Purpose Phase 1 clinical trials are generally conducted to identify the maximum tolerated dose (MTD) or the biologically active dose (BAD) using a traditional dose escalation design. This design may not be applied to cancer vaccines, given their unique mechanism of action. The FDA recently published “Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines.” However, many questions about the design of cancer vaccine studies remain unanswered. Experimental Design We analyzed the toxicity profile in 239 phase 1 therapeutic cancer vaccine trials. We addressed the ability of dose escalation to determine the MTD or the BAD in trials that used a dose escalation design. Results The rate of grade 3/4 vaccine-related systemic toxicities was 1.25 adverse event per 100 patients and 2 per 1000 vaccines. Only 2 out of the 127 dose escalation trials reported vaccine-related dose limiting toxicities, both of which used bacterial vector vaccines. Out of the 116 trials analyzed for the dose-immune response relationship, we found a statistically significant dose-immune response correlation only when the immune response was measured by antibodies (p<0.001) or delayed type hypersensitivity (p<0.05). However, the increase in cellular immune response did not appear further sustainable with the continued increase in dose. Conclusions Our analysis suggests that the risks of serious toxicities with therapeutic cancer vaccines are extremely low and that toxicities do not correlate with dose levels. Accordingly, the conventional dose escalation design is not suitable for cancer vaccines with few exceptions. Here we propose an alternative design for therapeutic cancer vaccine development.

BackgroundVascular endothelial growth factor (VEGF) contributes to the pathogenesis of polycystic ovary syndrome (PCOS), and genetic variations in VEGFA gene were suggested to contribute to VEGF secretion and PCOS.AimTo evaluate the association of altered VEGF levels, stemming from the presence of specific VEGFA variants, with altered risk of PCOS.Subjects and MethodsRetrospective case-control study, performed between 2012–2015. Study subjects comprised 382 women with PCOS, and 393 control subjects. ELISA measured VEGF levels; genotyping of VEGFA variants was done by allelic exclusion.ResultsAmong the 12 tested VEGFA SNPs, minor allele frequency of only rs3025020 was significantly higher in PCOS cases than control women. Increased and reduced PCOS risk was seen with rs3025020 and rs2010963 genotypes, respectively. Increases and reduction in VEGF levels were associated with rs3025020 and rs2010963, respectively. Increased fasting insulin and HOMA-IR, and bioactive testosterone were linked with rs3025020, while carriage of rs2010963 was linked with reduction in fasting insulin, and free and bioactive testosterone. Of the 12 VEGFA variants, 9 were in LD, thus allowing construction of 9-locus haplotypes. Increased frequency of CAACAGCGA haplotype was seen in PCOS cases, after controlling for BMI, free and bioactive testosterone, SHBG, free insulin and HOMA-IR.ConclusionThis study confirms the contribution of altered VEGF secretion, resulting from genetic variation in VEGFA gene into the pathogenesis of PCOS. This supports a role for VEGF as PCOS candidate locus.

Background: Decreased sex hormone-binding globulin (SHBG) levels were associated with polycystic ovary syndrome (PCOS). SHBG polymorphisms associated with reduced SHBG production were tested for their association with PCOS, but with inconclusive results. We tested whether altered SHBG levels and SHBG variants were associated with PCOS. Methods: The study subjects included 242 women with PCOS and 238 control women. SHBG genotyping was done by real-time PCR. Results: Higher minor allele frequency of rs13894, rs858521 and rs727428 was seen in PCOS cases, and significant differences in rs858521 and rs727428 genotypes distribution were seen between PCOS cases and controls. Multivariate regression analysis confirmed the association of only rs727428 with PCOS. Though it was not statistically significant, serum SHBG levels were reduced according to rs727428 genotypes in PCOS cases than in controls. Carriage of rs727428 minor allele was associated with significant increases in free/bioactive testosterone in PCOS cases. Seven-locus (rs9898876-rs13894-rs858521-rs1799941-rs6257-rs6259-rs727428) haploview analysis showed increased frequency of GCCGTGA, GTCGTGA and GTCATGG, and reduced frequency of GTCGTGG haplotypes in PCOS cases than in controls, thus conferring disease susceptibility and protective nature to these haplotypes, respectively. Conclusion: Specific SHBG variants affecting serum SHBG levels and SHBG haplotypes are associated with PCOS, suggesting the role for SHBG as PCOS candidate gene.

No abstract

Background: Polycystic ovary syndrome (PCOS) is a common endocrinopathy, which shares genetic features with type 2 diabetes mellitus (T2DM). Insofar as transcription factor 7-like 2 (TCF7L2) is consistently replicated T2DM susceptibility locus, this study evaluates whether common TCF7L2 variants are associated with PCOS and related metabolic features. Methods: The association between TCF7L2 rs4506565, rs7903146, rs12243326, and rs12255372 SNPs and PCOS was tested in 242 women with PCOS and in 236 control women. Results: The allelic distribution of rs4506565, rs7903146, rs12243326, and rs12255372 TCF7L2 variants was not significantly different between women with PCOS and control women. The genotype distribution of the 4 TCF7L2 loci was comparable between PCOS cases and controls, irrespective of the genetic analysis model used (additive, dominant, recessive). Carriage of rs4506565 minor allele correlated with free insulin and homeostasis model assessment of insulin resistance, while the presence of rs12243326 and rs12255372 minor allele correlated with waist changes. Four-locus (rs4506565-rs7903146, rs12243326, and rs12255372) haplotype analysis identified PCOS-susceptible (ACTG) and -protective (TTTG) haplotypes, which remained significant after controlling for multiple comparisons and for key covariates. Conclusions: Although individual TCF7L2 variants were not associated with the presence of PCOS in Bahraini women, specific TCF7L2 haplotypes were identified, which were both positively and negatively associated with PCOS.

No abstract

The high prevalence of diabetes mellitus (DM) and shortage of Diabetes Care and Education Specialists (DCES) in rural communities requires providers and patients to travel long distances to access care. This burden impedes optimal DM management and increases cost. Telemedicine for Reach, Education, Access, Treatment, and Ongoing Support (TREAT-ON) is a Diabetes Education and Support (DSMES) model, where a DCES provides DSMES to patients identified as high risk (A1c &gt;9% or unplanned care). TREAT-ON was initiated in February 2020, where DSMES was provided via telemedicine (TM) visits, previously delivered face-to-face (F2F) to high-risk patients. In this retrospective study, the DCES overall costs (fuel, tolls, and postage), travel time for care delivery, and number of patients seen over a 6-month period (March-August 2019) was compared to (March-August 2020) after TM practices were adopted. From March to August 2019, 59 of 91 patient referrals were completed, compared to 110 of 167 referrals from March to August 2020. The percentage of successful referrals were similar in both groups (64.8% vs. 65.9%). However, the percent of referrals declined by patients were higher in 2019 (18.7%) vs. 2020 (9.0%). Of 59 referrals completed in 2019, 54 were F2F and five TM whereas in 2020 twelve were F2F and 98 TM. Lower average cost per patient was noted in 2020 ($38.85 vs. $6.20). A similar reduction in average travel time per patient was seen, 99 min vs. 16 min in 2020. TREAT-ON model translated to a direct cost savings of $1,606 and reduction of DCES travel time of 67.6 hours equating to a gain of 8.4 workdays opening care opportunities for an additional 67 new referrals. DSMES is a pillar of DM care and alternative methods to expand DSMES services remain imperative. Our early TREAT-ON data shows that telemedicine offers a time and cost-effective approach to DSMES with potential to reach a larger population when compared to traditional F2F visits, and helps to address a current DSCES shortage. Disclosure E. Gammoh: None. P. A. Johnson: None. J. S. Krall: Research Support; Self; Becton, Dickinson and Company, Sanofi. J. Ng: Research Support; Self; Sanofi-Aventis. L. M. Siminerio: Advisory Panel; Self; Abbott Diabetes, Bayer U. S., Research Support; Self; Becton, Dickinson and Company. A. Bandi: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R34DK123370-01)

<p>Supplemental Table 3. Bacterial vector vaccine trials and their grade 3/4 vaccine-related toxicities.</p>