von Willebrand disease: A guide for the internist.

von Willebrand disease (VWD), the most common inherited bleeding disorder, results when patients either do not make enough von Willebrand factor (VWF) or make defective VWF. The pathophysiology of this disorder is complex but needs to be understood to interpret the diagnostic tests. Most patients have mild to moderate symptoms and can be adequately counseled and managed by a general internist, but some need to consult a hematologist. We review the pathophysiology of VWD, its subtypes, common presentations of each subtype, diagnostic testing, and management of mild as well as severe clinical manifestations of VWD.

Sensitising natural wool with green and brown coffee using a facile extraction method to optimise dye process parameters.

Green coffee powder is the raw powder of coffee cherries and all coffee's potential components are held within this green powder. A new natural colourant was extracted from Green Coffee using water as an extractant. To obtain a green-colored solution, a specific amount of green coffee was mixed with distilled water and left for 24 h at room temperature. Furthermore, the colouring performance of extracted colour has been studied using the conventional exhaust dyeing method on wool fabric. Different parameters viz. concentration of Green coffee powder, the temperature of the dye bath, the period for immersion, and solution pH were made to set to obtain a fine tone of green colour. The dyeing parameters (amount of the coffee: 2 g, 100 °C, 70 min & 6.7 pH) were optimised and selected to draw a comparison with the conventional Brown coffee powder. In experiments on wool, this potential solution of Green coffee offered rich green hues with good tonal variation. In addition, the colour fastness to washing was found superior in the case of both Green and Brown coffee and colour fastness to light, rubbing as well as perspiration also showed good performance. In this study, our main focus was to obtain the true and fast green tone of the fabric using Green Coffee and compare it with brown coffee using the same conditions used for dyeing with green coffee. The application of these dyes as natural dyes results in obtaining innovative natural fast colour with remarkable dyeing properties and a new inclusion to the existing commercial spectra of natural dyes.

Targeting aromatase to restrain oestrogen production and developing efficacious interventions against ER-positive cancer.

Being the most frequently diagnosed disease, breast cancer is mainly classified as ER+ cancers due to the detection of estrogen receptor (ER) expression. Irrespetive of the successes achieved in the treatment of ER+ cancers by the use of selective estrogen receptor modulator (SERM) drugs like tamoxifen, resistance to the drug is a major clinical obstacle. Working on alternative treatment approaches, here, on the basis of mode of action of aromatase for the conversion of androstenedione to oestrogen, a series of compounds was developed. Results of all the experiments performed with these compounds led to the identification of three highly potent compounds 5d, 5e and 7d with their IC50 61.0, 83.0 and 54.0 nM for aromatase. Indicating their effectiveness in the treatment of ER+ cancers, appreciable tumor growth inhibitory activities of these compounds were observed against breast cancer cell lines. Further, the physico-chemical experiments including plasma protein binding, HSA binding, kinetic studies, solubility, ADME properties and molecular modelling studies supported the drug like features of the compounds.

Improved survival for stage IV sinonasal small cell neuroendocrine carcinoma treated with chemotherapy and anti-PD-L1 therapy.

Small cell carcinoma neuroendocrine type (SCCNET) is a rare tumour of the head and neck. Due to its infrequency, a paucity of data exists on optimal treatment, and the current paradigm for advanced SCCNET mirrors that of extensive small cell lung cancer. Increasingly, the treatment for extrapulmonary small cell carcinomas like SCCNET has incorporated immune checkpoint inhibitors (ICIs), although the utility of ICIs is not fully understood. We present a case of stage IVC sinonasal SCCNET in a woman in her 90s, who experienced eyelid swelling and unintentional weight loss. After diagnostic work-up, she was treated with etoposide, carboplatin and atezolizumab with a complete response to therapy. The patient had one episode of inflammatory polyarthropathy which resolved with steroids but otherwise tolerated treatment well and is now living with an overall survival of greater than 27 months. This case highlights the long-term efficacy of combination ICIs and chemotherapy in the treatment of SCCNET.

Biomass-Derived Core-Shell Carbon Dots with Embedded Tripodal Receptors for the Selective Recognition of Mefenamic Acid in Pharmaceutical Formulations and Urine.

A tripodal amine (TPA) with -OH, N, and S donors is synthesized to functionalize a core-shell carbon dot composite (FCDs@SiO2-TPA) for sensing application. The TPA is characterized by spectroscopic and spectrometric techniques, and the composite is characterized by Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), Brunauer-Emmett-Teller (BET), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and energy-dispersive X-ray spectra (EDS) techniques. The composite has the ability to recognize mefenamic acid (MFA) selectively even in the presence of other drugs like ibuprofen sodium, acetylsalicylic acid, naproxen sodium, diclofenac sodium, and ketoprofen. It can also be used for the quantification of MFA by recording the emission quenching response of the sample at λexc. = 350 nm and λems. = 460 nm (linear range = 1-8 µM and LOD = 197 nM). The density functional theory calculations and 1H NMR titration suggest quenching of the emission signal due to photoinduced electron transfer via hydrogen bonding between the probe and MFA. The composite FCDs@SiO2-TPA has been demonstrated as a reliable and cost-effective sensing probe for the detection of MFA in pharmaceutical formulations, water samples, and cow urine samples.

Diagnosis and management of gastrointestinal SMARCA4-deficient undifferentiated tumors.

SMARCA4-deficient undifferentiated tumors are a rare clinical entity with an aggressive clinical course, poor prognosis, and no standard-of-care therapeutic approach. These have most frequently been documented in the lung and thoracic cavity. There is a growing body of evidence for the role of immunotherapy in SMARCA4-deficient lung cancer, a disease process that historically does very poorly with cytotoxic chemotherapy alone. We present three cases where the primary tumors were instead found within the gastrointestinal system: two originating from the small bowel and one from the esophagus. In all three cases, clinical response was seen with pembrolizumab therapy, with two of the three patients receiving long-term benefit. Our series suggests that anti-PD1 immunotherapy may have promising efficacy for undifferentiated carcinomas of the gastrointestinal tract with SMARCA4 deficiency.

Systemic Therapy for Melanoma: ASCO Guideline Update.

PURPOSE: To provide guidance to clinicians regarding the use of systemic therapy for melanoma. METHODS: American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature. RESULTS: The updated review identified 21 additional randomized trials. UPDATED RECOMMENDATIONS: Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti-PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF-mutated disease after progression on other therapies.This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update.Additional information is available at www.asco.org/melanoma-guidelines.

Systemic therapy for melanoma: ASCO guideline update

To provide guidance to clinicians regarding the use of systemic therapy for melanoma. American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature. The updated review identified 21 additional randomized trials. Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti­PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF-mutated disease after progression on other therapies. This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update. Additional information is available at www.asco.org/melanoma-guidelines

A Review of Sensing Applications of Molecularly Imprinted Fluorescent Carbon Dots for Food and Biological Sample Analysis.

Molecularly imprinted fluorescent carbon dots (MI-FCDs) find numerous applications in analytical chemistry due to their outstanding photoluminescent properties and having specific pockets for the recognition of target molecules. Despite significant advances, practical applications of MI-FCDs-based fluorescent sensors are still in their initial stages. Therefore, the topical developments in the synthesis, working, and application of MI-FCDs for sensing various target species (e.g., pharmaceuticals, biomolecules, pesticides, food additives, and miscellaneous species) in food and biological media have been highlighted. Moreover, a careful evaluation has been made to select the best methods based on their performance in terms of analytical parameters. To expand the horizons of this field, important challenges and future directions for developing MI-FCDs for practical use are also presented. This review will highlight important aspects of MI-FCDs-based fluorescent sensors for their applicability in food science, material science, environmental science, nanoscience, and biotechnology.

Selective quantification of diclofenac from groundwater and pharmaceutical samples by magnetic molecularly imprinted polymer-based sorbent coupled with the HPLC-PDA detection.

Diclofenac (DCF) is a pharmaceutical contaminant of water bodies and therefore, improvement of analytical techniques for its removal and quantitation is one of the current interests of analysts. Herein, DCF selective magnetic molecularly imprinted polymer (MMIP) has been fabricated and characterized by Fourier transform-infrared spectroscopy, thermogravimetric analysis, vibrating scanning magnetometer, scanning electron microscopy, high-resolution transmission electron microscope, energy-dispersive X-ray spectroscopy, and Brunauer-Emmett-Teller analyzer. Furthermore, the protocol for the quantification of DCF using MMIP-HPLC-PDA combo has been optimized by investigating the effect of the amount of MMIP, type and volume of eluent, and variation of pH. The optimized protocol suggested a method detection limit of 0.042 ng mL-1 and linearity of results in the range 0.1-100 ng mL-1 (R2 = 0.99). The fabricated material offered recovery of DCF up to 96.38-99.46% from groundwater and pharmaceutical samples with a relative standard deviation of <4%. In addition, the material was found selective and sensitive for DCF among its analogous drugs like mefenamic acid, ketoprofen, fenofibrate, aspirin, ibuprofen, and naproxen.

Synthesis of a trinuclear zinc(II) cluster composed of [4.4.3.01,5]tridecane cages: a rapid detection and degradation probe for the chemical warfare agent simulant diethyl cyanophosphonate in protein-rich food products.

Diethyl cyanophosphonate (DCNP), a simulant of Tabun, is a common pollutant in pharmaceutical waste and poses a high risk to living organisms. Herein, we demonstrate a compartmental ligand-derived trinuclear zinc(II) cluster [Zn3(LH)2(CH3COO)2] as a probe for the selective detection and degradation of DCNP. It consists of two pentacoordinated Zn(II) [4.4.3.01,5]tridecane cages bridged through a hexacoordinated Zn(II) acetate unit. The structure of the cluster has been elucidated by spectrometric, spectroscopic, and single-crystal X-ray diffraction studies. The cluster shows a two-fold increased emission as compared to the compartmental ligand (at λexc = 370 nm and λem = 463 nm) due to the chelation-enhanced fluorescence effect and acts as a turn-off signal in the presence of DCNP. It can detect DCNP at nano levels up to 186 nM (LOD). The direct bond formation between DCNP and Zn(II) via the -CN group degrades it to inorganic phosphates. The mechanism of the interaction and degradation is supported by spectrofluorimetric experiments, NMR titration (1H and 31P), time of flight mass spectrometry and density functional theory calculations. The applicability of the probe has been further tested by the bio-imaging of zebrafish larvae, analysis of high-protein food products (meat and fish) and vapour phase detection by paper strips.

Prognostic significance of extra-nodal extension and positive surgical margins in HPV positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Whether extra-nodal extension (ENE+) and surgical margin positivity (margin+) are poor prognostic factors in HPV-associated (HPV+) oropharyngeal carcinoma (OPC) remains uncertain. RESULTS: Our study evaluated if microscopic ENE+ and/or margin+ are associated poorer recurrence free survival (RFS) and overall survival (OS) in HPV+ OPC. Patients were classified as high risk (ENE+ and/or margin+) or low risk (ENE- and margins-). Of a total of 176 patients HPV+ OPC, 81 underwent primary surgery and dad data on ENE and margin status. There was no statistically significant difference in RFS (p = 0.35) or OS (p = 0.13) for high-risk versus low-risk groups. Ongoing smoking (p = 0.023), alcohol use (p = 0.044) and advanced stage (p = 0.019) were associated with higher risk of recurrence. Only advanced stage (p-value <0.0001) was associated poorer overall survival. CONCLUSIONS: The presence of ENE+ and/or margin+ was not an independent predictor of poor RFS or OS in HPV+ OPC.

Engineered organotin(IV) and vanadium(V) derivatives with distinct coordination modes and luminescent properties for the efficient detection and quantification of permanganate ions.

The distinction in coordination modes of metal complexes leads to their versatile structural features and unique properties. Here, we report two tetradentate Schiff base ligands (H2L1 and H2L2) bearing N2O2 donor sets, tactically selected to provide distinct coordination modes with different metal ions. The ligands were utilized to synthesize their organotin(IV) (1-4) and vanadium(V) (5) derivatives. The synthesized compounds were characterized using elemental analysis, FT-IR spectroscopy, multi-nuclei NMR (1H, 13C, and 119Sn) spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. The organotin(IV) derivatives (1-4) displayed hepta-coordination around both the Sn centres as they were achieved in their dimeric form. Contrariwise, the vanadium(V) compound (5) was isolated as a mononuclear entity exhibiting penta-coordinated geometry around the vanadium centre. The variation in the coordination modes was evident in their UV-vis and fluorescence spectra. The organotin(IV) compounds (1-4) exhibited a strong emission band centred at 468 nm when excited at a wavelength of 360 nm whereas the vanadium(V) (5) derivative displayed poor fluorogenic response. Compound 1 was further explored for the fluorogenic chemo-sensing of permanganate ions (MnO4-) amongst various anions by quenching response. A detailed investigation of the recognition of permanganate ions was accomplished by spectrofluorometric, spectroscopic (119Sn NMR), mass spectrometric, and computational studies.

Exploring risks of investor claims brought forth after the TRIPS waiver for COVID-19.

This research plans to explore the risks of the investment claims involved in the ongoing technology transfers to COVID-19 vaccine manufacturers based on the recently approved 'Agreement on Trade-Related Aspects of Intellectual Property Rights' (TRIPS) waiver. These investment claims are based on the various intellectual property rights protected under international investment laws. The recently approved TRIPS waiver only deals with the patent rights involved in producing the COVID-19 vaccine but does not deal with the other related intellectual property rights such as trade secrets. This work sounds the alarm of investment dispute for the mass-production of vaccines based on the TRIPS waiver. The research suggests a plan by which the Indian government can address the global issue of COVID-19 technology transfer in India.

Phase I/II clinical trial of a helper peptide vaccine plus PD-1 blockade in PD-1 antibody-naïve and PD-1 antibody-experienced patients with melanoma (MEL64).

BACKGROUND: A vaccine containing 6 melanoma-associated peptides to stimulate helper T cells (6MHP) is safe, immunogenic, and clinically active. A phase I/II trial was designed to evaluate safety and immunogenicity of 6MHP vaccines plus programmed death 1 (PD-1) blockade. PARTICIPANTS AND METHODS: Participants with advanced melanoma received 6MHP vaccines in an incomplete Freund's adjuvant (6 vaccines over 12 weeks). Pembrolizumab was administered intravenously every 3 weeks. Tumor biopsies at baseline and day 22 were analyzed by multiplex immunohistochemistry. Primary end points were safety (Common Terminology Criteria for Adverse Events V.4.03) and immunogenicity (ex vivo interferon-γ ELISpot assay). Additional end points included changes in the tumor microenvironment (TME) and clinical outcomes. RESULTS: Twenty-two eligible participants were treated: 6 naïve to PD-1 antibody (Ab) and 16 PD-1 Ab-experienced. Median follow-up was 24.4 months. Most common treatment-related adverse events (any grade) included injection site reactions, fatigue, anemia, lymphopenia, fever, elevated aspartate aminotransferase, pruritus, and rash. Treatment-related dose-limiting toxicities were observed in 3 (14%) participants, which did not cross the study safety bound. A high durable T cell response (Rsp) to 6MHP was detected in only one participant, but twofold T cell Rsps to 6MHP were detected in 7/22 (32%; 90% CI (16% to 52%)) by week 13. Objective clinical responses were observed in 23% (1 complete response, 4 partial responses), including 4/6 PD-1 Ab-naïve (67%) and 1/16 PD-1 Ab-experienced (6%). Overall survival (OS) was longer for PD-1 Ab-naïve than Ab-experienced participants (HR 6.3 (90% CI (2.1 to 28.7)). In landmark analyses at 13 weeks, OS was also longer for those with T cell Rsps (HR 6.5 (90% CI (2.1 to 29.2)) and for those with objective clinical responses. TME evaluation revealed increased densities of CD8+ T cells, CD20+ B cells, and Tbet+ cells by day 22. CONCLUSIONS: Treatment with the 6MHP vaccine plus pembrolizumab was safe, increased intratumoral lymphocytes, and induced T cell Rsps associated with prolonged OS. The low T cell Rsp rate in PD-1 Ab-experienced participants corroborates prior murine studies that caution against delaying cancer vaccines until after PD-1 blockade. The promising objective response rate and OS in PD-1 Ab-naïve participants support consideration of a larger study in that setting.

In-situ generation of fluorescent silica nano-aggregates of silatranyl appended furfural Schiff base and its application to the spectrofluorimetric analysis of phenolic brominated flame retardants in aqueous medium.

A silatranyl appended furfural Schiff base (Silt-FUR) has been synthesized and characterized by spectroscopic techniques, elemental analysis and mass spectrometry. The dissolution of Silt-FUR in methanol-water (90:10 v/v) results in the formation of fluorescent nano-aggregates due to the hydrolysis of the silatranyl ring. The formation of nano-aggregates has been confirmed by dynamic light scattering, scanning electron microscopy and transmission electron microscopy. The nano-aggregates exhibit quenching of fluorescence in the presence of phenolic brominated flame retardants such as 3,3',5,5'-tetrabromobisphenol A, 2,4-dibromophenol, 2,4,6-tribromophenol, and pentabromophenol. Density-Functional Theory and NMR titration suggest that acid-base pair formation between azomethinic functionality and flame retardants is the main cause of quenching of fluorescent signal as it causes photoinduced electron transfer. Due to the excellent spectrofluorimetric response of Silt-FUR nano-aggregates to detect brominated phenols, a spectrofluorimetric method has been standardized for the quantification of brominated flame retardants. The detection limit for pentabromophenol obtained is 0.432 µM under optimal experimental conditions, and the linear range of the determination is 0.0495-1.35 µM. Thus, the in-situ generation of nano-aggregates offers a user-friendly method for the detection, quantification and extraction of the brominated phenols with exceptionally high sensitivity and selectivity for pentabromophenol.

Assessment of the Heavy Metal Contamination of Roadside Soils Alongside Buddha Nullah, Ludhiana, (Punjab) India.

The present study was carried out to determine the physico-chemical characteristics and heavy metal contents in roadside soil samples collected during 2 sampling periods (September 2018 and April 2019) from 8 different roadside sites lying parallel to the Buddha Nullah, an old rivulet, flowing through Ludhiana, (Punjab) India. The contents (mg/kg) of seven metals (cadmium, chromium, cobalt, copper, lead, nickel and zinc) were estimated using a flame atomic absorption spectrophotometer. Among the metals analyzed, the contents of Cd, Co, Cu, Pb and Zn were found above the permissible limits. The results of the index of geoaccumulation (Igeo), contamination factor (CF), contamination degree (Cdeg), modified contamination degree (mCdeg), the Nemerow pollution index (PI) and pollution load index (PLI) indicate a moderate to high heavy metal contamination of the analyzed soil samples. The results of the potential ecological risk factor (ERi) and potential ecological risk index (RI) indicate a low to moderate risk of heavy metals in the studied soil samples. The Pearson correlation analysis revealed that most of the variables exhibited a statistically significant correlation with one or more variables during the two samplings. Multivariate analysis demonstrates that contents of heavy metals in the study area are influenced by anthropogenic and geogenic factors.

Image-Guided Versus Blind Corticosteroid Injections in Adults With Shoulder Pain: A Systematic Review and Meta-Analysis.

The present study aimed to compare the clinical effects of image-guided versus blind steroid injection to treat shoulder pain, which is always debatable. An electronic search of credible databases was conducted for randomized controlled trials (RCTs) comparing image-guided versus blind steroid injections. The continuous data were pooled as mean difference (MD) or standardized mean difference (SMD), and dichotomous data were grouped as odds ratio (OR) with 95% confidence interval (CI). Sensitivity analysis and leave-one-out analysis were performed. The meta-analysis of 20 RCTs comprising 1136 patients favored image-guided injection based on the MD of the visual analog score (VAS) and shoulder function scores, measured between six weeks follow-up and baseline (MD=0.63, 95% CI [0.13, 1.12], p=0.01 and SMD=0.35, 95% CI [0.05, 0.65], p=0.02, respectively). Meta-analysis did not favor either group regarding the shoulder disability scores or side effects (MD=-2.18, 95% CI [-12.19, 7.83], p=0.67, and OR=0.40, 95% CI [0.14, 1.15], p=0.09, respectively). The image-guided approach was associated with significant improvement in pain and shoulder functionality. However, no significant difference was observed between the two approaches in terms of disability scores and side effects.

COVID-19 phobia across the world: Impact of resilience on COVID-19 phobia in different nations.

Aim: This research study focused on exploring the impact of resilience on COVID-19 phobia (C19P) among individuals from different nations including a cluster of European countries, India, Indonesia, Pakistan and the United States of America (USA). Method: We recruited research participants via disseminating an electronic survey on Facebook Messenger (FM) that included 812 participants. The electronic survey assessed unidentifiable demographic information, the COVID-19 Phobia Scale (C19P-S; Arpaci et al., 2020) and the Brief Resilience Scale (BRS; Smith et al, 2008). Results: Based on simple linear regression, resilience had a statistically significant negative affect on all four C19P factors including psychological, psychosomatic, economic and social factors (p < .001). Resilience showed a statistically significant difference for at least two nations (p < .001) investigated in this research, as shown by using the Kruskal-Wallis test. Utilising linear regression analysis showed that age affects the resilience score positively significantly (p < .001). Based on the Kruskal-Wallis test, we found no statistically significant differences in resilience scores between genders, but found statistically significant differences in resilience scores based on marital status, educational level and professional status (p = .001). Conclusion: We concluded that the higher the resilience level, the lower the level of C19P. The level of resilience was highest in the USA, followed by Europe, Pakistan, India and Indonesia. Age affected the resilience level positively and resilience differed based on marital status, education levels, and professional status but not between genders. Implications are offered for effective counselling interventions during this COVID-19 pandemic and the aftermath.

Trial to evaluate the immunogenicity and safety of a melanoma helper peptide vaccine plus incomplete Freund's adjuvant, cyclophosphamide, and polyICLC (Mel63).

BACKGROUND: Peptide vaccines designed to stimulate melanoma-reactive CD4+ T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund's adjuvant (IFA) would be safe and would support strong, durable CD4+ T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity. PARTICIPANTS AND METHODS: An adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry. RESULTS: Forty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy. CONCLUSIONS: 6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses.