It has been proposed that the number and extent of tumors formed after chronic exposure to dimethylhydrazine (DMH) can be predicted by the indigenous number and distribution of DNA-synthesizing cells in the murine colonic mucosa, and that this sensitivity to DMH is genetically determined. In order to test this hypothesis we studied two genetically distinct inbred strains of mice; the DMH-sensitive A/J (A) mouse, and the relatively DMH-resistant C57BL/6J (B) mouse before and after a single exposure to DMH. The untreated A strain had the longer crypt column [33.2 +/- 0.8 (SD) cells versus 28.8 +/- 0.9 cells], a higher absolute number of labeled cells per crypt column (4.4 +/- 0.6 versus 2.6 +/- 0.9), a greater labeling index (13.4 +/- 1.6% versus 9.1 +/- 2.9%), a wider proliferative compartment, and a greater number and percentage of labeled cells in the middle and upper thirds of the crypt than the untreated B strain. After acute exposure to DMH the A strain lost 14 +/- 3% of their total body weight, while the B strain lost 0.5 +/- 2% total body weight 48 h post-DMH. There was an initial loss of cryptal cells, a drop in the labeling index, and a subsequent increase and overshoot in the number of labeled cells and the labeling index. This pattern of cell loss and recovery over time was parallel in both strains, and thus cannot explain the differences in ultimate tumor formation after chronic exposure to the carcinogen. The data are consistent with the theory that the susceptibility to DMH carcinogenesis can be predicted by the indigenous proliferative characteristics of the murine colonic mucosa. The acute proliferative response to DMH in these strains is similar and parallel; thus ultimate tumor load may depend on long term effects such as the establishment of stable transmissible mutations.
Abstract Introduction: While enhanced breast screening of germline BRCA1/2 carriers results in earlier stage at diagnosis, the impact of tumour biology and BRCA mutation on chemotherapy receipt in early stage disease remains understudied. Methods: We retrospectively reviewed treatment administered following a first diagnosis of BRCA1/2-associated breast cancer between 2003-2023 at our institution. Chemotherapy receipt (neoadjuvant or adjuvant) was evaluated according to tumor size, biologic subtype, and BRCA mutation. Current guidelines for PARP inhibitor use were applied to estimate the proportion of affected BRCA1/2 carriers that would be deemed eligible for targeted therapy in the future. Results: Overall, 251 affected BRCA1/2 carriers were included; 137 (54.6%) BRCA1 (median age 40 years, range 19-72) and 114 (45.4%) BRCA2 (median age 43, range, 24-80 years). Chemotherapy was administered in 70.1% of index breast cancer cases and was significantly associated with clinical tumor size (36.7% T1a-T1b, 90.9% T1c, 95.2% T2, 95.3% T3-T4, p< 0.001), nodal status (71.8% cN0 vs. 100% cN1-2, p=0.004), and biologic subtype (90.0% TNBC vs. 75.0% ER+HER2-, p=0.02). BRCA1-associated breast cancers were less likely to present with DCIS or T1 tumours (%Tis/T1; 46.7% BRCA1 vs. 70.8% BRCA2, p< 0.001) and more likely to present with triple negative disease (71.4% BRCA1 vs. 24.6% BRCA2, p< 0.001). BRCA1 carriers were more likely to require chemotherapy for index breast cancer (81.8% BRCA1 vs. 56.1% BRCA2, p< 0.001). In subgroup analysis of early stage, T1N0 disease, chemotherapy was administered in 79.0% BRCA1 and 52.2% BRCA2 patients (p=0.03). If recent guidelines incorporating biologic subtype, nodal involvement, and response to neoadjuvant chemotherapy were retrospectively applied to the cohort, 33.6% would be deemed eligible for PARP inhibitors in the adjuvant setting, including 40.9% BRCA1 and 17.5% BRCA2 affected carriers (p < 0.001). Conclusion: Chemotherapy receipt is high in BRCA-associated breast cancers including in early stage, node-negative disease. Overall, one third of affected carriers are expected to be eligible for PARP inhibitors in the adjuvant setting. Future studies exploring how this information may impact decisions around risk-reducing mastectomy are warranted. Citation Format: Stephanie Wong, Carla Apostolova, Amina Ferroum, Basmah Alhassan, Ipshita Prakash, Mark Basik, Karyne Martel, Sarkis Meterissian, David Fleiszer, Nora Wong, Talia Malagon, William Foulkes, Jean-Francois Boileau. Evaluating chemotherapy receipt and candidacy for PARP inhibitors in germline BRCA1/2 carriers with early and locally advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-08-07.
This study investigates the influence of two formula diets containing 20 g/100 g diet of either whey protein concentrate or casein or Purina mouse chow, on the humoral immune responsiveness and dimethylhydrazine induced colon carcinogenesis in A/J mice. After 20 weeks of dimethylhydrazine treatment, the number of plaque forming cells per spleen, following intravenous inoculation with 5 X 10(6) sheep red blood cells, was nearly three times greater in the whey protein-fed group than in the casein-fed mice although both values were substantially below normal. After 24 weeks of dimethylhydrazine treatment the incidence of tumors in the whey protein-fed mice was substantially lower than that in mice fed either the casein or Purina diet. Similarly, the tumor area was less in the whey protein group in comparison to either the casein or Purina groups, with some difference between casein and Purina groups. Body weight curves were similar in all dietary groups. In conclusion, a whey protein diet appears to significantly inhibit the incidence and growth of chemically induced colon tumors in mice.
Abstract: We describe the case of a 66-year-old woman with a palpable mass in her left breast. Although the diagnosis on core biopsy was an intraductal papilloma, the surgically excised lesion showed it to be an infiltrating carcinoma which appeared to arise in a complex sclerosing lesion and is similar to the recently described breast tumor resembling the tall cell variant of papillary thyroid carcinoma.
In 1997 the Faculty of Medicine at McGill University received a grant from the Molson Foundation. The primary project deliverable, which the authors describe, was an online, multimedia-enhanced, undergraduate medical curriculum. The decision to develop an electronic curriculum was predicated on the belief that the integration of educational technology within mainstream material delivered a "value added" component to both students and faculty, which would, in turn, facilitate teaching and learning. Pedagogical values were deemed to include: (1) the ability to use the media to implement adult learning principles such as learner-centered, self-directed and guided learning, (2) the inherent interactivity of the technology, (3) the potential of the technology to provide a powerful means for fostering forms of "termless" learning that students will need to practice medicine, (4) recognition that use of multimedia can address, in part, the variety of learning styles evidenced by students in the lecture hall and classroom, and (5) the provision of opportunities for horizontal and vertical curricular integration. In addition, it was anticipated that an electronic curriculum would permit: (1) easy incorporation of informatics within mainstream curricula, (2) centralization and standardization of curricular material, (3) editorial functionality for revisions and updates, (4) wide accessibility of material irrespective of venue, (5) search functionality for faculty and students, (6) the ability to perform curriculum inventory, and (7) the potential for use to compensate for decreased faculty time. The ongoing experience at McGill has shown that the merging of technology and pedagogy requires a substantial commitment of resources and recognition of faculty time and change-management issues.
