxel lipid suspension (2-weekly or 3-weekly) was effective and well tolerated in patients with metastatic castration-resistant prostate cancer.
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http://dx.doi.org/10.1155/2020/4242989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758141PMC
November 2020

Robots learn to identify objects by feeling.

Sci Robot 2020 Dec;5(49)

Biological Design Center, Boston University, Boston, MA, USA.

Multimodal tactile sensors help robot hands accurately identify grasped objects by measuring thermal properties in addition to contact loads.
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http://dx.doi.org/10.1126/scirobotics.abf1502DOI Listing
December 2020

How to improve robotic touch.

Science 2020 11;370(6518):768-769

Biological Design Center, Boston University, Boston, MA, USA.

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http://dx.doi.org/10.1126/science.abd3643DOI Listing
November 2020

Efficacy and safety of nanosomal docetaxel lipid suspension-based chemotherapy in squamous cell carcinoma of the head and neck: A multicenter retrospective study.

Oncol Lett 2020 Dec 8;20(6):344. Epub 2020 Oct 8.

Jina Pharmaceuticals Inc., Libertyville, IL 60048, USA.

Squamous cell carcinoma of the head and neck (SCCHN) is the most common cancer in Indian men. Docetaxel alone or in combination with other chemotherapeutic agents is recommended for the management of SCCHN. The present multicenter, retrospective study was conducted to evaluate the efficacy and safety of a novel docetaxel formulation 'nanosomal docetaxel lipid suspension (NDLS)'-based chemotherapy in SCCHN. The medical records of patients with SCCHN, who were treated with NDLS-based chemotherapy and followed up between August 2014 and September 2018, were reviewed. The efficacy endpoints were overall response rate [ORR; complete response (CR) + partial response (PR)] and disease control rate (DCR; CR + PR + stable disease) for patients receiving NDLS-based induction or palliative chemotherapy. Overall survival (OS) and safety were also evaluated. Efficacy evaluation was available in 30/34 patients (induction, 20/23; palliative, 10/11). NDLS-based induction chemotherapy showed an ORR and DCR of 95% and a median OS of 43.5 months (follow-up duration, 0.6-80.3 months). For NDLS-based palliative chemotherapy, the ORR and DCR were 50% and the median OS time was 4.6 months (follow-up duration, 1.8 to 14.3 months). At least one adverse event was reported in 82.6% patients. No new safety concerns were reported. Overall, NDLS-based chemotherapy was effective and well tolerated in the treatment of SCCHN.
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http://dx.doi.org/10.3892/ol.2020.12207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583840PMC
December 2020

Efficacy and safety of nanosomal docetaxel lipid suspension based chemotherapy in gastric and gastroesophageal junction adenocarcinoma.

Mol Clin Oncol 2020 Sep 6;13(3):14. Epub 2020 Jul 6.

Jina Pharmaceuticals Inc., Libertyville, IL 60048, USA.

The current retrospective multicenter study evaluated the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS; DoceAqualip) based chemotherapy in patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma. The medical charts of patients with gastric and GEJ adenocarcinoma, who were treated with NDLS (50-75 mg/m; 3 weekly cycles) based chemotherapy and followed-up from April 2014 to September 2018, were analyzed. The study endpoints included overall response rate (ORR) and disease control rate (DCR) in neoadjuvant and metastatic settings. Overall survival (OS) and safety were also evaluated. Of the 43 patients with gastric (n=39) and GEJ (n=4) adenocarcinoma, efficacy evaluation was available in 35 (neoadjuvant, 17/18 patients; metastatic, 18/25 patients). In the neoadjuvant setting, an ORR of 58.82% and a DCR of 94.11% were observed, whereas in the metastatic setting, the ORR was 77.77% and the DCR was 83.33%. In the neoadjuvant setting, at a follow-up ranging from 0.7 to 41.2 months, the median OS was not reached. In the metastatic setting, the median OS was 31.9 months at a follow-up ranging from 0.2 to 50.3 months. At least one adverse event (AE) was reported in 24 patients. Anemia, lymphopenia and thrombocytopenia were the most common hematological AEs, while nausea, vomiting and weakness were the most common non-hematological AEs. NDLS based treatment was well-tolerated without any new safety concerns. Overall, NDLS-based chemotherapy was effective and well-tolerated in the management of gastric and GEJ adenocarcinoma.
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http://dx.doi.org/10.3892/mco.2020.2084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391841PMC
September 2020

Effect of scapular stabilization exercise program in patients with subacromial impingement syndrome: a systematic review.

J Exerc Rehabil 2020 Jun 30;16(3):216-226. Epub 2020 Jun 30.

Department of Physiotherapy, Sakra Institute of Rehabilitation Sciences, Sakra World Hospital, Bangalore, India.

Scapular stabilization approaches have been a mainstay of therapeutic training programs in the recent past for patients with subacromial im-pingement syndrome, whereas its contributions solely in the clinical outcome of reducing shoulder pain and disability are largely unclear. This systematic review aims to evaluate and summarize the best evi-dence regarding the role of scapular stabilization interventions in allevi-ating shoulder dysfunction among subjects with subacromial impinge-ment syndrome. Six reviewers involved in this systematic review. Liter-ature was retrieved systematically through searching 5 electronic data-bases (PubMed, MEDLINE, CINAHL, Cochrane, and Google Scholar). Articles published from the year 2010 up to and including 2019 were in-cluded. The literature search included clinical trials those intervened subjects with scapular exercises or scapular stabilization exercises or scapular rehabilitation, as an intervention for subacromial impingement syndrome. Seven studies, totaling 228 participants were included in this systematic review. Articles included in this review were graded ac-cording to Lloyd-Smith hierarchy of evidence scale and critically ap-praised with a tool developed by National, Heart, Lung and Blood Insti-tute (United States), named as quality assessment of controlled inter-vention studies tool. There was a significant effect on the scapular sta-bilization exercise program on improving pain and disability among sub-jects with subacromial impingement syndrome. This systematic review provides sufficient evidence to suggest that scapular stabilization exer-cises offers effectiveness in reducing pain and disability among sub-jects with subacromial impingement syndrome. However, more trials with larger sample are needed to provide a more definitive evidence on the clinical outcomes of scapular stabilization exercises among pa-tients with impingement.
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http://dx.doi.org/10.12965/jer.2040256.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365732PMC
June 2020

Nanosomal Docetaxel Lipid Suspension-Based Chemotherapy in Breast Cancer: Results from a Multicenter Retrospective Study.

Breast Cancer (Dove Med Press) 2020 22;12:77-85. Epub 2020 May 22.

Jina Pharmaceuticals Inc., Libertyville, Illinois, USA.

Purpose: The purpose of this study was to evaluate the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS, DoceAqualip)-based chemotherapy in breast cancer.

Methods: Medical charts of patients with breast cancer, who were treated and followed up with NDLS (75-100 mg/m; 3-week cycle)-based chemotherapy from August 2014 to September 2018, were analyzed in this multicenter, retrospective study. The study endpoints were overall response rate (ORR: complete response [CR]+partial response [PR]) and disease control rate (DCR: CR+PR+stable disease [SD]) in neoadjuvant and metastatic settings. Overall survival (OS) and safety were evaluated for all settings.

Results: Of 91 patients (neoadjuvant: 12, adjuvant: 61, metastatic: 18), efficacy evaluation in 29 patients (neoadjuvant: 12/12, metastatic: 17/18) demonstrated an ORR and DCR of 100%, respectively, in the neoadjuvant setting, and an ORR of 64.7% and DCR of 70.6%, respectively, in the metastatic setting. At a median follow-up of 21.6 months (range: 2.1 to 49.9 months), median OS was not reached in neoadjuvant and adjuvant settings, and it was 30.4 months in metastatic settings. At least one adverse event (AE) was reported in 59.3% of patients. Anemia, thrombocytopenia, lymphopenia, and neutropenia were the most common hematological AEs reported while hyperglycemia and alteration in liver function tests were the most common non-hematological AEs. NDLS-based treatment was well tolerated without any new safety concerns.

Conclusion: Nanosomal docetaxel lipid suspension-based chemotherapy was efficacious and well tolerated in the treatment of breast cancer. Further, NDLS is being evaluated prospectively in patients with triple-negative breast cancer (ClinicalTrials.gov: NCT03671044).
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http://dx.doi.org/10.2147/BCTT.S236108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250303PMC
May 2020

Efficacy and Safety of Nanosomal Docetaxel Lipid Suspension-Based Chemotherapy in Sarcoma: A Multicenter, Retrospective Study.

Sarcoma 2019 15;2019:3158590. Epub 2019 Nov 15.

Jina Pharmaceuticals Inc., Libertyville, Green Oaks, Illinois 60048, USA.

Objective: To evaluate the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS, DoceAqualip) based chemotherapy in patients with sarcoma.

Methods: In this retrospective, multicenter (6 centers), observational study, we analyzed the medical charts of adult patients of either sex, who were treated with NDLS (75 mg/m in 3-weekly cycles) based chemotherapy for the treatment of sarcoma. The efficacy outcomes were overall response rate (ORR: complete response (CR) + partial response (PR)) and disease control rate (DCR: CR + PR + stable disease (SD)) in patients who received NDLS-based chemotherapy in neoadjuvant and metastatic settings. Overall survival (OS) and safety were evaluated for all settings.

Results: Of 11 patients (neoadjuvant: 1, adjuvant: 3, and metastatic: 7) in this study, majority had leiomyosarcoma (63.6%, 7/11) followed by extraskeletal myxoid chondrosarcoma (EMC), high grade pleomorphic sarcoma of mandible, malignant fibrous histiocytoma of right thigh, and osteosarcoma of femur (9.1% each, 1/11 each). NDLS plus gemcitabine combination was used in 10 patients (90.9%), and NDLS plus cyclophosphamide was used in one patient with EMC (9.1%). Efficacy evaluation was performed for 7 patients (neoadjuvant: 1/1; metastatic: 6/7). Complete response was reported in one patient (soft tissue sarcoma of mandible) treated in neoadjuvant setting. In metastatic setting, ORR was 50% and DCR was 66.7% (CR: 16.7% (1/6), PR: 33.3% (2/6), SD: 16.7% (1/6)). At a median follow-up of 6.5 months (range: 0.06-20.2 months), median OS was not reached in neoadjuvant and adjuvant settings, but it was 15.8 months in metastatic setting. At least 1 AE was reported in 7 (63.6%) patients. Neutropenia, thrombocytopenia, lymphopenia, and anemia were the hematological AEs, whereas nausea, vomiting, and diarrhea were the most common nonhematological AEs. NDLS treatment was well tolerated without any new safety concerns.

Conclusion: Nanosomal docetaxel lipid suspension-based chemotherapy was efficacious and well tolerated in the treatment of sarcoma. Further prospective trials are needed to confirm the data.
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http://dx.doi.org/10.1155/2019/3158590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881752PMC
November 2019

Topology optimization and 3D printing of multimaterial magnetic actuators and displays.

Sci Adv 2019 Jul 12;5(7):eaaw1160. Epub 2019 Jul 12.

Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Upcoming actuation systems will be required to perform multiple tightly coupled functions analogous to their natural counterparts; e.g., the ability to control displacements and high-resolution appearance simultaneously is necessary for mimicking the camouflage seen in cuttlefish. Creating integrated actuation systems is challenging owing to the combined complexity of generating high-dimensional designs and developing multifunctional materials and their associated fabrication processes. Here, we present a complete toolkit consisting of multiobjective topology optimization (for design synthesis) and multimaterial drop-on-demand three-dimensional printing for fabricating complex actuators (>10 design dimensions). The actuators consist of soft and rigid polymers and a magnetic nanoparticle/polymer composite that responds to a magnetic field. The topology optimizer assigns materials for individual voxels (volume elements) while simultaneously optimizing for physical deflection and high-resolution appearance. Unifying a topology optimization-based design strategy with a multimaterial fabrication process enables the creation of complex actuators and provides a promising route toward automated, goal-driven fabrication.
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http://dx.doi.org/10.1126/sciadv.aaw1160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625816PMC
July 2019

Learning the signatures of the human grasp using a scalable tactile glove.

Nature 2019 05 29;569(7758):698-702. Epub 2019 May 29.

Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.

Humans can feel, weigh and grasp diverse objects, and simultaneously infer their material properties while applying the right amount of force-a challenging set of tasks for a modern robot. Mechanoreceptor networks that provide sensory feedback and enable the dexterity of the human grasp remain difficult to replicate in robots. Whereas computer-vision-based robot grasping strategies have progressed substantially with the abundance of visual data and emerging machine-learning tools, there are as yet no equivalent sensing platforms and large-scale datasets with which to probe the use of the tactile information that humans rely on when grasping objects. Studying the mechanics of how humans grasp objects will complement vision-based robotic object handling. Importantly, the inability to record and analyse tactile signals currently limits our understanding of the role of tactile information in the human grasp itself-for example, how tactile maps are used to identify objects and infer their properties is unknown. Here we use a scalable tactile glove and deep convolutional neural networks to show that sensors uniformly distributed over the hand can be used to identify individual objects, estimate their weight and explore the typical tactile patterns that emerge while grasping objects. The sensor array (548 sensors) is assembled on a knitted glove, and consists of a piezoresistive film connected by a network of conductive thread electrodes that are passively probed. Using a low-cost (about US$10) scalable tactile glove sensor array, we record a large-scale tactile dataset with 135,000 frames, each covering the full hand, while interacting with 26 different objects. This set of interactions with different objects reveals the key correspondences between different regions of a human hand while it is manipulating objects. Insights from the tactile signatures of the human grasp-through the lens of an artificial analogue of the natural mechanoreceptor network-can thus aid the future design of prosthetics, robot grasping tools and human-robot interactions.
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http://dx.doi.org/10.1038/s41586-019-1234-zDOI Listing
May 2019

Effectiveness and tolerability of nimotuzumab in unresectable, locally advanced/metastatic esophageal cancer: Indian hospital-based retrospective evidence.

South Asian J Cancer 2019 Apr-Jun;8(2):112-115

Medical advisor, Biocon Ltd, Bengaluru, Karnataka, India.

Context: Epidermal growth factor receptor (EGFR) is overly expressed in esophageal squamous cell carcinoma (ESCC) and is important prognostic and predictive biomarker. Nimotuzumab is a humanized anti-EGFR monoclonal antibody and has documented promising clinical outcomes and survival rates in various solid tumors with high EGFR expression.

Aims: Attempt to fill gap on paucity of data in India on the efficacy of Nimotuzumab in the treatment of locally advanced/metastatic ESCC.

Settings And Design: Hospital records of 15 patients with unresectable, locally advanced/metastatic esophageal cancers, histologically confirmed squamous cell carcinoma being treated with Nimotuzumab along with standard treatments from October 2006 to November 2016 were retrospectively analyzed.

Subjects And Methods: The tumor response rate and overall survival (OS) were analyzed. All patients were assessed for toxicity and adverse events (AEs) as per Common Terminology Criteria for Adverse Events (CTCAE) v4.

Results: Majority had lower thoracic esophageal cancer. Tumor response rate observed was as follows 33% had a complete response, 67% had a partial response, and objective response rate was 100%. Survival rate at 1-, 3-, and 5-year was 58.33%, 29.17%, and 29.17%, respectively. Median OS was 26.8 months (95% confidence interval, 2.63-not reached). No Grade III or Grade IV AEs were observed. No added toxicity was observed due to nimotuzumab.

Conclusions: Nimotuzumab combined with standard treatment in locally advanced/metastatic ESCC improved the survival rate and achieved a better tumor response rate without accumulation of toxicity and was well tolerated.
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http://dx.doi.org/10.4103/sajc.sajc_89_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498719PMC
May 2019

Systematic Review on Effectiveness of shoulder taping in Hemiplegia.

J Stroke Cerebrovasc Dis 2019 Jun 5;28(6):1463-1473. Epub 2019 Apr 5.

Department of Physiotherapy, School of Medicine College of Medicine and Health Sciences, University of Gondar and Gondar University specialized comprehensive hospital, Gondar, Ethiopia.

Background: Shoulder pain and subluxation are the commonly encountered problems among subjects with hemiplegia. Rehabilitating the shoulder following stroke is a challenging task among physiotherapists in rehabilitation set up. There is a need to validate the effectiveness of externally applied taping materials in hemiplegic shoulder.

Objective: This systematic review analyses the efficacy of taping on hemiplegic shoulder in terms of alleviating pain and managing subluxation.

Methods: Systematic review of randomized controlled trials (RCTs) was conducted to determine the effects of taping on hemiplegic shoulder. Articles were electronically searched from the year 2000 to 2017 in the 4 databases, Google scholar, CINAHL, Pubmed, and Pedro. Reviewers graded the papers according to Lloyd-Smith's hierarchy of evidence scale. Papers were quality appraised using a systematic review of RCT tool developed by National Heart, Lung and Blood Institute (United States), named as quality assessment of controlled intervention studies tool.

Results: Eight papers were included, totaling 132 participants. All the RCT's included in this review were good quality. There was a significant effect on taping method for reduction of pain and subluxation among subjects with stroke.

Conclusions: This systematic review provides sufficient evidence to suggest taping is a beneficial method for reducing pain and shoulder subluxation among stroke subjects.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.03.021DOI Listing
June 2019

Photothermocapillary Oscillators.

Phys Rev Lett 2018 Oct;121(15):158001

Department of Polymer Science and Engineering, University of Massachusetts Amherst, Amherst, Massachusetts 01003, USA.

We present a new class of tunable light-driven oscillators based on mm-scale objects adsorbed at fluid interfaces. A fixed light source induces photothermal surface tension gradients (Marangoni stresses) that drive nanocomposite hydrogel discs away from a stable apex position atop a drop of water. The capillary forces on the disc increase with surface curvature; thus, they act to restore the disc to its original position. As the disc reenters the light source it again experiences Marangoni propulsion, leading to sustained oscillation for appropriate conditions. Propulsive forces can be modulated with incident light intensity, while the restoring force can be tuned via surface curvature-i.e., drop volume-providing highly tunable oscillatory behaviors. To our knowledge, this is the first example where Marangoni and capillary forces combine to incite sustained motion. As such, a model was developed that describes this behavior and provides key insights into the underlying control parameters. We expect that this simple approach will enable the study of more complex and coupled oscillatory systems.
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http://dx.doi.org/10.1103/PhysRevLett.121.158001DOI Listing
October 2018

Efficacy and safety of nimotuzumab in unresectable, recurrent, and/or metastatic squamous cell carcinoma of the head and neck: A hospital-based retrospective evidence.

South Asian J Cancer 2018 Jul-Sep;7(3):188-192

Medical affairs, Biocon Ltd, Bengaluru, Karnataka, India.

Context: Role of nimotuzumab in locally advanced head and neck cancer (HNC) is well established in India; however, no clinical evidence is available for its role in recurrent and/or metastatic HNC.

Aims: The aim of this study is to evaluate the efficacy and safety of nimotuzumab when added to standard treatment in unresectable, recurrent, and metastatic squamous cell carcinoma of the head and neck (SCCHN).

Settings And Design: Hospital records of 14 patients diagnosed with recurrent and/or metastatic HNC with histologically confirmed squamous cell carcinoma and being treated with nimotuzumab along with standard treatments from December 2010 to December 2016 were retrospectively evaluated.

Subjects And Methods: The tumor response rate and overall survival (OS) were analyzed. Toxicity and adverse events (AEs) were assessed as per common terminology criteria for adverse events (CTCAE) v 4.

Results: Oral cavity was most commonly involved region followed by hypopharynx and oropharynx. At 24 weeks after completion of treatment, overall response rate (complete response (CR) + partial response (PR)) was 75%. Survival rate at 1, 2, and 3 years was 77.80%, 64.81%, and 64.81%, respectively. At a median follow-up of 15.17 months, median OS was not reached. All AEs were either Grade I (66.7%) or Grade II (33.3%). No Grade III or Grade IV AEs were observed. No added toxicity was observed due to nimotuzumab.

Conclusions: In the first of its kind study, the addition of nimotuzumab to standard treatment showed promising response rate as well as survival outcomes in recurrent and/or metastatic SCCHN patients without producing additional toxicity.
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http://dx.doi.org/10.4103/sajc.sajc_87_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069342PMC
August 2018

Application of infrared scanning of the neck muscles to control a cursor in Human-Computer Interface.

Annu Int Conf IEEE Eng Med Biol Soc 2017 Jul;2017:787-790

The feasibility of using infrared (IR) spectroscopy of the neck muscles in controlling a cursor in a 2-dimensional screen was assessed. The proposed technique utilizes two IR photoplethysmography sensors (λ = 940nm) to monitor the morphological changes of the Scalene and Sternocleidomastoid muscles. Since the reflection of the light has valuable information about the type of contraction, the direction of the movement (right/left, up/down) can be simply derived using two sensors. A MATLAB platform was developed in which a cursor moves using the recorded signal. Three scenarios of high/low sensitivity and joystick mode were tested. The results from 4 different healthy subjects shows the feasibility of control in terms of throughput, overshoot, and path efficiency.
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http://dx.doi.org/10.1109/EMBC.2017.8036942DOI Listing
July 2017

3D-Printed Self-Folding Electronics.

ACS Appl Mater Interfaces 2017 Sep 8;9(37):32290-32298. Epub 2017 Sep 8.

Polymer Science and Engineering Department, University of Massachusetts , Amherst, Massachusetts 01003, United States.

Self-transforming structures are gaining prominence due to their general ability to adopt programmed shapes each tailored for specific functions. Composites that self-fold have so far relied on using the stimuli-responsive mechanisms focusing on reversible shape change. Integrating additional functions within these composites can rapidly enhance their practical applicability; however, this remains a challenging problem. Here, we demonstrate a method for spontaneous folding of three-dimensional (3D)-printed composites with embedded electronics at room temperature. The composite is printed using a multimaterial 3D-printing process with no external processing steps. Upon peeling from the print platform, the composite self-shapes itself using the residual forces resulting from polymer swelling during the layer-by-layer fabrication process. As a specific example, electrochromic elements are printed within the composite and can be electrically controlled through its folded legs. Our shape-transformation scheme provides a route to transform planar electronics into nonplanar geometries containing the overhangs. Integrating electronics within complex 3D shapes can enable new applications in sensing and robotics.
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http://dx.doi.org/10.1021/acsami.7b10443DOI Listing
September 2017

Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.

Breast Cancer Res Treat 2016 Feb 3;156(1):125-34. Epub 2016 Mar 3.

Sun Pharma Advanced Research Co. Ltd., 17/B Mahal Industrial Estate, Mahakali Caves Road, Andheri (E), Mumbai, 400093, India.

Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2) every 3 weeks was effective and well tolerated and showed similar tolerability compared with nab-paclitaxel 260 mg/m(2) every 3 weeks. Statistically, significant differences were not observed in the PICN and nab-paclitaxel treatment arms for radiologist-assessed ORR or median PFS. The novel paclitaxel formulation, PICN, offers apart from efficacy, potential safety advantage of decreased use of corticosteroid pretreatment and the absence of the risk of transmission of blood product-borne disease.
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http://dx.doi.org/10.1007/s10549-016-3736-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788678PMC
February 2016

Bulk mode piezoresistive thermal oscillators: time constants and scaling.

IEEE Trans Ultrason Ferroelectr Freq Control 2015 Aug;62(8):1554-62

This paper presents design and analysis for engineering the thermal and mechanical time constants of piezoresistive thermal oscillators. The optimal design is obtained by minimizing the threshold current density required to initiate self-sustained oscillations. Optimizing the oscillator geometry is of extreme practical importance given that the threshold current densities (GA/m(2)) are close to the breakdown current densities observed in silicon. The equivalent circuit model of the oscillator is used along with the lumped thermal, mechanical, and piezoresistive parameters to calculate the threshold current density of the oscillator. The optimal ratio of the thermal and mechanical time constants is found to be √3 for bulkmode oscillators where the in-plane dimensions control the mechanical resonant frequency. The final frequency of oscillations is obtained as a function of the mechanical resonant frequency, quality factor (Q), and the ratio of the time constants. Results show that scaling the dimension (or frequency) has a weak sub-linear effect on the oscillator performance. Finally, we compare different bulk modes, based on the calculated threshold dc currents for a 1-GHz oscillator.
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http://dx.doi.org/10.1109/TUFFC.2014.006918DOI Listing
August 2015

Diethylstilboestrol (1 mg) in the management of castration-resistant prostate cancer.

Urol Int 2015 21;94(3):307-12. Epub 2014 Oct 21.

Department of Urology, St. James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Objective: To investigate the efficacy of diethylstilboestrol (DES) in patients with advanced prostate cancer refractory to androgen suppression.

Methods: This retrospective study comprises 194 patients with prostate cancer treated with DES (1 mg daily) between 1976 and 2010. Study outcome parameters included demographic data, tumour characteristics, treatment history, prostate-specific antigen (PSA) responses, radiologic studies, adverse events and overall survival.

Results: At initiation of oestrogen therapy the mean patient age was 69 years (range: 48-89) and the median PSA was 96 ng/ml (range: 1.9-9,500). The median duration of prior prostate cancer treatment was 29 months (range: 1-365). DES was the second-line treatment in 58 patients and the third/fourth-line therapy in 136 men. A formal (≥50%) PSA response was observed in 95 patients (48.9%) and the median time to progression (TTP) was 250 days (95% CI, 180-360) for this group. An additional 62 patients (31.9%) had a partial PSA response with a median TTP of 150 days (95% CI, 92-180). Thirty-seven patients (19.1%) did not have a PSA response and the median TTP was 90 days (95% CI, 90-97). The median overall survival from the start of oestrogen therapy for the entire cohort was 576 days (95% CI, 482-690). The median overall survival of patients who had a formal (≥50%), partial (<50%) and no PSA response was 756 (95% CI, 670-1,429), 428 (95% CI, 340-630) and 329 (95% CI, 287-510) days, respectively. Thirty-nine patients (20.1%) were still alive at the end of the study. No treatment-related deaths occurred.

Conclusions: In the age of chemotherapy this study highlights the efficacy of oestrogen therapy in castration-refractory prostate cancer. The optimal point in the therapeutic pathway at which DES should be prescribed remains to be established.
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http://dx.doi.org/10.1159/000365198DOI Listing
April 2016

Histopathological pattern of lymphomas and clinical presentation and outcomes of diffuse large B cell lymphoma: A multicenter registry based study from India.

Indian J Med Paediatr Oncol 2013 Oct;34(4):299-304

Cancer Care Clinic, Nagpur, Maharashtra, India.

Context: The distribution of various subtypes of lymphomas in India is different from other parts of the world. There is scarce multicentric data on the pattern and outcomes of lymphomas in India.

Aims: The aim of this study is to evaluate the histopathological and the clinical pattern and treatment outcomes of lymphomas in India based on the retrospective data collected from a multicenter registry.

Materials And Methods: Retrospective data was collected at 13 public and private hospitals in India for patients diagnosed with lymphoma between January 2005 and December 2009. The data collection was performed in the setting of a multicenter lymphoma registry Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test.

Results: Non-Hodgkin's lymphoma (NHL) constituted 83.17% and Hodgkin's lymphoma (HL) for 16.83% of the 1733 registered and analyzed cases. Diffuse large B cell lymphoma (DLBCL) was the most common NHL (55%) followed by follicular lymphoma (11%). CHOP was the most common chemotherapy regimen administered (84%) while rituximab was used in 42.7% of those with DLBCL. Survival analysis of treatment naïve DLBCL patients (n = 791) was performed. Of these, 29% were lost to follow-up, 20% with active disease. The median follow-up in surviving patients is 31 (range: 1-88) months. Median progression-free survival (PFS) and overall survival (OS) in DLBCL patients has not reached. There was no significant difference in median PFS (69 months vs. 61 months, P = 0.1341), but OS was significant not reached (NR) vs. NR, P = 0.0012) within international prognostic index high or intermediate subgroups. Rituximab use was associated with significantly prolonged PFS (NR vs. 82 months, P = 0.0123), but not OS (NR vs. NR, P = 0.2214). Cox regression analysis in treatment naïve DLBCL patients showed a performatnce status, stage and receipt of six or more cycles of chemotherapy to be significantly associated with OS and all of the preceding plus rituximab use significantly associated with PFS.

Conclusions: Our analysis confirms previous reports of distribution of lymphoma subtypes in India and suggests that patients who are able to receive the full course of chemotherapy achieve a better outcome. This indicates the importance of ensuring compliance to treatment utilizing various measures including patient and family counseling. Prospective studies are required to confirm these findings.
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http://dx.doi.org/10.4103/0971-5851.125250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932599PMC
October 2013

Open-label, multi-center, non-randomized, single-arm study to evaluate the safety and efficacy of dendritic cell immunotherapy in patients with refractory solid malignancies, on supportive care.

Cytotherapy 2014 Feb;16(2):234-44

Department of Medical Oncology and Hematology, Medanta-the Medicity, Gurgaon, India.

Background Aims: A phase II clinical trial of an autologous dendritic cell (DC) formulation for the management of refractory solid malignant tumors was conducted across six sites in India with an objective to study safety and efficacy.

Methods: A total of 51 patients with refractory cancer (either sex) with life expectancy ≥3 months, Eastern Cooperative Oncology Group score ≤2, available tumor tissue and adequate organ and bone marrow function were recruited. Monocytes obtained by leukapheresis, differentiated into DCs by cytokines and primed with autologous tumor lysate (fresh tissue biopsy or paraffin block). On the 8th day, mature DCs were analyzed for expression of CD40, CD80, CD83, CD86, DC205 and DC209. The treatment regime consisted of six doses (intravenous) over 14 weeks with 2 post-treatment follow-up visits, 6 weeks apart. Safety was assessed at all visits and responses were evaluated on days 58, 100 and 184 or at end of the study.

Results: A total of 38 patients were evaluated for safety and efficacy. One adverse event classified as possibly related was an episode of rigors or chills with mild pyrexia during one infusion. Objective response rate by Response Evaluation Criteria In Solid Tumors was 28.9% (11/38) and immune-related response criteria was 42.1% (16/38); 90% confidence interval for objective response rate was (17.2, 43.3) and (28.5, 56.7) by Response Evaluation Criteria In Solid Tumors and immune-related response criteria, respectively. The median time to treatment progression was >9 weeks. Median overall survival was 397 days. An increase in the expression of interferon-γ was not significant.

Conclusions: Therapy was safe. The responses, time to treatment progression and survival are encouraging for patients with aggressive refractory disease.
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http://dx.doi.org/10.1016/j.jcyt.2013.11.013DOI Listing
February 2014

Differences in time to disease progression do not predict for cancer-specific survival in patients receiving immediate or deferred androgen-deprivation therapy for prostate cancer: final results of EORTC randomized trial 30891 with 12 years of follow-up.

Eur Urol 2014 Nov 24;66(5):829-38. Epub 2013 Jul 24.

EORTC Headquarters, Department of Statistics, Brussels, Belgium.

Background: Trials assessing the benefit of immediate androgen-deprivation therapy (ADT) for treating prostate cancer (PCa) have often done so based on differences in detectable prostate-specific antigen (PSA) relapse or metastatic disease rates at a specific time after randomization.

Objective: Based on the long-term results of European Organization for Research and Treatment of Cancer (EORTC) trial 30891, we questioned if differences in time to progression predict for survival differences.

Design, Setting, And Participants: EORTC trial 30891 compared immediate ADT (n=492) with orchiectomy or luteinizing hormone-releasing hormone analog with deferred ADT (n=493) initiated upon symptomatic disease progression or life-threatening complications in randomly assigned T0-4 N0-2 M0 PCa patients.

Outcome Measurements And Statistical Analysis: Time to first objective progression (documented metastases, ureteric obstruction, not PSA rise) and time to objective castration-resistant progressive disease were compared as well as PCa mortality and overall survival.

Results And Limitations: After a median of 12.8 yr, 769 of the 985 patients had died (78%), 269 of PCa (27%). For patients receiving deferred ADT, the overall treatment time was 31% of that for patients on immediate ADT. Deferred ADT was significantly worse than immediate ADT for time to first objective disease progression (p<0.0001; 10-yr progression rates 42% vs 30%). However, time to objective castration-resistant disease after deferred ADT did not differ significantly (p=0.42) from that after immediate ADT. In addition, PCa mortality did not differ significantly, except in patients with aggressive PCa resulting in death within 3-5 yr after diagnosis. Deferred ADT was inferior to immediate ADT in terms of overall survival (hazard ratio: 1.21; 95% confidence interval, 1.05-1.39; p [noninferiority]=0.72, p [difference] = 0.0085).

Conclusions: This study shows that if hormonal manipulation is used at different times during the disease course, differences in time to first disease progression cannot predict differences in disease-specific survival. A deferred ADT policy may substantially reduce the time on treatment, but it is not suitable for patients with rapidly progressing disease.
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http://dx.doi.org/10.1016/j.eururo.2013.07.024DOI Listing
November 2014
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