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CONTEXT.: The year 2023 marks the centenary of the Nobel Prize honoring the discovery of insulin. Little-known experimental pathologists Lydia DeWitt, MD, at the University of Michigan and Mary Kirkbride, DSc [Hon], at Columbia University, both just beginning their academic careers, made independent contributions to the discovery that have never been critically examined. This happened at a time when it was exceedingly rare for women to work in pathology. OBJECTIVE.: To explore the facilitative roles of DeWitt and Kirkbride in the discovery of insulin and to examine their trail-breaking careers in academic pathology. DESIGN.: Available primary and secondary historical resources were reviewed. RESULTS.: DeWitt made and tested pancreatic extracts from duct-ligated atrophic pancreas (ie, Frederick Banting's great idea to prevent digestion of its hypothetical internal secretion) 15 years before Banting; Banting was unaware of her work. His idea came from reading a paper by pathologist Moses Barron. Prior duct-ligation studies had sometimes been viewed with skepticism because histologic identification of islets in atrophic duct-ligated pancreata was imperfect; Kirkbride addressed this with histochemical staining, convincing Barron and, therefore, indirectly influencing and motivating Banting. The lives and convoluted careers of these 2 early-20th-century women are explored and compared with those of other contemporary women in pathology. A unifying pattern becomes clear: careers in experimental pathology and bacteriology were accepted but performing clinical work in anatomic pathology was not. CONCLUSIONS.: Both DeWitt and Kirkbride are prototypical early-20th-century women in academic pathology whose careers were constrained by gender. However, Kirkbride made a unique and unrecognized contribution to the discovery of insulin.
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Insulina , Prêmio Nobel , Feminino , Humanos , Insulina/históriaRESUMO
Maud Menten was born and raised in remote regions of Canada. She obtained her MB/MD at the University of Toronto (1907/1911) and her PhD in biochemistry at the University of Chicago (1916). From 1907 to 1916, she trained at the Rockefeller Institute for Medical Research, the New York Infirmary for Women and Children, Western Reserve University in Cleveland, the Berlin Municipal Hospital in Germany, and the Barnard Free Skin and Cancer Hospital in St Louis. In 1916, she was appointed as pathologist at the Elizabeth Steel Magee Hospital, a charitable maternity hospital in Pittsburgh. She received a faculty appointment at the University of Pittsburgh (1918) and was appointed pathologist at Pittsburgh Children's Hospital (1926). In addition to being one of the first woman academic pathologists, she was likely the first perinatal, the second pediatric-perinatal, and the fourth pediatric pathologist to practice in North America. The importance of Menten's overall scientific contributions place her in the very upper echelon of 20th century pathologists. Her enzyme kinetic work resulted in the Michaelis-Menten equation, and her work in George Crile's laboratory in Cleveland provided a physiological basis for improved surgical outcomes. Her work in Pittsburgh was equally innovative, including initiating the field of enzyme histochemistry.
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Patologistas , Feminino , Gravidez , Humanos , Criança , Canadá , América do Norte , Alemanha , New YorkRESUMO
Dick van Velzen practiced as a pediatric pathologist at Alder Hey Children's Hospital in Liverpool, England from September 1988 until December 1995; he then relocated to the IWK-Grace Health Centre, a children's and maternity hospital in Halifax, Nova Scotia, Canada, where he practiced until he was fired for cause in January 1998. About a year and a half later, his practice in Liverpool came under increasing scrutiny, with the initial focus on the massive collection of post-mortem pediatric organs he had accumulated for planned future research on sudden infant death syndrome. Soon, a Parliamentary Inquiry began investigating the full scope of his Liverpool practice. During the Inquiry, another organ-hoarding scandal erupted; van Velzen, when leaving Halifax after his dismissal, had put his family's personal belongings into a storage facility at Burnside Industrial Park and then did not pay bills. As his belongings were being prepared for auction, formalin-fixed organs were found, and a Canada-wide arrest warrant for disrespect for human remains was issued by the Halifax Police. While the Alder Hey scandal resulted in a 535-page-long Parliamentary Report and the Human Tissue Act, van Velzen was never charged criminally in the UK. The largely unknown story of his second organ scandal in Halifax, is related here. Although he had obtained the body parts with the consent of the parents of the child to which they had belonged, his failure to properly identify and store them traumatized parents already impacted by his organ-hoarding in the UK, traumatized additional parents in Halifax, and resulted in significant waste of public resources in investigating the case. He pled guilty to "indignity to a human body" in Canada and was fined and placed on 12 months' probation.
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Corpo Humano , Feminino , Gravidez , Humanos , Criança , Nova Escócia , Autopsia , InglaterraRESUMO
Purpose: Fluoro-2-deoxyglucose positron-emission tomography (FDG-PET/CT) is now considered a standard investigation for the staging of new cases of stage III NSCLC. However, there is not published level 3 evidence demonstrating the impact of FDG-PET/CT on appropriate therapy in this setting. Using retrospective population-based data, we sought to examine the role and timing that FDG-PET/CT scans play in influencing treatment choice, as well as survival in patients diagnosed with stage III NSCLC. Materials and methods: A retrospective cohort of patients diagnosed with stage III NSCLC from 2009-2017 in Ontario were identified from the IC/ES (formerly Institute of Clinical Evaluative Sciences) database. FDG-PET/CT utilization over time, trends in mediastinal biopsy technique and usage, the impact of FDG-PET/CT on overall survival (OS), and its influence on use of concurrent chemoradiotherapy (CRT) were explored. The impact of timing of pre-treatment FDG-PET/CT on OS was also analyzed (≤28 days prior to treatment, 29-56 days prior, and >56 days prior). Results: Between 2007 and 2017, a total of 13 796 people were diagnosed with stage III NSCLC in Ontario. FDG-PET/CT utilization increased over time with 0% of cases in 2007 and 74% in 2017 with pre-treatment FDG-PET/CT scans. The number of patients who received a mediastinal biopsy similarly increased in this timeframe increasing from 41% to 53%. More patients with pre-treatment FDG-PET/CT scans received curative-intent therapy than those who did not: 23% vs 13% for CRT (p<0.001), and 23% vs 10% for surgery (p<0.001). Median OS was longer in those with FDG-PET/CT scans prior to treatment (17 vs 11 months), as was 5-year survival (22% vs 14%, p<0.001), and this held true on both univariate and multivariate analyses. Timing of FDG-PET/CT scan relative to treatment was not associated with differences in OS. Conclusion: Improvements in OS were seen in this cohort of stage III NSCLC patients who underwent a pre-treatment FDG-PET/CT scan. This can likely be attributed to stage-appropriate therapy due to more complete staging using FDG-PET/CT. This study stresses the importance of complete staging for suspected stage III NSCLC using FDG-PET/CT, and a need for continued advocacy for increased access to FDG-PET/CT scans.
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BACKGROUND: Adjuvant radiotherapy is prescribed after breast-conserving surgery to reduce the risk of local recurrence. However, radiotherapy is inconvenient, costly, and associated with both short-term and long-term side effects. Clinicopathologic factors alone are of limited use in the identification of women at low risk for local recurrence in whom radiotherapy can be omitted. Molecularly defined intrinsic subtypes of breast cancer can provide additional prognostic information. METHODS: We performed a prospective cohort study involving women who were at least 55 years of age, had undergone breast-conserving surgery for T1N0 (tumor size <2 cm and node negative), grade 1 or 2, luminal A-subtype breast cancer (defined as estrogen receptor positivity of ≥1%, progesterone receptor positivity of >20%, negative human epidermal growth factor receptor 2, and Ki67 index of ≤13.25%), and had received adjuvant endocrine therapy. Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25% or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast. In consultation with radiation oncologists and patients with breast cancer, we determined that if the upper boundary of the two-sided 90% confidence interval for the cumulative incidence at 5 years was less than 5%, this would represent an acceptable risk of local recurrence at 5 years. RESULTS: Of 740 registered patients, 500 eligible patients were enrolled. At 5 years after enrollment, recurrence was reported in 2.3% of the patients (90% confidence interval [CI], 1.3 to 3.8; 95% CI, 1.2 to 4.1), a result that met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1 to 3.2), and recurrence of any type was observed in 2.7% (90% CI, 1.6 to 4.1). CONCLUSIONS: Among women who were at least 55 years of age and had T1N0, grade 1 or 2, luminal A breast cancer that were treated with breast-conserving surgery and endocrine therapy alone, the incidence of local recurrence at 5 years was low with the omission of radiotherapy. (Funded by the Canadian Cancer Society and the Canadian Breast Cancer Foundation; LUMINA ClinicalTrials.gov number, NCT01791829.).
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Neoplasias da Mama , Mastectomia Segmentar , Recidiva Local de Neoplasia , Radioterapia Adjuvante , Feminino , Humanos , Neoplasias da Mama/classificação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Canadá , Antígeno Ki-67/biossíntese , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Estudos Prospectivos , Prognóstico , Pessoa de Meia-Idade , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossíntese , Receptor ErbB-2/biossíntese , Antineoplásicos Hormonais/uso terapêuticoRESUMO
INTRODUCTION: Eosinophilic/T-cell chorionic vasculitis (E/TCV), an incidental finding primarily in third trimester placentas, is characterized by eosinophils and CD3+ T lymphocytes infiltrating at least 1 chorionic and/or stem villous vessels. Its etiology and clinical significance are unclear. METHODS: Placental pathology reports issued by 8 pediatric-perinatal pathologists at Alberta Children's Hospital were retrieved from the lab information system (2010-2022), and candidate reports were identified using a Perl script searching for "eosinophil." Candidate diagnoses of E/TCV were validated by pathologist review. RESULTS: 38,058 placenta reports from 34,643 patients were reviewed; 328 cases of E/TCV were identified, for an overall incidence of 0.86%. Incidence increased 23% per year, from 0.11% in 2010 to 1.5% in 2021 (P < .01). This temporal change was observed for all pathologists; the incidence of identified multifocality also increased over time (P < .01). Umbilical vascular involvement was exceedingly rare. No variation in incidence was attributable to season. We received more than 1 placenta from 46 mothers with an E/TCV placental diagnosis; examination of >1 placenta did not reveal any mother with >1 E/TCV diagnosis. CONCLUSIONS: The incidence of E/TCV increased steadily over a ~12-year period and no recurrent cases were observed.
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Doenças Placentárias , Vasculite , Humanos , Gravidez , Feminino , Criança , Placenta/patologia , Doenças Placentárias/diagnóstico , Doenças Placentárias/epidemiologia , Doenças Placentárias/patologia , Incidência , Linfócitos T , Vasculite/diagnóstico , Vasculite/epidemiologia , Vasculite/patologiaRESUMO
Background: Noncompaction of ventricular myocardium is a cardiomyopathy that typically involves the left ventricle or both ventricles; it has often been associated with mutations in genes encoding sarcomere proteins. Little is known about isolated right ventricular noncompaction, as only a few cases have been reported. Case Report: A 30 year old G2P1 woman experienced a spontaneous fetal loss at 19 weeks and 4 days. An ultrasound examination at 19 weeks showed right ventricular and tricuspid valve abnormalities, ascites, and early hydrops. At autopsy, the right ventricular chamber was dilated with numerous prominent trabeculations and deep intrabecular recesses as well as a dysplastic tricuspid valve. Histologic examination confirmed isolated right ventricular noncompaction. Whole exome sequencing showed a likely pathogenic variant in the MYH7 gene. Conclusions: This appears to be the first report of isolated right ventricular noncompaction associated with a gene mutation as well as the first diagnosis in a fetus.
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Cardiomiopatias , Cardiopatias Congênitas , Gravidez , Feminino , Humanos , Adulto , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiopatias Congênitas/patologia , Miocárdio/patologia , Ventrículos do Coração , Diagnóstico Pré-Natal , Cadeias Pesadas de Miosina/genética , Miosinas Cardíacas/genéticaRESUMO
After the discovery of insulin at the University of Toronto in 1921-22, Frederick Banting and Charles Best downplayed the contributions of physiology professor John James Rickard Macleod, the director of the laboratory where the discovery was made. Banting and Best, their allies, and to a lesser extent the university promoted a "fairy tale" version in which the two young investigators made the discovery on their own, creating the so-called "Banting and Best myth." Over the next 60 years, the myth prevailed and Macleod's reputation became increasingly tarnished, with both Banting and Best actively maligning their former mentor. While the publication of Michael Bliss' The Discovery of Insulin in 1982 placed Macleod's reputation on the road to recovery, there are still many lingering issues that have been raised, and Macleod remains misunderstood, misinterpreted, and maligned. This paper, using primary and secondary historical sources, addresses topics that have been repetitively raised by Macleod's detractors over the past century.
Résumé. Après la découverte de l'insuline à l'Université de Toronto en 19211922, Frederick Banting et Charles Best ont minimisé les contributions du professeur de physiologie John James Rickard Macleod, directeur du laboratoire où la découverte a été faite. En compagnie de leurs alliés et dans une certaine mesure de l'Université, Banting et Best ont propagé un conte de fée dans lequel les deux jeunes chercheurs auraient fait cette découverte par eux-mêmes, donnant ainsi naissance au « mythe Banting et Best ¼. Au cours des 60 années suivantes, ce mythe a prévalu et la réputation de Macleod a été ternie, Banting et Best s'employant à calomnier leur ancien mentor. Si la publication de The Discovery of Insulin (1982) par Michael Bliss a quelque peu rétabli la réputation de Macleod, celui-ci est encore largement incompris, mal interprété et dénigré. En s'appuyant sur des sources historiques premières et secondaires, cet article aborde les enjeux qui ont été soulevés de manière répétée par les détracteurs de Macleod au cours du XXe siècle.
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Insulina , História do Século XX , Humanos , Insulina/história , CanadáRESUMO
Many populations of long-distance migrant shorebirds are declining rapidly. Since the 1970s, the lesser yellowlegs (Tringa flavipes) has experienced a pronounced reduction in abundance of ~63%. The potential causes of the species' decline are complex and interrelated. Understanding the timing of migration, seasonal routes, and important stopover and non-breeding locations used by this species will aid in directing conservation planning to address potential threats. During 2018-2022, we tracked 118 adult lesser yellowlegs using GPS satellite tags deployed on birds from five breeding and two migratory stopover locations spanning the boreal forest of North America from Alaska to Eastern Canada. Our objectives were to identify migratory routes, quantify migratory connectivity, and describe key stopover and non-breeding locations. We also evaluated predictors of southbound migratory departure date and migration distance. Individuals tagged in Alaska and Central Canada followed similar southbound migratory routes, stopping to refuel in the Prairie Pothole Region of North America, whereas birds tagged in Eastern Canada completed multi-day transoceanic flights covering distances of >4000 km across the Atlantic between North and South America. Upon reaching their non-breeding locations, lesser yellowlegs populations overlapped, resulting in weak migratory connectivity. Sex and population origin were significantly associated with the timing of migratory departure from breeding locations, and body mass at the time of GPS-tag deployment was the best predictor of southbound migratory distance. Our findings suggest that lesser yellowlegs travel long distances and traverse numerous political boundaries each year, and breeding location likely has the greatest influence on migratory routes and therefore the threats birds experience during migration. Further, the species' dependence on wetlands in agricultural landscapes during migration and the non-breeding period may make them vulnerable to threats related to agricultural practices, such as pesticide exposure.
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Purpose: To report on the Stereotactic Body Radiation Therapy (SBRT) credentialing experience during the Phase III Ontario Clinical Oncology Group (OCOG) LUSTRE trial for stage I non-small cell lung cancer. Methods: Three credentialing requirements were required in this process: (a) An institutional technical survey; (b) IROC (Imaging and Radiation Oncology Core) thoracic phantom end-to-end test; and (c) Contouring and completion of standardized test cases using SBRT for one central and one peripheral lung cancer, compared against the host institution as the standard. The main hypotheses were that unacceptable variation would exist particularly in OAR definition across all centres, and that institutions with limited experience in SBRT would be more likely to violate per-protocol guidelines. Results: Fifteen Canadian centres participated of which 8 were new, and 7 were previously established (≥2 years SBRT experience), and all successfully completed surveys and IROC phantom testing. Of 30 SBRT test plans, 10 required replanning due to major deviations, with no differences in violations between new and established centres (p = 0.61). Mean contouring errors were highest for brachial plexus in the central (C) case (12.55 ± 6.62 mm), and vessels in the peripheral (P) case (13.01 ± 12.55 mm), with the proximal bronchial tree (PBT) (2.82 ± 0.78 C, 3.27 ± 1.06 P) as another variable structure. Mean dice coefficients were lowest for plexus (0.37 ± 0.2 C, 0.37 ± 0.14 P), PBT (0.77 ± 0.06 C, 0.75 ± 0.09 P), vessels (0.69 ± 0.29 C, 0.64 ± 0.31 P), and esophagus (0.74 ± 0.04 C, 0.76 ± 0.04 P). All plans passed per-protocol planning target volume (PTV) coverage and maximum/volumetric organs-at-risk constraints, although variations existed in dose gradients within and outside the target. Conclusions: Clear differences exist in both contouring and planning with lung SBRT, regardless of centre experience. Such an exercise is important for studies that rely on high precision radiotherapy, and to ensure that implications on trial quality and outcomes are as optimal as possible.
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BACKGROUND: Workload measurement is important to help determine optimal staffing and workload distribution for pathology laboratories. The Level 4 Equivalent (L4E) System is the most widely used Anatomical Pathology (AP) workload measurement tool in Canada. However, it was initially not developed with subspecialties in mind. METHODS: In 2016, a Pan-Canadian Pediatric-Perinatal Pathology Workload Committee (PCPPPWC) was organized to adapt the L4E System to assess Pediatric-Perinatal Pathology workload. Four working groups were formed. The Placental Pathology Working Group was tasked to develop a scheme for fair valuation of placental specimens signed out by subspecialists in the context of the L4E System. Previous experience, informal time and motion studies, a survey of Canadian Pediatric-Perinatal Pathologists, and interviews of Pathologists' Assistants (PA) informed the development of such scheme. RESULTS: A workload measurement scheme with average L4E workload values for examination and reporting of singleton and multiple gestation placentas was proposed. The proposal was approved by the Canadian Association of Pathologist - Association canadienne des pathologistes Workload and Human Resources Committee for adoption into the L4E System. CONCLUSION: The development of a workload measurement model for placental specimens provides an average and fair valuation of these specimen types, enabling its use for resource planning and workload distribution.
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Serviço Hospitalar de Patologia , Placenta , Feminino , Gravidez , Humanos , Criança , Canadá , Carga de TrabalhoRESUMO
CONTEXT.: In the late 19th century, mutual autopsy societies formed, first in Paris, France (1876) and later in Philadelphia, Pennsylvania. Members, who were often a who's who of anthropologists, physicians, intellectuals, and highly accomplished citizens, pledged to submit their bodies for autopsies to be performed by living society members so that their brains could be weighed and surface topography studied, with the results to be correlated with the decedents' intelligence and personal strengths during life. OBJECTIVE.: To explore the short history of these societies, the science they produced, and their extensive newspaper coverage in the United States. DESIGN.: Available primary and secondary historic sources were reviewed. RESULTS.: The Société Mutuelle d'Autopsie in Paris and the American Anthropometric Society in Philadelphia had different motives, as the former was heavily influenced by French Third Republic politics and secularism. The American press provided titillating coverage of both and was particularly fascinated by scandals. In America, Burt Wilder formed a splinter group and established the Wilder Brain Collection at Cornell University. In a period where many anthropologists were making untrue claims that brain and skull measurements were largely determined by race and sex, Wilder and Franklin P. Mall of the Wistar Institute in Philadelphia independently published carefully conducted studies proving this was not the case. CONCLUSIONS.: Mutual autopsy societies and brain clubs conclusively established that brain weight was not an accurate predictor of intelligence but accomplished little else; they were phased out shortly after World War I but are the predecessor to modern-day brain banks.
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Encéfalo , Cabeça , Estados Unidos , História do Século XIX , História do Século XX , Autopsia , I Guerra Mundial , ParisAssuntos
Corioamnionite , Líquido Amniótico , Corioamnionite/patologia , Feminino , Humanos , Semântica , Cordão Umbilical/patologiaRESUMO
Eosinophilic/T-cell chorionic vasculitis was initially defined as "a new form of chorionic vasculitis characterized by an infiltrate composed primarily of eosinophils and CD3+ T lymphocytes ... [that] occurs in the absence of any evidence of chorioamnionitis." No subsequent reports have directly addressed whether histologic evidence suggestive of amniotic fluid infection should preclude its diagnosis. The case reported here describes a term placenta with mild acute chorionitis, moderate acute subchorionitis, mild acute chorionic vasculitis, and funisitis associated with multifocal eosinophilic/T-cell chorionic vasculitis. It shows unequivocally, with immunohistochemical staining, that eosinophilic/T-cell chorionic vasculitis and acute chorionic vasculitis can be seen and histologically distinguished in the same case. The paper shows how differing interpretations of inclusion and exclusion criteria by investigators have affected estimates of the incidence of this rare lesion. There is a need to harmonize diagnostic criteria; the report describes how cases with both entities can be documented carefully.
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Corioamnionite , Vasculite , Corioamnionite/diagnóstico , Corioamnionite/patologia , Córion/patologia , Feminino , Humanos , Placenta/patologia , Gravidez , Linfócitos T , Vasculite/diagnóstico , Vasculite/patologiaRESUMO
INTRODUCTION: Recurrence risk of villitis of unknown etiology (VUE) remains uncertain because of few studies and their methodologic limitations. We calculated recurrence risk in a large population of deliveries after minimizing important biases and compared it to others via systematic review and meta-analysis. METHODS: Over 11 years of placenta pathology reports on singleton deliveries were retrieved and searched for 'villitis' or 'VUE'. Cases of acute villitis and chronic villitis from infections were eliminated via pathologist review. Reports were merged to data containing gestational age, parity and gravida. Recurrence risk of VUE per patient, per parity and per gravida was determined among patients with ≥2 placentas examined for deliveries ≥20 weeks gestation. Results were compared to those from articles and their references identified by a MEDLINE® search. Recurrence risks among methodologically similar studies were pooled using a random effects model. RESULTS: Among 29 124 placenta pathology reports from 27 087 patients, there were 2423 cases of VUE among 2382 patients, of which 153 had ≥2 placentas examined. There were 41 recurrent cases of VUE for a recurrence risk of 27% per patient, 22% per parity, and 19% per gravida. We identified 64 articles, of which 4 were retained. One examined all placentas from all births over a â¼3-year period, finding a recurrence risk of 27%. The remaining 3 studies, along with our own, used indications for placental examination and had a pooled recurrence risk of 30% (95% Confidence Interval: 0.21-0.41). DISCUSSION: In our study, which is the largest, most comprehensive, and methodologically robust to date, VUE recurrence risk was â¼30%.
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Corioamnionite , Doenças Placentárias , Corioamnionite/patologia , Vilosidades Coriônicas/patologia , Feminino , Humanos , Placenta/patologia , Doenças Placentárias/epidemiologia , Doenças Placentárias/etiologia , Doenças Placentárias/patologia , Gravidez , Estudos RetrospectivosRESUMO
Historians of diabetes have long claimed that physicians were aware of two distinct types of diabetes mellitus by the 1880s, and that these were the direct forerunners of type 1, juvenile-onset and type 2, adult-onset diabetes. French physician Étienne Lancereaux (1829-1910), based on autopsy and clinical studies, classified diabetes either as diabète maigre (thin, or more accurately emaciated, diabetes), which he believed to be pancreatic in origin with a poor prognosis, or diabète gras (fat diabetes), which he believed had a much better prognosis and was not pancreatic in origin. Historians citing Lancereaux have claimed that he observed the former to occur in young and the latter in middle-aged and elderly people. We review the papers of Lancereaux to clarify his clinical observations and understanding of diabetes. Lancereaux's description of diabète maigre bores little resemblance to juvenile diabetes and all of his thin patients were middle-aged or older. On the other hand, his diabète gras is akin to type 2 diabetes and he might well deserve credit for its characterization.