Waverly Hematology Oncology

Abundant cirripedes of Pliocene age (Piacenzian Stage) are described from two localities in North Carolina. These include seven species, of which the most abundant are the large balanids Arossia glyptopoma (Pilsbry, 1916), previously known from the Pliocene of Florida and Virginia, and Chesaconcavus proteus (Conrad, 1834), known from the Pliocene of Virginia and Florida. Abundant material of the scalpellid Scalpellum multangulatum (Lea, 1843) permits the first description of all the plates of this species and allows a reconstruction to be made. A new species of Membranobalanus Hoek, 1913, M. distortus sp. nov., a genus which has an obligate relationship with clionaid sponges, represents only the second fossil record of this extant genus. New records of the extinct whale barnacle Coronula bifida Bronn, 1931 are the first from the Atlantic Coastal Plain of the eastern USA and indicate that the migration paths of humpback whales in the Pliocene ran close to the palaeocoastline. The material includes the only known juvenile specimens of the species and allows reconstruction of the ontogeny of C. bifida. We report the second and third North American occurrences of the verrucid barnacle Verruca stroemia (O.F. Müller, 1778) and the second known record of Fistulobalanus multiseptatus (Ross, 1964). The barnacle assemblage represents a warm water fauna, brought into the region during the Mid-Piacenzian Warm Period by the basal Rushmere Member transgression at 3.25 Ma. Only 1 of the 7 species recorded is still extant.

Therapeutic proteins may first be developed as intravenous (i.v.) therapies with new subcutaneous (s.c.) dosage forms being subsequently developed to provide an alternative route of administration. As of August 2022, there have been 9 therapeutic proteins which were developed as a new s.c. dosage form after the approval of the corresponding i.v. product. This article provides a systematic review of prior experiences in the i.v. to s.c. switch development programs. We describe what types of clinical studies were conducted to support the i.v. to s.c. switch for these nine therapeutic proteins. Publicly available scientific advice from health authorities is summarized, particularly regarding recommendations on overall development strategy, dose selection, immunogenicity assessment, and indication extrapolation. The clinical data from these i.v. to s.c. development programs demonstrate that: (1) when switching from i.v. dosing to s.c. dosing, trough drug concentration (Ctrough ) from s.c. dosing should not be inferior to i.v. dosing with average drug concentration (Cavg ; equivalent to AUC, area under the curve after correcting for dosing intervals between i.v. and s.c. administration) being matched or non-inferior to i.v. dosing; and (2) with appropriate s.c. dose regimens, treatment with s.c. therapeutic proteins can generally achieve similar efficacy and safety as the corresponding i.v. products, suggesting that the much higher maximum concentration (Cmax ) after i.v. infusion as compared with that from s.c. injection is often not relevant to the treatment effect.

Introduction: Colorectal cancer (CRC) is the number 3 cancer in the US and the second most common cause of cancer-related deaths, affecting approximately 4% of the population1. Barriers to obtaining a screening colonoscopy include discomfort, financial strain, or lack of access2,3. Cologuard is a noninvasive method of detecting blood and altered DNA in stool that can be indicative of CRC4. Cologuard is increasingly being prescribed to circumvent barriers to colonoscopy but is not appropriate for patients with family history of CRC or personal history of polyps, who should be directly referred for colonoscopy2. Therefore, we sought to determine the prevalence of inappropriately ordered Cologuard tests in a community setting. Methods: We performed an IRB approved retrospective analysis of medical records for patients with a positive Cologuard test referred to Wake Endoscopy between May 2019 and May 2021. We identified contraindications to the Cologuard test as family history of CRC and/or personal history of polyps and calculated prevalence rates for patients who met either criteria. Results: A total of N = 202 patients with a positive Cologuard test were referred for a colonoscopy. The median age was 63.8 ± 8.7 years, with 98% over the age of 50. 54% of patients were female. Nearly one-quarter (48/202, 24%) of patients were inappropriately prescribed Cologuard; 11% (23/202) had a known family history of colon cancer, 10% (21/202) had a personal history of polyps, and 2% (4/202) had both contraindications. Conclusion: The Cologuard test is intended to combat barriers to routine screenings for colon cancer and is effective when used appropriately. In our practice, which reflects community-based care, nearly 25% of patients who were prescribed Cologuard should have been directly referred for colonoscopy. However, this study involved patients at a single site and only evaluated two broad categories of elevated risk. Further research in community settings and increased education for providers and patients is warranted to reduce patient anxiety and the number of inappropriately ordered tests.

502 Background: The 70-gene MammaPrint (MP) assay predicts risk of distant recurrence (DR) in hormone-receptor positive early-stage breast cancer and classifies cancers as Low Risk or High Risk. NSABP B-42 evaluated ELT in patients (pts) who had completed 5 yrs of adjuvant endocrine therapy (tx). The primary objective was to determine the utility of MP to identify pts enrolled in NSABP B-42 who are likely to benefit from ELT. Methods: A total of 1,866 pts from B-42 had available MP results. Primary endpoint is DR. Secondary endpoints are disease-free survival (DFS) and breast cancer-free interval (BCFI). For the primary analysis, pts were classified as High Risk (MP-H) (MP score ≤0.000) or Low Risk (MP-L) (MP score > 0.000). Exploratory analyses were performed for MP-L subcategories: MP Ultralow Risk (MP-UL) (MP score > 0.355) and MP-L but not MP-UL (MP-LNUL) (MP score > 0.000, ≤0.355). Likelihood ratio test based on stratified Cox proportional hazards (PH) model was used for treatment by risk group interaction. Stratified log-rank test was used to compare treatment groups. Hazard ratios and 95% CI were computed based on the stratified Cox PH model. Results: Among 1,866 pts, 706 (38%) were MP-H and 1,160 (62%) were MP-L. Of the MP-L, 252 (22%) were MP-UL. There were no significant differences in the distribution of patient and tumor characteristics between the MP group and the rest of the B-42 cohort, except for HER2 status. ELT effect was more pronounced in the MP cohort than in the overall B-42 population. For DR, there was statistically significant ELT benefit in MP-L (HR = 0.43, 95% CI 0.25-0.74, p = 0.002), but not MP-H (HR = 0.65, 0.34-1.24, p = 0.19) (interaction p = 0.38). For DFS, there was statistically significant ELT benefit in MP-L, but not MP-H (interaction p = 0.015). Similar findings were observed for BCFI (interaction p = 0.006). Within subcategories of MP-L, there was statistically significant ELT benefit in MP-LNUL, but not in MP-UL for all three endpoints, however the power in MP-UL was limited due to low number of pts (Table). Clinical trial information: 00382070. Conclusions: Statistically significant ELT benefit was observed for MP-L, but not MP-H. The treatment by risk group interaction was not statistically significant for DR, but it was for DFS and BCFI. The benefit appears to be stronger in MP-LNUL than in MP-UL. NCT: 00382070. Support: U10CA180868, -180822, U24CA196067; Novartis; Agendia.[Table: see text]

Nontuberculous mycobacteria (NTM) are a rare cause of infectious tenosynovitis of the upper extremity. Using molecular methods, clinical microbiology laboratories are increasingly reporting identification down to the species level. Improved methods for speciation are revealing new insights into the clinical and epidemiologic features of rare NTM infections. We encountered 3 cases of epidemiologically linked upper extremity NTM tenosynovitis associated with exposure to hurricane-damaged wood. We conducted whole-genome sequencing to assess isolate relatedness followed by a literature review of NTM infections that involved the upper extremity. Despite shared epidemiologic risk, the cases were caused by 3 distinct organisms. Two cases were rare infections caused by closely related but distinct species within the Mycobacterium terrae complex that could not be differentiated by traditional methods. The third case was caused by Mycobacterium intracellulare. An updated literature review that focused on research that used modern molecular speciation methods found that several species within the M. terrae complex are increasingly reported as a cause of upper extremity tenosynovitis, often in association with environmental exposures. These cases illustrate the importance of molecular methods for speciating phenotypically similar NTM, as well as the limitations of laboratory-based surveillance in detecting point-source outbreaks when the source is environmental and may involve multiple organisms.

Abstract Background: In the NSABP B-42 trial we aimed to determine whether 5 yrs of letrozole (L) v placebo (P) improves DFS in patients (pts) who have completed 5 yrs of hormonal therapy (tx). 3966 postmenopausal pts with stage I-III, hormone-receptor+ BC, disease-free after 5 yrs of an AI or tamoxifen (TAM) for ≤3 years → AI for the remainder of 5 yrs, were randomized to L 2.5 mg or P daily for an additional 5 yrs. In the primary analyses the beneficial effect of extended tx with 5 yrs of L did not reach statistical significance on disease-free survival (DFS). There was no significant improvement in overall survival (OS) with L, but L did provide a significant improvement in breast-cancer-free interval (BCFI) and distant recurrence (DR). The updated results based on the data received as of April 30, 2019, are presented here. Methods: Stratification was by pathological nodal status, prior adjuvant TAM or not, and baseline dexa T scores (>-2.0, ≤-2.0 SD). Primary endpoint was DFS including local, regional, distant recurrence, second primary cancers, and deaths from any cause as first event. Secondary endpoints included OS, BCFI (including recurrence or contralateral BC as first event), DR, osteoporotic fractures (OF), and arterial thrombotic (AT) events. Differences in DFS, OS, BCFI, DR, OF, and AT between L and P were assessed by the stratified log-rank tests and Cox proportional hazards models. Statistical significance level was set at 0.05. Results: Median follow-up for 3923 pts included in the current analyses was 9.3 yrs. As of 4/30/19, 890 DFS events had occurred (L=411, P=479); L resulted in a statistically significant increase in DFS v P (HR=0.84; 95% CI 0.74, 0.96; p=0.011); 10-yr DFS was L=76.1% and P=72.1%. The effect of L was statistically significantly different for pts with baseline T score ≤-2.0 (HR=0.63; 95% CI 0.49, 0.82) v those with a score >-2.0 (HR=0.93; 95% CI 0.80, 1.09) (interaction p=0.013). 495 deaths occurred (L=243, P=252); there was no statistically significant difference in OS with L v P (HR=0.97, 95% CI 0.82, 1.16; p=0.77); 10-yr OS was L=86.1% and P=85.5%. 413 BCFI events occurred (L=178, P=235); L v P resulted in a statistically significant 26% decrease in BCFI events (HR=0.74, 95% CI 0.61, 0.91; p=0.003); 10-yr cumulative incidence (Cum In) of BCFI was L=10.3% v P=13.3%. 229 DRs occurred (L=96, P=133); L v P resulted in a statistically significant 29% reduction in DR (HR=0.71, 95% CI 0.55, 0.93; p=0.01); 10-yr Cum In of DR was L=5.7% v P=7.5%. There were 209 OF (L=109, P=100). There were no significant differences in time to OF with L v P (P=0.46). Cum In of OF through 10 yrs was L=6.5% v P=6.4%. There were 154 AT events (L=82, P=72). Treatment with L did not result in an overall statistically significant increase in AT events compared to P (p=0.38). Cum In of AT through 10 yrs was L=4.7% v P=4.1%. Conclusions: The effect of extended tx with 5 yrs of L on DFS persisted in the updated analyses and reached statistical significance. There was no significant improvement in OS with L, but L continued to provide a significant improvement in BCFI and DR. Support: U10CA180868, -180822; UG1CA189867; Korea Health Technology R&D Project; Novartis. Citation Format: Eleftherios P Mamounas, Hanna Bandos, Barry C Lembersky, Jeon Hyeon Jeong, Charles E Geyer, Jr, Priya Rastogi, Louis Fehrenbacher, Mark L Graham, Stephen K Chia, Adam M Brufsky, Janice M Walshe, Gamini S Soori, Shaker R Dakhil, Thomas E Seay, James L Wade, III, Edward C McCarron, Soonmyung Paik, Sandra M Swain, D Lawerence Wickerham, Norman Wolmark. Ten-year results from NRG Oncology/NSABP B-42: A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy with letrozole (L) in postmenopausal women with hormone-receptor+ breast cancer (BC) who have completed previous adjuvant therapy with an aromatase inhibitor (AI) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS4-01.

Abstract This article extends the discussion introduced in this journal by Haab et al. (2013), who critique a 2012 article on contingent valuation (CV) by Hausman. We agree with Haab et al. “that the intellectual debate over [CV] is ongoing and that plenty of work remains to be done for the truly curious researcher” (593). However, our paper illuminates the limitations of current approaches to guide future research.

Toshiro Daigo . Kodansha International, 2005 . 288 paginas, 26x19 cm. I.S.B.N.: 4-7700-2330-8 .