Efficient 3D Molecular Design with an E(3) Invariant Transformer VAE.

This work introduces a three-dimensional (3D) invariant graph-to-string transformer variational autoencoders (VAE) (Vagrant) for generating molecules with accurate density functional theory (DFT)-level properties. Vagrant learns to model the joint probability distribution of a 3D molecular structure and its properties by encoding molecular structures into a 3D-aware latent space. Directed navigation through this latent space implicitly optimizes the 3D structure of a molecule, and the latent embedding can be used to condition a generative transformer to predict the candidate structure as a one-dimensional (1D) sequence. Additionally, we introduce two novel sampling methods that exploit the latent characteristics of a VAE to improve performance. We show that our method outperforms comparable 3D autoregressive and diffusion methods for predicting quantum chemical property values of novel molecules in terms of both sample quality and computational efficiency.

Fixed dose combination of capecitabine and cyclophosphamide in metastatic breast cancer: Results from THE ENCLOSE phase 2/3 randomized multicenter study.

AIM: To evaluate pharmacokinetics, efficacy and safety of fixed-dose combination (FDC) of oral capecitabine + cyclophosphamide in metastatic breast cancer (MBC) patients progressing after anthracycline and/or taxane chemotherapy. METHODS: In this prospective, adaptive, phase-2/3, open-label study (CTRI/2014/12/005234), patients were randomized (1:1:1) to three FDC doses (doses/day: D1, capecitabine + cyclophosphamide 1400 mg + 60 mg; D2, 1800 mg + 80 mg; D3, 2200 mg + 100 mg) for 14 days, in 21-day cycles. In Part-I, multiple-dose pharmacokinetics and optimal dose(s) were evaluated with futility analysis. Group(s) with <3 responders based on best overall response rate (BOR, complete response [CR]+partial response [PR]), were discontinued. Efficacy (BOR, disease control rates [DCR; CR + PR + stable disease]) and safety of optimal dose(s) were evaluated in Part-II. RESULTS: Of 66 patients (n = 22/group) in Part-I, pharmacokinetics (D1 = 7/22, D2 = 9/22, D3 = 8/22) showed dose-proportionality for cyclophosphamide and greater than dose-proportionality for capecitabine. Modified intent-to-treat (mITT) analysis showed BOR of 7.14% (1/14) in D1 (discontinued), and 22.22% (4/18) each in D2 and D3, respectively. In Part-II, 50 additional patients were randomized in D2 and D3 (n = 144; total 72 [22 + 50] patients/group). mITT analysis in D2 (n = 54) and D3 (n = 58) showed BOR of 29.63% (16/54, 95%CI: 17.45-41.81%) and 22.41% (13/58, 95%CI: 11.68-33.15%), respectively. DCR in D2 and D3 were 87.04% (47/54, 95%CI: 78.08-96.00%) and 82.76% (48/58; 95%CI: 73.04-92.48%) after 3 and 57.41% (31/54; 95%CI: 52.41-79.50%) and 50.00% (29/58; 95%CI: 40.40-67.00%), after 6-cycles, respectively. Hand-foot syndrome (16.67%), vomiting (9.72%) in D2, and hand-foot syndrome (18.06%), asthenia (15.28%) in D3 were most-common adverse events. CONCLUSION: FDC of capecitabine + cyclophosphamide (1800 + 80 mg/day) showed high disease control rates and good safety profile in MBC patients.

Attention-based generative models for de novo molecular design.

Attention mechanisms have led to many breakthroughs in sequential data modeling but have yet to be incorporated into any generative algorithms for molecular design. Here we explore the impact of adding self-attention layers to generative ß-VAE models and show that those with attention are able to learn a complex "molecular grammar" while improving performance on downstream tasks such as accurately sampling from the latent space ("model memory") or exploring novel chemistries not present in the training data. There is a notable relationship between a model's architecture, the structure of its latent memory and its performance during inference. We demonstrate that there is an unavoidable tradeoff between model exploration and validity that is a function of the complexity of the latent memory. However, novel sampling schemes may be used that optimize this tradeoff. We anticipate that attention will play an important role in future molecular design algorithms that can make efficient use of the detailed molecular substructures learned by the transformer.

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

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/m2; 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.

Biweekly DoceAqualip in mCRPC patients beyond 20 cycles: A case series.

INTRODUCTION: Docetaxel 75 mg/m2 every 3 weeks for up to 10 cycles is an accepted standard regimen in metastatic castration-resistant prostate cancer (mCRPC). We report our experience with >20 cycles of biweekly nanosomal docetaxel lipid suspension (NDLS) treatment in patients with mCRPC. CASE REPORTS: Cases with long-term treatment of NDLS treatment in mCRPC patients were identified from the medical records of Jawaharlal Nehru Cancer Hospital & Research Centre Bhopal, India. A total of three cases with >20 cycles of NDLS are presented here. MANAGEMENT AND OUTCOMES: Overall, the 3 patients received biweekly NDLS at a dose of 45 mg/m2 for 22, 36, and 40 cycles, respectively, except for one patient where NDLS was initiated at 50 mg/m2 and later reduced to 45 mg/m2. All the 3 patients reported prostate-specific antigen (PSA) response (>50% decline in PSA levels from baseline). The time to treatment failure (TTF) was 14.8, 18.2, and 20.6 months in these 3 patients, respectively. PSA nadir occurred after 14, 6 and 13 cycles, respectively. The OS was 21.6, 22.2 and 25.8 months, respectively. Anemia, lymphopenia, and neutropenia were the most common adverse events. NDLS treatment was overall well-tolerated without any new safety concerns. CONCLUSIONS: Biweekly NDLS for >20 cycles was effective and well-tolerated in patients with mCRPC. NDLS can potentially be used for long-term management, which may be a requirement for most patients with mCRPC.

Data Science in Chemical Engineering: Applications to Molecular Science.

Chemical engineering is being rapidly transformed by the tools of data science. On the horizon, artificial intelligence (AI) applications will impact a huge swath of our work, ranging from the discovery and design of new molecules to operations and manufacturing and many areas in between. Early adoption of data science, machine learning, and early examples of AI in chemical engineering has been rich with examples of molecular data science-the application tools for molecular discovery and property optimization at the atomic scale. We summarize key advances in this nascent subfield while introducing molecular data science for a broad chemical engineering readership. We introduce the field through the concept of a molecular data science life cycle and discuss relevant aspects of five distinct phases of this process: creation of curated data sets, molecular representations, data-driven property prediction, generation of new molecules, and feasibility and synthesizability considerations.

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

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/m2) or 3-weekly regimens (75 mg/m2). 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.

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

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.

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

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/m2; 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.

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

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/m2; 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).

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

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/m2 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.

Nanosomal docetaxel lipid suspension based chemotherapy in a pregnant MBC patient - a case report.

The current report presents a case of a pregnant woman with breast cancer metastasized to liver and lungs. The standard of care for breast cancer in pregnancy is anthracycline/taxane-based chemotherapy regimens. Docetaxel has shown a favorable toxicity profile during the second and third trimesters of pregnancy. A novel nanosomal docetaxel lipid suspension (NDLS) (DoceAqualip), with a proven efficacy and tolerability profile, has been approved in India for the treatment of advanced solid tumors since 2013. We present here a case of a pregnant woman with metastatic breast cancer managed with NDLS based TAC regimen showing a partial response after six cycles. The patient delivered a healthy male child with normal Apgar score and weight at the 32nd week of gestation.

Novel formulations of docetaxel, paclitaxel and doxorubicin in the management of metastatic breast cancer.

The management of breast cancer with advanced disease or metastasis is a common problem in India and other countries. A panel of 13 oncology experts deliberated on the sidelines of the 35th Indian Cooperative Oncology Network Conference held in Mumbai to formulate an expert opinion recommendation on the novel drug delivery system (NDDS) formulations in the treatment of metastatic breast cancer (MBC). The survey comprised of 39 questions related to limitations of conventional formulations and therapeutic positioning of NDDS formulations of docetaxel, paclitaxel and doxorubicin in the management of MBC. The experts used data from published literature and their practical experience to provide expert opinion and recommendations for use by the community oncologists. The experts opined that the newer NDDS formulations should provide a significant efficacy advantage in terms of overall survival and progression-free survival, or demonstrate better tolerability when compared with conventional formulations. The newer NDDS formulations of taxanes should be considered in special circumstances such as diabetes, in patients who have had hypersensitivity reactions and in cases where steroids need to be avoided. The novel formulations of doxorubicin should be used in the elderly and in patients with borderline cardiac function.