Safety and Efficacy of Endoscopic Full Thickness Resection of Upper Gastrointestinal Lesions Using a Full Thickness Resection Device: A Systematic Review and Meta-analysis.

INTRODUCTION: Endoscopic full-thickness resection (EFTR) is a promising technique that allows for a minimally invasive resection of mucosal and submucosal lesions in the gastrointestinal (GI) tract. The data regarding the efficacy and safety of performing EFTR of upper GI lesions using a full-thickness resection device (FTRD) is limited. Hence, we performed a systematic review and meta-analysis of the studies that evaluated this technique. METHODS: We performed a comprehensive systematic search of multiple electronic databases and conference proceedings that reported outcomes of EFTR using the FTRD system. The weighted pooled rates of technical success, complete (R0) resection, adverse events (AE), and residual or recurrent lesions were analyzed with 95% CI using the random effects model. RESULTS: Eight studies with a total of 139 patients who underwent EFTR of upper GI lesions were included in the study. The pooled, weighted rate of technical success was 88.2% (95% CI: 81.4-92.7%, I2 : 0). The R0 resection rate was 70.7% (95% CI: 62.5-77.8%, I2 : 0). Overall AE rates were 22.1% (95% CI: 15.8-30.1%, I2 : 0), however, most of the AEs were minor. Of the patients who had follow-up endoscopies, the residual and/or recurrent lesion rate was 6.1% (95% CI: 2.4-14.4%, I2 : 0). Heterogeneity in the analysis was low. CONCLUSIONS: EFTR using the FTRD seems to be effective and safe with acceptable R0 resection rates and low recurrence rates. Further prospective studies are required to validate our results and to compare various modalities of endoscopic resection with this single-step EFTR device.

A Case of McLeod's Syndrome Presenting with Severe Decompensated Heart Failure.

McLeod's syndrome (MLS) is an X-linked disorder caused by mutations in the XK gene with neurological manifestations as well as cardiomyopathy. This is a case of acute exacerbation of heart failure in a 44-year-old White male with a confirmed diagnosis of MLS, which was managed with guideline-directed medical therapy and placement of an implantable cardioverter defibrillator with recovery in ejection fraction.

A dose-finding study to guide use of verapamil as an adjunctive therapy in tuberculosis.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/ml (AUC 0-12h), similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Norverapamil:verapamil, R:S verapamil and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin, suggesting that rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers. Finally, rifampin exposures were significantly greater after verapamil administration. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

Endovascular Management of Spontaneous Subclavian Artery Dissection.

Spontaneous subclavian artery dissection (SCAD) is a rare clinical observation with very few cases reported in the medical literature. We describe a rare case of a 50-year-old female patient who presented with symptoms of critical limb ischemia of the right upper extremity. A digital subtraction angiogram (DSA) revealed a dissection in the proximal course of the subclavian artery (SCA). Prompt recanalization with endovascular therapy produced an excellent result.

Corroborating various material-sparing techniques with hot melt extrusion for the preparation of triclabendazole amorphous solid dispersions.

Amorphous solid dispersions (ASD) are one of the most adopted technologies for improving the solubility of novel molecules. Formulation of ASDs using solvent free methods such as hot melt extrusion (HME) has been in the spotlight off-lately. However, early-stage formulation development is tricky and a difficult bridge to pass due to limited drug availability. Material-sparing techniques (theoretical & practical) have been used for selecting suitable polymeric carriers for formulating ASDs. However, these techniques have limitations in predicting the effect of process parameters. The objective of this study is to use both theoretical and practical material-sparing techniques to optimize a polymer for the developing Triclabendazole (TBZ) ASDs. Initial screening by theoretical approaches suggested that TBZ is highly miscible with Kollidon®VA64 (VA64) and poorly miscible with Parteck®MXP (PVA). However, results from ASDs prepared using SCFe were opposite to these predictions. ASDs prepared using either technique and both VA64 and PVA showed >200x increase in solubility. Each formulation released >85% of drug in less than 15 mins. Although the thermodynamic phase diagram suggested that VA64 was the ideal polymer for TBZ-ASDs, it has certain limitations in factoring the different elements during melt-processing and hence, practical approaches like SCFe could help in predicting the drug-polymer miscibility for HME processing.

Targeted Radiation and Immune Therapies-Advances and Opportunities for the Treatment of Prostate Cancer.

Prostate cancer is the most diagnosed malignancy in men in the United States and the second leading cause of cancer-related death. For localized disease, radiation therapy is a standard treatment that is often curative. For metastatic disease, radiation therapy has been primarily used for palliation, however, several newer systemic radiation therapies have been demonstrated to significantly improve patient outcomes and improve survival. In particular, several targeted radionuclide therapies have been approved for the treatment of advanced-stage cancer, including strontium-89, samarium-153, and radium-223 for bone-metastatic disease, and lutetium-177-labeled PSMA-617 for patients with prostate-specific membrane antigen (PSMA)-expressing metastatic castration-resistant prostate cancer (mCRPC). Contrarily, immune-based treatments have generally demonstrated little activity in advanced prostate cancer, with the exception of the autologous cellular vaccine, sipuleucel-T. This has been attributed to the presence of an immune-suppressive prostate cancer microenvironment. The ability of radiation therapy to not only eradicate tumor cells but also potentially other immune-regulatory cells within the tumor immune microenvironment suggests that targeted radionuclide therapies may be well poised to combine with immune-targeted therapies to eliminate prostate cancer metastases more effectively. This review provides an overview of the recent advances of targeted radiation agents currently approved for prostate cancer, and those being investigated in combination with immunotherapy, and discusses the challenges as well as the opportunities in this field.

Role of B cells as antigen presenting cells.

B cells have been long studied for their role and function in the humoral immune system. Apart from generating antibodies and an antibody-mediated memory response against pathogens, B cells are also capable of generating cell-mediated immunity. It has been demonstrated by several groups that B cells can activate antigen-specific CD4 and CD8 T cells, and can have regulatory and cytotoxic effects. The function of B cells as professional antigen presenting cells (APCs) to activate T cells has been largely understudied. This, however, requires attention as several recent reports have demonstrated the importance of B cells within the tumor microenvironment, and B cells are increasingly being evaluated as cellular therapies. Antigen presentation through B cells can be through antigen-specific (B cell receptor (BCR) dependent) or antigen non-specific (BCR independent) mechanisms and can be modulated by a variety of intrinsic and external factors. This review will discuss the pathways and mechanisms by which B cells present antigens, and how B cells differ from other professional APCs.

Antitumor efficacy of 90Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors.

BACKGROUND: Systemic radiation treatments that preferentially irradiate cancer cells over normal tissue, known as targeted radionuclide therapy (TRT), have shown significant potential for treating metastatic prostate cancer. Preclinical studies have demonstrated the ability of external beam radiation therapy (EBRT) to sensitize tumors to T cell checkpoint blockade. Combining TRT approaches with immunotherapy may be more feasible than combining with EBRT to treat widely metastatic disease, however the effects of TRT on the prostate tumor microenvironment alone and in combinfation with checkpoint blockade have not yet been studied. METHODS: C57BL/6 mice-bearing TRAMP-C1 tumors and FVB/NJ mice-bearing Myc-CaP tumors were treated with a single intravenous administration of either low-dose or high-dose 90Y-NM600 TRT, and with or without anti-PD-1 therapy. Groups of mice were followed for tumor growth while others were used for tissue collection and immunophenotyping of the tumors via flow cytometry. RESULTS: 90Y-NM600 TRT was safe at doses that elicited a moderate antitumor response. TRT had multiple effects on the tumor microenvironment including increasing CD8 +T cell infiltration, increasing checkpoint molecule expression on CD8 +T cells, and increasing PD-L1 expression on myeloid cells. However, PD-1 blockade with TRT treatment did not improve antitumor efficacy. Tregs remained functional up to 1 week following TRT, but CD8 +T cells were not, and the suppressive function of Tregs increased when anti-PD-1 was present in in vitro studies. The combination of anti-PD-1 and TRT was only effective in vivo when Tregs were depleted. CONCLUSIONS: Our data suggest that the combination of 90Y-NM600 TRT and PD-1 blockade therapy is ineffective in these prostate cancer models due to the activating effect of anti-PD-1 on Tregs. This finding underscores the importance of thorough understanding of the effects of TRT and immunotherapy combinations on the tumor immune microenvironment prior to clinical investigation.

Mebendazole plus lomustine or temozolomide in patients with recurrent glioblastoma: A randomised open-label phase II trial.

Background: Recurrent glioblastoma (GBM) has dismal outcomes and limited treatment options. Mebendazole (MBZ) has activity in glioma both in-vivo and in-vitro, and is well tolerated in combination with lomustine (CCNU) and temozolomide (TMZ). In this study, we sought to determine whether the addition of MBZ to CCNU or TMZ would improve overall survival (OS) in recurrent GBM. Methods: In this phase II randomized open-label trial, adult patients with ECOG PS 0-3, with recurrent GBM who were not eligible for re-radiation, were randomized 1:1 to the CCNU-MBZ and TMZ-MBZ arms. CCNU was administered at 110 mg/m2 every 6 weeks with MBZ 800 mg thrice daily and TMZ was administered at 200 mg/m2 once daily on days 1-5 of a 28 days cycle with MBZ 1600 mg thrice daily. The primary endpoint was OS at 9 months. A 9-month OS of 55% or more in any arm was hypothesized to warrant further evaluation and a value below 35% was too low to warrant further investigation. OS was analyzed using intention to treat (ITT) and per-protocol (PP) analyses. Per-protocol analysis was used for safety analysis. Clinical Trials Registry-India number, CTRI/2018/01/011542. Findings: Participants were recruited from 14th March 2019 to 18th June 2021, 44 patients were randomised on each arm. At 17.4 months, 68 events for OS analysis had occurred, 33 in the TMZ-MBZ and 35 in the CCNU-MBZ arm. The 9-month OS was 36.6% (95% CI 22.3-51.0) and 45% (95% CI 29.6-59.2) in the TMZ-MBZ and CCNU-MBZ arms respectively, in the ITT population. ECOG PS was the only independent prognostic factor impacting OS (HR-0.48, 95% CI 0.27-0.85; P = 0.012). Grade 3-5 adverse events were seen in 8 (18.6%; n = 43) and 4 (9.5%; n = 42) patients in the TMZ-MBZ and CCNU-MBZ arms respectively. There were no treatment related deaths. Interpretation: The addition of MBZ to TMZ or CCNU failed to achieve the pre-set benchmark of 55% 9-month OS. This was probably due to 28.6% of patients having poor PS of 2-3. Funding: Brain Tumor Foundation (BTF) of India, Indian Cooperative Oncology Network (ICON), and India Cancer Research Consortium (ICRC) under ICMR (Indian Council of Medical Research).

GM-CSF elicits antibodies to tumor-associated proteins when used as a prostate cancer vaccine adjuvant.

Antibody responses to off-target cancer-associated proteins have been detected following immunotherapies for cancer, suggesting these may be the result of antigen spread. We have previously reported that serum antibodies to prostate cancer-associated proteins were detectable using a high-throughput peptide array. We hypothesized that the breadth of antibody responses elicited by a vaccine could serve as a measure of the magnitude of its induced antigen spread. Consequently, sera from patients with prostate cancer, treated prior to or after vaccination in one of four separate clinical trials, were evaluated for antibody responses to an array of 177,604 peptides derived from over 1600 prostate cancer-associated gene products. Antibody responses to the same group of 5680 peptides previously reported were identified following vaccinations in which patients were administered GM-CSF as an adjuvant, but not with vaccine in the absence of GM-CSF. Hence, antibody responses to off-target proteins following vaccination may not necessarily serve as evidence of antigen spread and must be interpreted with particular caution following vaccine strategies that use GM-CSF, as GM-CSF appears to have direct effects on the production of antibodies. The evaluation of T cell responses to non-target antigens is likely a preferred approach for detection of immune-mediated antigen spread.

Material-Sparing Approach using Differential Scanning Calorimeter and Response Surface Methodology for Process Optimization of Hot-Melt Extrusion.

The objective of the present investigations was to demonstrate the applicability of DSC combined with response surface methodology as a material-sparing tool for determination of the processing conditions for HME during initial stages of development. Mefenamic acid (MFA) and Eudragit EPO (EPO) were used as a model drug and the polymeric carrier, respectively. Initial screening was performed using film-casting, polarized light microscopy, and TGA analysis to determine the levels for the experimental design. A Box-Behnken design was used to study the effect of the independent parameters, viz. drug loading, heating rate, and processing temperature, on the dependent parameters, viz. residual crystallinity and drug degradation. The results showed a quadratic relationship between independent and dependent parameters. Based on the design space, MFA-EPO dispersions with 20% drug loading were prepared using HME and vacuum compression molding (VCM). Both the HME and VCM samples did not show any signs of residual crystallinity. However, degradation of MFA was observed in VCM sample and the HME filaments processed at 100 rpm, but not at 150 rpm. The results demonstrate that DSC has potential to be a material-sparing tool to optimize drug loading and processing temperature for HME and will help product development using HME cost-effective.

Submucosal gastric heterotopia presenting as an upper esophageal nodule.

Esophageal gastric heterotopia (GH), the presence of differentiated gastric tissue in the esophagus, is estimated in up to 14% of populations worldwide and has always been reported on the surface of the esophagus, where it is also known as inlet patch. However, submucosal GH, in any tissue, is a rare finding. We report the case of a 50 year-old male presenting with chronic cough, heartburn and raspy vocalizations. Endoscopic examination showed a single 7 mm esophageal nodule, 20 cm from the incisors, interpreted as a submucosal mass. Pathologic examination of the endoscopically excised nodule showed well-differentiated gastric mucosa within the submucosa underneath the overlying squamous mucosa, consistent with submucosal GH. This case raises the awareness of an atypical presentation and location of GH seen as a submucosal mass on endoscopy.

Quantitative conversion of biomass in giant DNA virus infection.

Bioconversion of organic materials is the foundation of many applications in chemical engineering, microbiology and biochemistry. Herein, we introduce a new methodology to quantitatively determine conversion of biomass in viral infections while simultaneously imaging morphological changes of the host cell. As proof of concept, the viral replication of an unidentified giant DNA virus and the cellular response of an amoebal host are studied using soft X-ray microscopy, titration dilution measurements and thermal gravimetric analysis. We find that virions produced inside the cell are visible from 18 h post infection and their numbers increase gradually to a burst size of 280-660 virions. Due to the large size of the virion and its strong X-ray absorption contrast, we estimate that the burst size corresponds to a conversion of 6-12% of carbonaceous biomass from amoebal host to virus. The occurrence of virion production correlates with the appearance of a possible viral factory and morphological changes in the phagosomes and contractile vacuole complex of the amoeba, whereas the nucleus and nucleolus appear unaffected throughout most of the replication cycle.

Application of Thermodynamic Phase Diagrams and Gibbs Free Energy of Mixing for Screening of Polymers for Their Use in Amorphous Solid Dispersion Formulation of a Non-Glass-Forming Drug.

The objective of the present investigations was to assess the use of thermodynamic phase diagrams and the Gibbs free energy of mixing, ΔGmix, for the screening of the polymeric carriers by determining the ideal drug-loading for an amorphous solid dispersion formulation and optimum processing temperature for the hot-melt extrusion of a non-glass-forming drug. Mefenamic acid (MFA) was used as a model non-glass-forming drug and four chemically distinct polymers with close values of the solubility parameters, viz. Kollidon® VA64, Soluplus®, Pluronic® F68, and Eudragit® EPO, were used as carriers. The thermodynamic phase diagrams were constructed using the melting point depression data, Flory-Huggins theory, and Gordan-Taylor equation. The Gibbs free energy of mixing was estimated using the values of the drug-polymer interaction parameter, χ, and Flory-Huggins theory. The rank order miscibility of MFA in the four polymeric carriers estimated based on the difference in the values of their solubility parameters, Δδ, did not correlate well with the thermodynamic phase diagrams and Gibbs free energy plots. The study highlights the limitation of using the solubility parameter method in screening the polymeric carriers for poorly glass-forming drugs and reiterates the applicability of thermodynamic phase diagrams and Gibbs free energy plots in determining the ideal drug-loading and optimum processing temperature for hot-melt extrusion.

A Comprehensive Review on Pellets as a Dosage Form in Pharmaceuticals.

Oral route of administration is widely accepted and desired because of its versatility, convenience, and, most importantly, patient compliance. Multiparticulate systems like granules and pellets are more advantageous when compared to single-unit dosage forms, as they are capable of distributing the drug more evenly in the gastrointestinal tract. The current paper focuses on pellets, the merits and demerits associated, various pelletization techniques, and their characterization. It also focuses on how pellets can be employed for drug delivery is controlled and sustained release formulations. It gives a complete emphasis on the drug and excipients that can be used in pellet formation, the marketed formulations, and the research pertaining to pellets.

Theranostic Nanoparticles for Pancreatic Cancer Treatment.

Pancreatic cancer is one of the low vascular permeable tumors with a high mortality rate. The five-year survival period is ~5%. The field of drug delivery is at its pace in developing unique drug delivery carriers to treat high mortality rate cancers such as pancreatic cancer. Theranostic nanoparticles are the new novel delivery carriers where the carrier is loaded with both diagnostic and therapeutic agents. The present review discusses various therapeutic and theranostic nanocarriers for pancreatic cancer.

Process optimization of twin-screw melt granulation of fenofibrate using design of experiment (DoE).

The purpose of this study was to optimize the melt granulation process of fenofibrate using twin-screw granulator. Initial screening was performed to select the excipients required for melt granulation process. A 3 × 3 factorial design was used to optimize the processing conditions using the % drug loading (X1) and screw speed (X2) as the independent parameters and granule friability (Y1) % yield (Y2) as the dependent parameters. The effect of the independent parameters on the dependent parameters was determined using response surface plots and contour plots. A linear relationship was observed between % drug loading (X1) and % friability (Y1) and a quadratic relationship was observed between the independent parameters (X1 and X2) and % yield (Y2). The processing conditions for optimum granules were determined using numerical and graphical optimization and it was found that 15% drug loading at 50 rpm results in maximum % yield of 82.38% and minimum friability of 7.88%. The solid-state characterization of the optimized granules showed that the drug turned from crystalline state to amorphous state during melt granulation process. The optimized granules were compressed into tablets using Purolite® as the super disintegrating agent. The optimized formulation showed >85% drug release in 0.75% SLS solution within 60 min.

Antibody profiling of patients with prostate cancer reveals differences in antibody signatures among disease stages.

BACKGROUND: Previous studies of prostate cancer autoantibodies have largely focused on diagnostic applications. So far, there have been no reports attempting to more comprehensively profile the landscape of prostate cancer-associated antibodies. Specifically, it is unknown whether the quantity of antibodies or the types of proteins recognized change with disease progression. METHODS: A peptide microarray spanning the amino acid sequences of the gene products of 1611 prostate cancer-associated genes was synthesized. Serum samples from healthy male volunteers (n=15) and patients with prostate cancer (n=85) were used to probe the array. These samples included patients with various clinical stages of disease: newly diagnosed localized prostate cancer (n=15), castration-sensitive non-metastatic prostate cancer (nmCSPC, n=40), castration-resistant non-metastatic prostate cancer (n=15) and castration-resistant metastatic disease (n=15). The patients with nmCSPC received treatment with either standard androgen deprivation therapy (ADT) or an antitumor DNA vaccine encoding prostatic acid phosphatase. Serial sera samples from these individuals were also used to probe the array, to secondarily determine whether this approach could be used to detect treatment-related changes. RESULTS: We demonstrated that this peptide array yielded highly reproducible measurements of serum IgG levels. We found that the overall number of antibody responses did not increase with disease burden. However, the composition of recognized proteins shifted with clinical stage of disease. Our analysis revealed that the largest difference was between patients with castration-sensitive and castration-resistant disease. Patients with castration-resistant disease recognized more proteins associated with nucleic acid binding and gene regulation compared with men in other groups. Our longitudinal data showed that treatments can elicit antibodies detectable by this array, and notably vaccine-treated patients developed increased responses to more proteins over the course of treatment than did ADT-treated patients. CONCLUSIONS: This study represents the largest survey of prostate cancer-associated antibodies to date. We have been able to characterize the classes of proteins recognized by patients and determine how they change with disease burden. Our findings further demonstrate the potential of this platform for measuring antigen spread and studying responses to immunomodulatory therapies.

Is Idiopathic Hirsutism Truly Idiopathic?

OBJECTIVE: To determine whether other androgens [androstenedione (A4), 17-hydroxy progesterone (17OHP) and dehydroepiandrosterone (DHEA)] were elevated in women with classically defined idiopathic hirsutism (IH)/patient-important hirsutism (PIH). STUDY DESIGN: Retrospective analysis. SETTING: Outpatient endocrine department of a tertiary care hospital. PATIENTS: In total, 30 consecutive women with IH/PIH were included. IH/PIH was defined as presentation with hirsutism with normal menstrual cycles (25-35 days), normal total (< 45 ng/dL) and free T (fT) (< 0.6 ng/dL) and normal ovaries sonologically (transabdominal ultrasonogram ovarian volume < 10 cm3) without any other signs of virilization. Clinical and biochemical details were collected and analyzed. Androgens were measured by LC-MS/MS. A4 ≥ 2.5 ng/mL, DHEA ≥ 15 (age < 18) or ≥ 11.8 (age ≥ 18) ng/mL, DHEAS ≥ 2847 ng/mL or 17OHP ≥ 2 ng/mL were considered high. RESULTS: With the mean age of 22 years and mean BMI of 25 kg/m2, 12/30 (40%) had IH and remaining PIH. DHEA alone was elevated in 60% and A4 alone in 33%. Overall, 23/30 (73%) had any one elevated androgen with normal total and free testosterone. There was no correlation with modified Ferriman-Gallwey score, and there was no significant difference in androgens between IH and PIH. CONCLUSION: A high proportion of women with classically defined IH/PIH have elevated DHEA and/or A4. Though on pharmacotherapy basis, there would be no change in management, the role of hyperandrogenemia detected by sensitive assays on metabolic functions and cardiovascular risk has to be studied.

Treatment Combinations with DNA Vaccines for the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC).

Metastatic castration-resistant prostate cancer (mCRPC) is a challenging disease to treat, with poor outcomes for patients. One antitumor vaccine, sipuleucel-T, has been approved as a treatment for mCRPC. DNA vaccines are another form of immunotherapy under investigation. DNA immunizations elicit antigen-specific T cells that cause tumor cell lysis, which should translate to meaningful clinical responses. They are easily amenable to design alterations, scalable for large-scale manufacturing, and thermo-stable for easy transport and distribution. Hence, they offer advantages over other vaccine formulations. However, clinical trials with DNA vaccines as a monotherapy have shown only modest clinical effects against tumors. Standard therapies for CRPC including androgen-targeted therapies, radiation therapy and chemotherapy all have immunomodulatory effects, which combined with immunotherapies such as DNA vaccines, could potentially improve treatment. In addition, many investigational drugs are being developed which can augment antitumor immunity, and together with DNA vaccines can further enhance antitumor responses in preclinical models. We reviewed the literature available prior to July 2020 exploring the use of DNA vaccines in the treatment of prostate cancer. We also examined various approved and experimental therapies that could be combined with DNA vaccines to potentially improve their antitumor efficacy as treatments for mCRPC.