Survival of Patients With Head and Neck Merkel Cell Cancer: Findings From the Pan-Canadian Merkel Cell Cancer Collaborative.

Importance: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. Due to its relatively low incidence and limited prospective trials, current recommendations are guided by historical single-institution retrospective studies. Objective: To evaluate the overall survival (OS) of patients in Canada with head and neck MCC (HNMCC) according to American Joint Committee on Cancer 8th edition staging and treatment modalities. Design, Setting, and Participants: A retrospective cohort study of 400 patients with a diagnosis of HNMCC between July 1, 2000, and June 31, 2018, was conducted using the Pan-Canadian Merkel Cell Cancer Collaborative, a multicenter national registry of patients with MCC. Statistical analyses were performed from January to December 2022. Main Outcomes and Measures: The primary outcome was 5-year OS. Multivariable analysis using a Cox proportional hazards regression model was performed to identify factors associated with survival. Results: Between 2000 and 2018, 400 patients (234 men [58.5%]; mean [SD] age at diagnosis, 78.4 [10.5] years) with malignant neoplasms found in the face, scalp, neck, ear, eyelid, or lip received a diagnosis of HNMCC. At diagnosis, 188 patients (47.0%) had stage I disease. The most common treatment overall was surgery followed by radiotherapy (161 [40.3%]), although radiotherapy alone was most common for stage IV disease (15 of 23 [52.2%]). Five-year OS was 49.8% (95% CI, 40.7%-58.2%), 39.8% (95% CI, 26.2%-53.1%), 36.2% (95% CI, 25.2%-47.4%), and 18.5% (95% CI, 3.9%-41.5%) for stage I, II, III, and IV disease, respectively, and was highest among patients treated with surgery and radiotherapy (49.9% [95% CI, 39.9%-59.1%]). On multivariable analysis, patients treated with surgery and radiotherapy had greater OS compared with those treated with surgery alone (hazard ratio [HR], 0.76 [95% CI, 0.46-1.25]); however, this was not statistically significant. In comparison, patients who received no treatment had significantly worse OS (HR, 1.93 [95% CI, 1.26-2.96)]. Conclusions and Relevance: In this cohort study of the largest Canada-wide evaluation of HNMCC survival outcomes, stage and treatment modality were associated with survival. Multimodal treatment was associated with greater OS across all disease stages.

Patient opinions on contralateral prophylactic mastectomy: A patient-driven discussion in need of tuning?

BACKGROUND: Rates of contralateral prophylactic mastectomy (CPM) are increasing among women with unilateral breast cancer despite low rates of contralateral recurrence and lack of survival benefit. We aimed to investigate the decisional needs and supports required to ensure adequate and quality decision-making by patients with breast cancer facing the decision regarding CPM. METHODS: In this qualitative study, we used semistructured interviews developed with the use of the Ottawa Decision Support Framework to investigate the decisional needs and supports of women (aged > 18 yr) with nonhereditary breast cancer who had previously discussed CPM with their care provider. Patients were recruited from 2 academic cancer centres in Toronto, Ontario. Interviews were conducted between June 2016 and October 2017. We analyzed responses to the open-ended questions iteratively and inductively to establish major themes within the results. RESULTS: Ten patients were recruited. Eight patients reported having initiated the discussion about CPM. Although most patients reported feeling supported, 6 mentioned some degree of decisional conflict. Cancer risk reduction was the most commonly reported perceived benefit of CPM (9 patients), followed by improved psychologic well-being (7). Most patients (8) did not mention the lack of survival benefit of CPM as a disadvantage of the procedure. Patients indicated that information resources (in 8 cases) and improved counselling from their health care team (in 7) would assist in decision-making. CONCLUSION: Our findings illustrate the disconnect between true and perceived risks (i.e., surgical risk) and benefits (potential recurrence and survival benefit) of CPM, which is not being managed adequately despite support from the health care team. A decision aid may address unmet patient need by providing a reliable resource regarding the benefits and risks of this procedure, while helping patients understand their values and realign their expectations.

A competing risk analysis of colorectal cancer recurrence after curative surgery.

BACKGROUND: This study examines the effect of prognostic patient and disease characteristics on colorectal cancer (CRC) recurrence after curative resection. We used competing risk analysis with death as a competing risk. This method provides the clinician a perspective into a patient's actual risk of experiencing a recurrence. METHODS: A retrospective cohort study of patients diagnosed with CRC who underwent curative resection for CRC from 2003-2007 at the Royal University Hospital in Saskatoon was completed. The outcome of interest was the first CRC recurrence, either local or distant metastasis. Demographic data, tumor characteristics, adjuvant treatment and follow-up data, date of local recurrence or metastasis were recorded from the medical record. Univariate analysis was completed to look at the relationship between each of the prognostic indicators and recurrence. Multivariable modelling (subdistribution regression modelling) was done to identify the main risk factors in determining recurrence. RESULTS: Of 148 patients, 38 (25.7%) experienced a recurrence, 16 (10.8%) died without evidence of recurrence, and 94 (63.5%) experienced neither outcome. The median follow-up was 30.5 months (interquartile range 10.6-50). In univariable subdistribution regression, T-stage, N-stage, vascular invasion and positive margins were all predictive of cancer recurrence, with p ≤ 0.001, with subdistribution hazard ratios for T4 stage at 11.93, T3 stage at 2.46, N2 stage at 10.58, and presence of vascular invasion at 4.27. N-stage remained as the sole predictor in multivariable regression. Cumulative incidence function (CIF) of recurrence at 48 months after surgery was 15%, 27% and 90% for N1/2, N3 and N4 respectively. CONCLUSION: The highest CIF of recurrence was associated with T4 stage, N2 stage, and vascular invasion. Patient's age, tumour location, type, or histological grade were not found to have a significant effect on the success of CRC surgery in precluding a recurrence.

Abnormal screens among nonmutation carriers in the High Risk Ontario Breast Screening Program.

BACKGROUND: The Ontario Breast Screening Program was expanded in 2011 to offer annual MRI and mammography to women with high-risk genetic mutations (e.g., BRCA1/2) and women with strong family histories and ≥25% estimated lifetime risk of breast cancer. Data to support high-risk screening is less clear in the nonmutation carrier group, as MRI has lower specificity among this population. The potential unintended consequences may be considerable and need to be explored. We aimed to describe the frequency of abnormal screens and biopsies. METHODS: Demographic surveys and chart review consent were sent to a sample of 441 individuals enrolled in a high-risk screening program at two tertiary care hospitals in Toronto, Ontario. Retrospective cross-sectional chart review was undertaken for clinicopathologic data. The frequencies of abnormal screens and biopsies were calculated. RESULTS: One hundred sixty-nine nonmutation carriers were included. The majority were white, employed, and highly educated. The median International Breast Cancer Intervention Study lifetime risk of breast cancer was 28.0% (range 24.5%-89.0%). 108 individuals (64%) experienced at least 1 abnormal screen and 13 (8%) had 3 or more over a median 3 years of screening (range 1-6 years). Of 55 biopsies, 3 (5.5%) were malignant. The cancer detection rate was 8.4/1000 screens (95% CI 3.2-22.4). CONCLUSIONS: An MRI-based screening program for nonmutation carriers was effective at diagnosing breast cancer. However, this population experienced a high rate of abnormal screens and intervention. Further research is needed to improve the performance of MRI-based screening in these women.

Practitioner Opinion on Contralateral Prophylactic Mastectomy: How Do We Steer a Patient-Driven Discussion?

BACKGROUND: Contralateral prophylactic mastectomy (CPM) is increasing despite a recent statement from The American Society of Breast Surgeons discouraging average-risk women with unilateral breast cancer (BC) from undergoing CPM. The objective of our study was to conduct a needs assessment of BC health practitioners to gather information about their opinions, attitudes, and experiences surrounding CPM. METHODS: The Ottawa Decision Support Framework was the theoretical framework for the development of the interview guide. Semistructured interviews were conducted until data saturation with a convenience sample of 16 BC practitioners (Ontario, Canada), including oncologic and reconstructive surgeons, medical oncologists, and nurse navigators. RESULTS: Nearly all practitioners identified the discussion regarding CPM as patient-initiated. The majority of practitioners (13/16) described their role as supporting the patient in the decision-making process. Practitioners described educating patients on the lack of survival benefit and in general discouraging CPM. Practitioners agreed that most patients demonstrate decisional conflict (11/16) as a barrier to decision-making, and it is a challenge to realign patients' understanding and expectations. Almost all practitioners (15/16) identified a need for information materials to help educate patients on the risks and benefits of CPM and to help realign expectations. CONCLUSIONS: Practitioners have identified CPM in average-risk women with unilateral BC as a patient-driven phenomenon that is on the rise, despite highlighting the increased risk of complications and lack of survival benefit. Our practitioner needs assessment identifies the need for a dynamic decision aid to help guide the shared decision-making process for practitioners and patients.

Clinical and operative outcomes of patients with acute cholecystitis who are treated initially with image-guided cholecystostomy.

BACKGROUND: Percutaneous cholecystostomy (PC) tube placement followed by delayed cholecystectomy has been shown to be an effective treatment option in high-risk populations such as older and critically ill patients. The goal of this study was to review the short- and long-term clinical and operative outcomes of patients with acute cholecystitis initially treated with PC tube placement. METHODS: We conducted a retrospective review of patients who underwent image-guided PC tube insertion between 2001 and 2011 at the Royal University Hospital or St. Paul's Hospital, Saskatoon. Clinical outcomes, complications and elective cholecystectomy follow-up were noted. RESULTS: A total of 140 patients underwent PC tube insertion, 76 men and 64 women with a mean age of 68.4 (standard deviation 17.7) years. Of the 140, 94 (67.1%) had an American Society of Anesthesiologists classification score of III or IV. Percutaneous cholecystostomy tubes remained in place for a median of 21.0 days, and the median hospital stay was 7.0 days. Readmission owing to complications from PC tubes occurred in 21 patients (15.0%), and 10 (7.1%) were readmitted with recurrent cholecystitis after tube removal. Forty-four patients (31.4%) returned for subsequent elective cholecystectomy, of whom 32 (73%) underwent laparoscopic cholecystectomy, 4 (9%) underwent open cholecystectomy, and 8 (18%) underwent laparoscopic converted to open cholecystectomy. CONCLUSION: Percutaneous cholecystostomy is a safe procedure that can be performed in patients who are older or have numerous comorbidities. However, less than one-third of such patients in our cohort subsequently had the definitive intervention of elective cholecystectomy, with a high rate of conversion from laparoscopic to open cholecystectomy.

CONTEXTE: Il a été démontré que la pose d'un drain de cholécystostomie percutanée suivie d'une cholécystectomie tardive serait une option thérapeutique efficace chez les populations à risque élevé, comme les patients âgés et gravement malades. L'objectif de cette étude était de revoir l'issue clinique et chirurgicale à court et à long terme chez les patients ayant présenté une cholécystite aiguë traitée par cholécystostomie percutanée. MÉTHODES: Nous avons procédé à une revue rétrospective des patients ayant subi une cholécystostomie percutanée guidée à l'aide de l'imagerie entre 2001 et 2011 à l'Hôpital royal universitaire ou à l'Hôpital St. Paul de Saskatoon. Nous avons ensuite pris note de l'issue clinique, des complications et des cholécystectomies non urgentes subséquentes. RÉSULTATS: En tout, 140 patients ont subi une cholécystostomie percutanée, 76 hommes et 64 femmes âgés en moyenne de 68,4 ans (écart-type 17,7 ans). Sur les 140 patients, 94 (67,1 %) présentaient un score ASA (American Society of Anesthesiologists) de III ou IV. Les drains de cholécystostomie percutanée sont restés en place pendant une période médiane de 21,0 jours et la durée médiane des séjours hospitaliers a été de 7,0 jours. Vingt-et-un patients (15,0 %) ont dû être réadmis en raison de complications liées aux drains de cholécystostomie, et 10 patients (7,1 %), en raison d'une récurrence de la cholécystite après le retrait du drain. Quarante-quatre patients (31,4 %) sont revenus pour une cholécystectomie non urgente, dont 32 (73 %) ont subi une cholécystectomie laparoscopique, 4 (9 %), une cholécystectomie laparotomique, et 8 (18 %) une cholécystectomie laparoscopique convertie en cholécystectomie laparotomique. CONCLUSION: La cholécystostomie percutanée est une approche sécuritaire envisageable chez les patients plus âgés présentant plusieurs comorbidités. Toutefois, dans notre cohorte, moins du tiers de ces patients ont par la suite subi la cholécystectomie non urgente définitive, et le taux de conversion de cholécystectomie laparoscopique en cholécystectomie laparotomique a été élevé.

Metastatic ductal carcinoma of the breast to colonic mucosa.

Breast cancer is the most common malignancy among women, while invasive ductal carcinoma is the most common type of invasive breast cancer. Metastatic spread to the colon and rectum in breast cancer is rare. This report describes a case of a 69-year-old woman with metastatic ductal breast cancer to the rectosigmoid, presenting as an incidental finding on screening colonoscopy. The breast carcinoma was first diagnosed 2 years prior. Colonic biopsies from colonoscopy confirmed metastatic adenocarcinoma consistent with a breast primary. Ultimately her clinical condition worsened as she developed malignant ascites, a small bowel obstruction, and new bone metastases, and the patient succumbed to her illness. Cases of metastatic breast cancer to the gastrointestinal tract have predominantly been lobular breast carcinoma. Increased awareness of colonic metastasis may lead to more accurate diagnosis and earlier systemic treatment.

Damage to the optic chiasm in myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis mice.

Optic chiasm lesions in myelin oligodendrocyte glycoprotein (MOG)-experimental autoimmune encephalomyelitis (EAE) mice were characterized using magnetic resonance imaging (MRI) and validated using electron microscopy (EM). MR images were collected from 3 days after induction to remission, approximately 20 days after induction. Hematoxylin and eosin, solochrome cyanin-stained sections, and EM images were obtained from the optic chiasms of some mice approximately 4 days after disease onset when their scores were thought to be the highest. T2-weighted imaging and apparent diffusion coefficient map hyperintensities corresponded to abnormalities in the optic chiasms of EAE mice. Mixed inflammation was concentrated at the lateral surface. Degeneration of oligodendrocytes, myelin, and early axonal damage were also apparent. A marked increase in chiasm thickness was observed. T2-weighted and diffusion-weighted MRI can detect abnormalities in the optic chiasms of MOG-EAE mice. MRI is an important method in the study of this model toward understanding optic neuritis.

Blood-brain barrier disruption in CCL2 transgenic mice during pertussis toxin-induced brain inflammation.

BACKGROUND: The chemokine CCL2 has an important role in the recruitment of inflammatory cells into the central nervous system (CNS). A transgenic mouse model that overexpresses CCL2 in the CNS shows an accumulation of leukocytes within the perivascular space surrounding vessels, and which infiltrate into the brain parenchyma following the administration of pertussis toxin (PTx). METHODS: This study used contrast-enhanced magnetic resonance imaging (MRI) to quantify the extent of blood-brain barrier (BBB) disruption in this model pre- and post-PTx administration compared to wild-type mice. Contrast-enhanced MR images were obtained before and 1, 3, and 5 days after PTx injection in each animal. After the final imaging session fluorescent dextran tracers were administered intravenously to each mouse and brains were examined histologically for cellular infiltrates, BBB leakage and tight junction protein. RESULTS: BBB breakdown, defined as a disruption of both the endothelium and glia limitans, was found only in CCL2 transgenic mice following PTx administration and seen on MR images as focal areas of contrast enhancement and histologically as dextrans leaking from blood vessels. No evidence of disruption in endothelial tight junctions was observed. CONCLUSION: Genetic and environmental stimuli were needed to disrupt the integrity of the BBB in this model of neuroinflammation.

Magnetic resonance imaging indicators of blood-brain barrier and brain water changes in young rats with kaolin-induced hydrocephalus.

BACKGROUND: Hydrocephalus is associated with enlargement of cerebral ventricles. We hypothesized that magnetic resonance (MR) imaging parameters known to be influenced by tissue water content would change in parallel with ventricle size in young rats and that changes in blood-brain barrier (BBB) permeability would be detected. METHODS: Hydrocephalus was induced by injection of kaolin into the cisterna magna of 4-week-old rats, which were studied 1 or 3 weeks later. MR was used to measure longitudinal and transverse relaxation times (T1 and T2) and apparent diffusion coefficients in several regions. Brain tissue water content was measured by the wet-dry weight method, and tissue density was measured in Percoll gradient columns. BBB permeability was measured by quantitative imaging of changes on T1-weighted images following injection of gadolinium diethylenetriamine penta-acetate (Gd-DTPA) tracer and microscopically by detection of fluorescent dextran conjugates. RESULTS: In nonhydrocephalic rats, water content decreased progressively from age 3 to 7 weeks. T1 and T2 and apparent diffusion coefficients did not exhibit parallel changes and there was no evidence of BBB permeability to tracers. The cerebral ventricles enlarged progressively in the weeks following kaolin injection. In hydrocephalic rats, the dorsal cortex was more dense and the white matter less so, indicating that the increased water content was largely confined to white matter. Hydrocephalus was associated with transient elevation of T1 in gray and white matter and persistent elevation of T2 in white matter. Changes in the apparent diffusion coefficients were significant only in white matter. Ventricle size correlated significantly with dorsal water content, T1, T2, and apparent diffusion coefficients. MR imaging showed evidence of Gd-DTPA leakage in periventricular tissue foci but not diffusely. These correlated with microscopic leak of larger dextran tracers. CONCLUSIONS: MR characteristics cannot be used as direct surrogates for water content in the immature rat model of hydrocephalus, probably because they are also influenced by other changes in tissue composition that occur during brain maturation. There is no evidence for widespread persistent opening of BBB as a consequence of hydrocephalus in young rats. However, increase in focal BBB permeability suggests that periventricular blood vessels may be disrupted.

Histochemical visualization and diffusion MRI at 7 Tesla in the TgCRND8 transgenic model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has been characterized by gross cortical atrophy, cellular neurodegeneration, reactive gliosis, and the presence of microscopic extracellular amyloid plaques and intracellular neurofibrillary tangles. Earlier diagnoses of AD would be in the best interest of managing the patient and would allow for earlier therapeutic intervention. By measuring the apparent diffusion coefficient (ADC) using diffusion-weighted imaging (DWI), a type of magnetic resonance imaging (MRI), one can quantify alterations in water diffusivity resulting from microscopic structural changes in the cell at early stages that are associated with pathophysiological processes of brain injury and/or disease progression. Whether or not this methodology is useful for AD is a question under examination. For example, DWI in suspected AD patients has shown increases in mean ADC values in the hippocampus and diminished diffusion anisotropy in the posterior white matter. However, in some cases, hippocampal ADC values appear not to change in AD patients. Moreover, to our knowledge, all DWI studies in suspected AD patients to date are technically incomplete in experimental design, because corresponding histological sections demonstrating actual plaque deposition are lacking and so it is not clear that ADC changes actually correspond to plaque deposition. In our study, we used DWI in the TgCRND8 transgenic model of Alzheimer's disease in conjunction with histological techniques and found robust plaque deposition in the transgenic strain in older animals (12-16 months old). However, we did not find statistically significant changes (p > 0.05) in ADC values (although ADC values in TgCRND8 mice did decrease in all regions examined) in mice 12-16 months old. Collectively, recent results from human studies and in rodent AD transgenic models support our findings and suggest that amyloid beta plaque load is not likely the major or primary component contributing to diffusional changes, if they occur.

Magnetic resonance imaging of blood-spinal cord barrier disruption in mice with experimental autoimmune encephalomyelitis.

Inflammation, demyelination, and blood-spinal cord barrier (BSB) breakdown occur in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. The purpose of this study was to evaluate the utility of MRI for detecting lesions and BSB disruption in vivo during EAE in the mouse lumbar spinal cord, to determine how MR features of BSB disruption change during the course of disease, and to relate such changes to clinical signs and histological features of disease. Following induction of EAE in C57BL/6 mice, contrast-enhanced (CE) T(1)-weighted MR images were acquired to detect BSB disruption in the lumbar spinal cord at the early stage of disease, at peak disease, and at remission, and T(2)-weighted images were obtained to monitor spinal cord morphology. Following imaging the spinal cords were assessed in situ for general features of inflammation, BSB leakage, activated macrophages/microglia, and demyelination. No focal lesions were evident on T(2)-weighted MR images. BSB disruption was greatest at the onset of signs of disease, and decreased progressively thereafter. Inflammation and demyelination were pronounced at the initial stage of disease and at peak disease, and were decreased at remission. Nonuniform contrast enhancement indicated that breakdown of the BSB occurred predominantly within the white matter (WM) of the spinal cord.

Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine CCL2 in the central nervous system.

Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation. This involves cellular migration across various structures associated with the blood-brain barrier: the vascular endothelium, the glia limitans, and the perivascular space between them. Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic (Tg) mice that overexpress CCL2 under control of a CNS-specific promoter. The Tg mice show no clinical symptoms, even though leukocytes have crossed the endothelial basement membrane. Pertussis toxin (PTx) given i.p. induced encephalopathy and weight loss in Tg mice. We used flow cytometry, ultra-small superparamagnetic iron oxide-enhanced magnetic resonance imaging, and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma, identifying this as the critical step in inducing clinical symptoms. Metalloproteinase (MPs) enzymes are implicated in leukocyte infiltration in neuroinflammation. Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase-1, matrix metalloproteinase (MMP)-10, and -12 mRNA in the brain. PTx further induced expression of tissue inhibitor of metalloproteinase-1, metalloproteinase disintegrins-12, MMP-8, and -10 in brains of Tg mice. Levels of the microglial-associated MP MMP-15 were not affected in control or PTx-treated Tg mice. PTx also up-regulated expression of proinflammatory cytokines IL-1beta and TNF-alpha mRNA in Tg CNS. Weight loss and parenchymal infiltration, but not perivascular accumulation, were significantly inhibited by the broad-spectrum MP inhibitor BB-94/Batimastat. Our finding that MPs mediate PTx-induced parenchymal infiltration to the chemokine-overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation, such as multiple sclerosis.

Spectroscopic studies on the darkening of lead white.

Lead white is an historically important paint used by artists since antiquity. The darkening of lead white has been well documented in works of art such as paintings. In this paper, mid-infrared (MIR) and visible spectroscopy were used to examine spectral changes accompanying the darkening of lead white paint as a result of exposure to H2S(g). Laboratory-prepared paint and a commercial lead white paint were used to observe the darkening reaction over time. Structural changes to the pigment, 2PbCO3.Pb(OH)2, in lead white were readily detected using MIR by applying a thin film on a KBr pellet. Spectral changes at 3541 (O-H stretch), 1400 (C-O), and 680 cm-1 (C-O) were the most significant over time as the paint darkened. Visible spectra were also collected to provide a semi-quantitative measure of color change with structural changes observed by MIR. Experiments in the visible region were also conducted to compare the spectral response as % reflected and % transmitted light as lead white darkened. The effect of different binding agents (egg tempera, linseed oil, water, and gum Arabic) on the rate of darkening of lead white was also examined. Other sulfur-containing pigments such as orpiment and realgar were also tested for their ability to darken lead white. By applying paint as a thin film inside a sealed cuvette, darkening of lead white was observed in the visible spectra (800 nm) when either powdered orpiment or realgar was in placed in the cuvette for 24 h.