Maintenance low-dose fixed duration lenalidomide and rituximab following bendamustine and rituximab induction in previously untreated chronic lymphocytic leukemia and small lymphocytic lymphoma.

Lenalidomide (LEN) and rituximab (RTX) have independently improved progression-free survival (PFS) in CLL, leading to interest in use of LEN + RTX (R2) following induction chemoimmunotherapy. Patients with previously untreated CLL received bendamustine + RTX (BR) for 6 cycles, then 24 cycles of R2. LEN dosing was 5-10 mg daily; RTX was given odd cycles (12 doses). The primary endpoint is PFS; secondary endpoints are response and overall survival. Thirty-six patients enrolled, median age 64.5 years. Twenty-nine received R2; 12 completed a full course R2 (33.3%), 5 completed R2 with premature discontinuation of LEN. Dose reductions/holds were most often for neutropenia. Complete response was achieved in 33.3%. After median >4 years follow-up, 2-year and 3-year PFS were 86.1% and 69.4%. Five-year overall survival was 92.3%. R2 maintenance may improve PFS after BR induction, and a lower dose of 5 mg/day and ≤1 year of R2 may be most tolerable (NCT00974233).

Combining Obinutuzumab With Radiation for Refractory DLBCL: Retrospective Safety and Efficacy Analysis.

Purpose: Approximately 30% of patients with diffuse large B cell lymphoma (DLBCL) will develop relapsed or treatment-refractory disease after primary chemotherapy. Patients unable to undergo aggressive chemotherapy and stem cell transplant or chimeric antigen receptor T-cell (CAR T-cell) therapy have limited treatment options. Here, we investigated the safety and efficacy of combining obinutuzumab with cytoreductive radiation to all areas of disease in patients with relapsed DLBCL. Methods and Materials: A retrospective review of patients with treatment refractory DLBCL was performed. All patients were treated with external beam radiation to all sites of refractory disease with concurrent and adjuvant obinutuzumab. Toxicities were evaluated based on Common Terminology Criteria for Adverse Events v5.0 criteria. Kaplan-Meier analysis was used to calculate progression-free survival and overall survival. Results: Between 2016 and 2022, 7 patients with refractory DLBCL were treated with concurrent radiation and obinutuzumab. No grade 3 or greater treatment-related toxicity was observed. Four of the 7 patients had a complete response at the radiated site on first postradiation imaging. The median progression-free survival and overall survival were 30 months. Conclusions: In this small cohort of treatment-refractory patients with DLBCL, the combination of radiation and obinutuzumab was well tolerated without excessive treatment-related toxicity. The combination resulted in durable disease control with a prolonged overall survival without additional treatment in a subset of patients.

Myxoid Inflammatory Myofibroblastic Sarcoma: Clinicopathologic Analysis of 25 Cases of a Distinctive Sarcoma With Deceptively Bland Morphology and Aggressive Clinical Behavior.

The number of recognized sarcoma types harboring targetable molecular alterations continues to increase. Here we present 25 examples of a distinctive myofibroblastic tumor, provisionally termed "myxoid inflammatory myofibroblastic sarcoma," which might be related to inflammatory myofibroblastic tumor, and which occurred in 13 males (52%) and 12 females at a median age of 37 years (range: 7 to 79 years). Primary tumor sites were peritoneum (18 patients; 72%), paratesticular (2; 8%), chest wall (1), upper extremity (1), esophagus (1), retroperitoneum (1), and uterus (1). Nine peritoneal tumors (50%) were multifocal at presentation; all other tumors were unifocal. Tumors showed bland-to-mildly-atypical neoplastic myofibroblasts in a myxoid stroma, with prominent inflammatory infiltrates in 22 cases (88%). Most tumors showed delicate branching stromal vessels like those of myxoid liposarcoma, and most showed infiltrative growth through non-neoplastic tissue. Immunohistochemistry demonstrated expression of SMA (19/25 tumors; 76%), desmin (13/22; 59%), and CD30 (5/11; 45%), while ALK was expressed in 1 tumor (of 25; 4%) that was negative for ALK rearrangement. Sequencing of 11 tumors showed seven to harbor tyrosine kinase fusions (4 PDGFRB, 2 PML::JAK1, 1 SEC31A::PDGFRA). Two instead harbored hot spot KRAS mutations (G12V and Q61H), and 2 were negative for known driving alterations. Clinical follow-up was available for 18 patients (72%; median: 2.7 years; range: 4 mo-12.3 years). Nine patients (50%) were alive with no evidence of disease, 5 (28%) died of disease, and 4 (22%) were alive with disease. Seven patients (39%) experienced peritoneal relapse or distant metastasis. Two patients showed disease progression on conventional, nontargeted chemotherapy. The patient whose tumor harbored SEC31A::PDGFRA was treated after multiple relapses with imatinib and sunitinib therapy, with progression-free periods of 5 and 2 years, respectively. Despite its bland appearance, myxoid inflammatory myofibroblastic sarcoma harbors a significant risk for disseminated disease, particularly when it occurs in the peritoneum. Targeted therapy could be considered for patients with disseminated disease.

Ewing Sarcoma of the Female Genital Tract: Clinicopathologic Analysis of 21 Cases With an Emphasis on the Differential Diagnosis of Gynecologic Round Cell, Spindle, and Epithelioid Neoplasms.

Ewing sarcoma is an uncommon neoplasm considered in the differential diagnosis of tumors with "small round cell" morphology, but its occurrence in the gynecologic tract has only been sporadically documented. Herein, we describe the largest cohort of Ewing sarcoma localized to the female genital tract to date, and emphasize their clinicopathologic resemblance to more common gynecologic neoplasms. Ewing sarcoma (n=21) was retrospectively identified from 5 institutions. The average patient age was 35 (range 6-61) years. Tumor sites included uterus (n=8), cervix (n=4), vulva (n=5), vagina (n=1), broad ligament (n=1), inguinal area (n=1), and pelvis (n=1). Nine of 18 cases in which slides were available for review demonstrated only classic round cell morphology, with the remainder showing a variable combination and prominence of variant ovoid/spindle or epithelioid appearance. Tumors showed diffuse membranous reactivity for CD99 (20/20) and were positive for NKX2.2 (8/8, diffuse) and cyclin D1 (7/7, of which 3/7 were patchy/multifocal and 4/7 were diffuse). They were negative for ER (0/6) and CD10 (0/6). Three cases were initially diagnosed as endometrial stromal sarcomas. EWSR1 rearrangement was confirmed in 20/21 by fluorescence in situ hybridization (n=15) and/or sequencing (n=8). Of the eight tumors that underwent sequencing, 6 harbored FLI1, 1 ERG, and 1 FEV as the fusion partner. Of 11 patients with available follow-up, 5 died of disease, 1 developed lung metastases and 5 are alive with no evidence of disease. Ewing sarcoma of the gynecologic tract is a rare, aggressive entity that shares some morphologic and immunohistochemical features with other more common gynecologic neoplasms. In addition to the typical round cell appearance, variant spindled/ovoid to epithelioid morphology may also be observed and should prompt consideration of this entity with appropriate immunohistochemical and/or molecular studies.

Integration of a clinical pharmacist practitioner-led pharmacogenomics service in a Veterans Affairs hematology/oncology clinic.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: This article describes the implementation and evaluation of pharmacogenomic testing within the hematology/oncology ambulatory care clinic at the William S. Middleton Memorial Veterans Hospital in Madison, WI. SUMMARY: The Pharmacogenomic Testing for Veterans (PHASER) program provides preemptive pharmacogenomic testing for veterans nationally. Program implementation at the Madison Veterans Affairs site began in the hematology/oncology clinic with the goal of integrating the offer for pharmacogenomic testing, testing completion, and review of the results by the hematology/oncology clinical pharmacist practitioner (CPP) into current workflows to create a sustainable process for PHASER. The hematology/oncology CPP designed workflows outlining how testing would be offered to patients, how results would be reported and to whom, and how documentation would occur in the electronic medical record. Veterans are offered preemptive PHASER testing, before needing therapy requiring pharmacogenomic results. Exceptions to pharmacogenomic testing were patients with a history of liver or allogeneic hematopoietic stem cell transplantation. CONCLUSION: This article provides a summary of the role of the hematology/oncology CPP in the implementation of a pharmacogenomics service and the impact on medication management in a hematology/oncology clinic.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Using latent class analysis to operationalize a wholistic assessment of Inuit health and well-being.

Many indigenous cultures conceptualize health wholistically, whereby physical, mental, spiritual and relational dimensions of health are interconnected. Yet, quantitative approaches to studying Indigenous health remain anchored in western perspectives, that separate the dimensions of health. This paper aims to operationalize a wholistic indicator of health based on the IQI model of Inuit health. Variables from the 2017 Nunavik Health Survey (N = 1196) were selected based on their representativeness of IQI model. Exploratory Latent Class Analysis (LCA) was used to identify wholistic health profiles. Once participants assigned to their health profile, sociodemographic characteristics were compared across profiles, and multinomial regression models were used to examine the relationship between community-level social determinants of health and the profiles. The LCA revealed three health profiles, labelled as "excellent", "good" and "fair" based on the distribution of answers to the indicators. Nunavimmiut in "excellent" and "good" health were more likely to: rate their health positively; be over 30 years old; be in a relationship; and have participated or volunteered in community events. Nunavimmiut in "fair" health tended to report lower levels of community cohesion, family relationships, and emotional support. Intergrating culturally relevant models of health can support improved health status assessments and identify opportunities for health promotion.

The Qanuilirpitaa? 2017 Nunavik Health Survey: design, methods, and lessons learned.

OBJECTIVE: To depict the design, methods, sociodemographic characteristics of the population, and lessons learned during the Qanuilirpitaa? 2017 Nunavik Inuit Health Survey, the third major health survey to be conducted among youth and adults residing in Nunavik (Northern Quebec, Canada). METHODS: Qanuilirpitaa? 2017 is a cross-sectional survey that served to update information regarding various aspects of physical health, mental health, and general well-being of Nunavimmiut. The survey was guided by the ethics principles of Ownership, Control, Access, and Possession (OCAP®) ( https://fnigc.ca/ocap ). Questionnaires and clinical tests were administered to residents from the 14 coastal communities onboard the Canadian Coast Guard Ship Amundsen during late summer and early fall 2017. As part of the community component of the survey, qualitative interviews were performed with key respondents, and services and resources supporting health and well-being in the 14 communities were inventoried and characterized. RESULTS: A total of 1326 Nunavimmiut aged 16 and over participated in the survey. Despite difficulties encountered with the recruitment of participants, co-interpretation sessions with Inuit partners revealed that the survey had succeeded in capturing cultural, socio-economic, and lifestyle characteristics of Nunavimmiut. In all, 20 thematic reports have been published covering various aspects of health and well-being of Nunavimmiut. Regional and local reports pertaining to the community component were produced. More in-depth analyses have ensued, and results are presented in articles published in this CJPH supplement issue. CONCLUSION: Information from this survey is being used to update health services and programs in the region and for the development of health policies and public health interventions to tackle key health-related issues faced by Nunavimmiut. Drawing lessons from challenges and successes encountered in Qanuilirpitaa? 2017, this survey paved the way to the upcoming Inuit-led Qanuippitaa? National Inuit Health Survey to be conducted every 5 years throughout Inuit Nunangat.

RéSUMé: OBJECTIF: Décrire la conception, les méthodes, les caractéristiques sociodémographiques de la population et les leçons tirées de l'Enquête sur la santé des Inuits du Nunavik Qanuilirpitaa? 2017, la troisième grande enquête de santé menée auprès de jeunes et d'adultes résidant au Nunavik (Nord du Québec, Canada). MéTHODES: Qanuilirpitaa? 2017 est une enquête transversale qui a permis la mise à jour des informations concernant divers aspects de la santé physique, de la santé mentale et du bien-être général des Nunavimmiut. L'enquête a été guidée par les principes de propriété, de contrôle, d'accès et de possession (OCAP®) ( https://fnigc.ca/ocap ). Des questionnaires et des tests cliniques ont été administrés à des résidents des 14 communautés côtières, à bord du navire Amundsen de la Garde côtière canadienne, à la fin de l'été et au début de l'automne 2017. Des entrevues qualitatives ont également été réalisées avec des répondants clé dans le cadre de la composante communautaire. RéSULTATS: Au total, 1 326 Nunavimmiut âgés de 16 ans et plus ont été recrutés. Malgré les difficultés rencontrées lors du recrutement des participants, les rencontres de co-interprétation ont permis de vérifier que l'enquête avait réussi à capturer les caractéristiques culturelles, socioéconomiques et les habitudes de vie de la population. Au total, 20 rapports thématiques ont été publiés, lesquels couvrent différents aspects de la santé et du bien-être des Nunavimmiut. Un rapport régional et des rapports locaux liés à la composante communautaire ont également été produits. Des analyses plus approfondies ont également été réalisées, dont les résultats sont présentés dans les articles publiés dans ce numéro supplémentaire de la Revue canadienne de santé publique. CONCLUSION: Les informations issues de cette enquête sont utilisées pour la mise à jour des services de santé dans la région et pour le développement de politiques de santé et d'interventions de santé publique, ayant pour cibles les principaux défis auxquels les Nunavimmiut sont confrontés. Grâce aux leçons apprises lors de sa réalisation, cette enquête a pavé la voie aux prochaines enquêtes Qanuippitaa ? qui seront menées tous les 5 ans dans tout l'Inuit Nunangat.

Sociocultural determinants of alcohol and cannabis use and misuse among Nunavimmiut.

OBJECTIVE: Stemming from historical traumas and changes in the Inuit way of life, substance use and its intertwined problems are a major cause of concern for Nunavimmiut. This study's objective is to investigate sociocultural determinants of substance use and misuse to inform culturally appropriate public health programs. METHODS: The 2017 Qanuilirpitaa? survey was conducted among a sample intended to be representative of Nunavimmiut aged 16 and over (total n = 1326). Sociocultural factors included cultural identity, land-based activities, involvement in community activities, social support, and family and community cohesion. The frequency of binge drinking (5 or more drinks on one occasion), cannabis use, and problematic substance use (CAGE and DAST-10) were documented. Data were analyzed using weighted multivariate logistic regressions. Inuit partners were involved from the planning of analyses to the co-interpretation of results. RESULTS: Nearly a third of Nunavimmiut aged 16 and over reported binge drinking at least once a week (29.3%), and 68.6% of drinkers were at risk of potential drinking problems. Forty-five percent (45%) reported using cannabis at least once a week, and 30% of drug users were at risk of potential drug abuse problems. Volunteering and participation in community activities were associated with lower odds of cannabis use, as was frequently going on the land with weekly binge drinking, potential drinking problems, and weekly cannabis use. Social support and community cohesion were associated with higher odds of weekly binge drinking, as was cultural identity (centrality scale) with potential drinking problems. CONCLUSION: Key determinants of substance use relevant to Inuit culture were identified. Results are in line with our Inuit partners' experience in their communities and are coherent with current land-based interventions implemented in Nunavik. A thorough understanding of substance use contexts and related stressors should guide the content and implementation of substance use programs in Nunavik.

RéSUMé: OBJECTIF: Suite aux traumas historiques et changements au mode de vie, l'usage de substance et les problèmes associés sont une source d'inquiétude majeure pour les Nunavimmiut. L'objectif de cette étude est d'investiguer les déterminants socioculturels de l'usage de substances pour adapter les programmes de santé publique à la culture Inuit. MéTHODES: L'enquête Qanuilirpitaa? 2017 repose sur un échantillon sélectionné pour être représentatif des Nunavimmiut (16 ans et plus; n = 1 326). Les déterminants socioculturels incluent : identité culturelle, activités sur le territoire, activités communautaires, support social, cohésion familiale et communautaire. La fréquence de consommation excessive d'alcool (5 consommations ou plus), l'usage du cannabis et l'usage problématique (CAGE et DAST-10) ont été documentés. Données analysées par régression multiple pondérée. Nos partenaires Inuit ont été impliqués de la planification des analyses à la co-interprétation des résultats. RéSULTATS: Près du tiers des Nunavimmiut de 16 ans et plus ont rapporté une consommation hebdomadaire excessive d'alcool (29,3 %) et 68,6 % de ceux consommant de l'alcool étaient potentiellement à risque de consommation problématique. Quarante-cinq pourcent (45 %) ont rapporté consommer du cannabis au moins une fois par semaine et 30 % des consommateurs de drogue étaient à risque de consommation potentiellement problématique. Le bénévolat et la participation aux activités communautaires étaient associés à une cote plus faible d'usage de cannabis, tout comme la pratique fréquente d'activités sur le territoire avec la consommation hebdomadaire excessive d'alcool, d'usage potentiellement problématique d'alcool et d'usage hebdomadaire de cannabis. Le support social et la cohésion communautaire étaient associés à une cote plus élevée de consommation excessive hebdomadaire d'alcool, tout comme l'identité culturelle (centralité) avec l'usage potentiellement problématique d'alcool. CONCLUSION: Des déterminants clés de l'usage de substance spécifiques aux Inuit ont été identifiés. Les résultats concordent avec le vécu de nos partenaires dans leurs communautés et le cadre théorique d'interventions déjà implémentées impliquant des activités sur le territoire et de guérison. Les contextes de consommation et les stresseurs associés devraient guider l'élaboration des programmes au Nunavik.

Profiles of childhood adversities in Inuit from Nunavik: description and associations with indicators of socioeconomic characteristics, support, and community involvement.

OBJECTIVES: Distress and associated health problems reported by Nunavik Inuit emanate from heterogeneous roots, including adverse childhood experiences. This study aims to (1) identify distinct childhood adversity profiles and (2) examine associations between these profiles and sex, socioeconomic characteristics, social support, and community involvement among Nunavimmiut. METHODS: In a sample of 1109 adult Nunavimmiut, sex, socioeconomic characteristics, support, community involvement, residential school attendance, and 10 forms of adverse childhood experiences (ACEs) were documented using questionnaires. Latent class analyses and weighted comparisons were performed for three subgroups: 18-49 years; 50 years and above with experience of residential school; and 50 years and above without experience of residential school. The analysis design, the manuscript drafts, and the key findings were discussed and co-interpreted with the collaboration of community representatives, taking into consideration Inuit culture and needs. RESULTS: A total of 77.6% of Nunavimmiut reported having experienced at least one form of childhood adversity. Three ACE profiles were identified among the 18-49-year-olds: low ACEs (43.0%), household stressors (30.7%), and multiple ACEs (26.3%). Two profiles characterized ACEs experienced among the 50-year-olds and over with and without history of residential schooling: low ACEs (80.1% and 77.2%, respectively) and multiple ACEs (19.9% and 22.8%, respectively). Among the group of 18-49-year-olds, as compared to the low ACE profile, the profile with household stressors included proportionally more women (odds ratio [OR] = 1.5) and was associated with lower involvement in volunteering and community activities (mean score reduced by 0.29 standard deviation [SD]) and lower family cohesion (SD = - 0.11), while the multiple ACE profile was related to a lower rate of employment (OR = 0.62), lower family cohesion (SD = - 0.28), and lower satisfaction with ability to practice traditional activities (SD = - 0.26). CONCLUSION: Childhood adversities among Nunavimmiut do not occur in isolation and experiencing multiple forms of childhood adversities predicts lower socioeconomic status, support, and community involvement in adulthood. Implications for the planning of health and community services in Nunavik are discussed.

RéSUMé: OBJECTIFS: La détresse et les problèmes de santé associés rapportés par les Inuits du Nunavik émanent de racines hétérogènes, notamment des expériences négatives durant l'enfance. Cette étude vise à : 1) identifier des profils distincts d'adversités vécues durant l'enfance; et 2) examiner les associations entre ces profils et le sexe, les caractéristiques socioéconomiques, le soutien social et l'engagement communautaire des Nunavimmiut. MéTHODES: Dans un échantillon de 1 109 adultes Nunavimmiut, le sexe, les caractéristiques socioéconomiques, le soutien, l'engagement communautaire, la fréquentation des pensionnats et 10 formes d'expériences négatives durant l'enfance (ENE) ont été documentés à l'aide de questionnaires. Des analyses de classes latentes et des comparaisons pondérées ont été réalisées pour trois sous-groupes : 18­49 ans; 50 ans et plus avec et sans expérience de pensionnat. Le plan d'analyses, les ébauches de manuscrit et les principaux résultats ont été discutés et co-interprétés avec la collaboration de représentants des communautés, en tenant compte de la culture et des besoins inuits. RéSULTATS: Un total de 77,6 % des Nunavimmiut ont déclaré avoir vécu au moins une forme d'adversité durant l'enfance. Trois profils d'ENE ont été identifiés chez les 18­49 ans : ENE faibles (43,0 %), facteurs de stress domestiques (30,7 %) et ENE multiples (26,3 %). Deux profils caractérisaient les ENE vécus chez les 50 ans et plus avec et sans antécédents de pensionnat : faibles ENE (80,1 % et 77,2 %, respectivement) et ENE multiples (19,9 % et 22,8 %, respectivement). Parmi le groupe des 18­49 ans, par rapport au profil des ENE faibles, le profil avec facteurs de stress domestiques incluait proportionnellement plus de femmes (rapport de cotes [RC] = 1,5) et était associé à une plus faible implication dans le bénévolat et les activités communautaires (score moyen réduit de 0,29 écart-type [ET]) et une cohésion familiale plus faible (ET = -0,11), tandis que le profil d'ENE multiples était lié à un taux d'emploi plus faible (RC = 0,62), à une cohésion familiale plus faible (ET = -0,28) et à une plus faible satisfaction à l'égard de la capacité à pratiquer des activités traditionnelles (ET = -0,26). CONCLUSION: Les adversités vécues en enfance par les Nunavimmiut ne surviennent pas de manière isolée et le fait de vivre de multiples formes d'ENE prédit un statut socio-économique, un soutien et une implication communautaire inférieurs à l'âge adulte. Les implications pour la planification des services de santé et communautaires au Nunavik sont discutées.

CYP1A1 immunohistochemistry is highly specific for angiofibroma of soft tissue among morphological mimics.

AIMS: Angiofibroma of soft tissue (AFST) is a benign, morphologically distinctive tumour type that harbours recurrent AHRR::NCOA2 fusions in 60-70% of cases and shows a non-specific immunophenotype, expressing EMA in roughly half of cases. The AHRR::NCOA2 fusion results in increased expression of cytochrome P450 1A1 (CYP1A1); a recent study demonstrated CYP1A1 immunohistochemistry (IHC) to be moderately sensitive and highly specific for AFST. METHODS AND RESULTS: In this study, we sought to validate these findings in a larger independent cohort of 30 AFST, as well as 215 morphological mimics, including 30 solitary fibrous tumours, 29 myxoid liposarcomas, 28 low-to-intermediate grade myxofibrosarcomas (MFS), 20 atypical spindle cell lipomatous tumours (ASCLT), 20 cellular angiofibromas, 10 cases each of spindle cell lipoma, neurofibroma, malignant peripheral nerve sheath tumour, superficial angiomyxoma, cellular myxoma, soft tissue perineurioma and deep fibrous histiocytoma, and nine cases each of low-grade fibromyxoid sarcoma and mammary-type myofibroblastoma. We found CYP1A1 IHC to be 70% sensitive for AFST, with granular cytoplasmic staining in 21 of 30 tumours, and 98% specific, with staining in only five morphological mimics: two deep fibrous histiocytomas, one MFS, one cellular angiofibroma and one ASCLT. CONCLUSIONS: These findings confirm that CYP1A1 is 70% sensitive, consistent with the prevalence of AHRR::NCOA2 fusions that up-regulate this protein, and that it is highly specific among morphological mimics.

Papillary Hemangioma Harbors Somatic GNA11 and GNAQ Mutations.

Papillary hemangioma (PH) is a small, primarily dermal lesion occurring predominantly in the head and neck in both children and adults. Its signature characteristics are dilated thin-walled channels containing papillary clusters of mainly capillary-sized vessels and endothelial cytoplasmic eosinophilic inclusions. Given certain histopathologic similarities to congenital hemangioma which harbor mutations in GNAQ and GNA11 , we investigated whether similar mutations are present in PH. Seven PH specimens were studied. All presented in the first 4 years of life, with one being noted at birth. With the exception of one lesion, all were in the head and neck. Lesions were bluish and ranged in size from 0.5 to 2.8 cm. Four samples had GNA11 p.Q209L and 3 had GNAQ p.Q209L missense mutations. Mutations in GNA11 and GNAQ are associated with other types of somatic vascular lesions including capillary malformation, congenital hemangioma, anastomosing hemangioma, thrombotic anastomosing hemangioma, and hepatic small cell neoplasm. Shared mutations in GNA11 and GNAQ may account for some overlapping clinical and pathologic features in these entities, perhaps explicable by the timing of the mutation or influence of the germline phenotype.

Melanotic PEComa: A Rare But Distinctive Subtype Analyzed in a Series of 7 Cases.

Perivascular epithelioid cell neoplasms (PEComas) are tumors of uncertain cell lineage that show a strong female predominance. Their hallmark is the presence of combined smooth muscle and melanocytic differentiation. In most cases, melanocytic differentiation is detectable only by immunohistochemistry, but there are rare reports of PEComa with extensive melanin accumulation (so-called "melanotic PEComa"). Here we report a clinicopathologic series of 7 melanotic PEComas that occurred across a wide patient age range of 21 to 82 years (median: 41 y) and with a wide anatomic distribution, including 2 cases in the pelvis and 1 case each in the gallbladder, cervix, eyelid, epidural space, and femur. All tumors were heavily pigmented and, like conventional PEComas, were composed of variably sized neoplastic cells with voluminous granular, or less commonly clear, cytoplasm with prominent nucleoli. All tumors expressed HMB45 by immunohistochemistry, and 6 of 7 showed nuclear TFE3 expression. Where tested, tumors were uniformly negative for Mart-1/Melan-A, S100, desmin, and smooth muscle actin. Molecular analysis identified TFE3 gene rearrangement in 5 of 7 cases, 4 of which were demonstrated by fluorescence in situ hybridization and one by whole-exome RNA sequencing which revealed a SFPQ::TFE3 fusion. The one tumor negative for TFE3 by immunohistochemistry was found instead to harbor a SFPQ::TFEB fusion, the first reported example to our knowledge of TFEB fusion in a PEComa. Clinical follow-up was available for 6 of 7 patients (median: 2.5 y: range: 0.75 to 7 y). The patient whose tumor harbored SFPQ::TFEB died of metastatic disease 9 months after diagnosis. The other tumors behaved in an indolent fashion: 4 patients were alive without evidence of disease at the most recent follow-up and 1 patient died of an unrelated cancer 4 years after diagnosis of the melanotic PEComa. Our results expand the morphologic and molecular spectrum of melanotic PEComa, and awareness of this rare but distinctive subtype is important to ensure accurate diagnosis within the broader family of heavily pigmented neoplasms.

"The needle is already ready to go": communities' and health care professionals' perceptions of routine vaccination in Nunavik, Canada.

Inuit living in the northern region of Nunavik continue to experience significant health inequalities, which are rooted in colonialism that still have repercussions on their health-related perceptions and practices, including vaccination. This study aimed to explore the perceptions and determinants of routine vaccination among the Inuit of Nunavik by describing factors influencing vaccination decisions from the perspective of community members and health professionals. Semi-structured interviews focusing on the perception of vaccination and experience with vaccination and health services were conducted with 18 Inuit and 11 non-Inuit health professionals. Using the socio-ecological model, factors acting at the community and public policy (e.g. rumours and misinformation about vaccination, language barrier), organisational (e.g. complexity of the vaccination process, staff turnover, lack of specialised vaccination workers and interpreters), and intrapersonal and interpersonal (e.g. past experiences with vaccination, vaccine attitudes, social norms) levels were identified as having an impact on vaccination decisions. Improving vaccination coverage in Nunavik requires a more global reflection on how to improve and culturally adapt the health care and services offered to the Inuit population.

Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor.

PURPOSE: Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST. PATIENTS AND METHODS: GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome. RESULTS: Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P = .0006) and 0.0% (P < .0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation. CONCLUSION: Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.

Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.

Neutrophils - the first responders in innate immunity - perform a variety of effector functions associated with specific metabolic demand. To maintain fitness and support functions, neutrophils have been found to utilize extracellular glucose, intracellular glycogen, and other alternative substrates. However, the quantitative contribution of these nutrients under specific conditions and the relative dependence of various cell functions on specific nutrients remain unclear. Here, using ex vivo and in vivo isotopic tracing, we reveal that under resting condition, human peripheral blood neutrophils, in contrast to in vitro cultured human neutrophil-like cell lines, rely on glycogen as a major direct source of glycolysis and pentose phosphate pathway. Upon activation with a diversity of stimuli, neutrophils undergo a significant and often rapid nutrient preference shift, with glucose becoming the dominant metabolic source thanks to a multi-fold increase in glucose uptake mechanistically mediated by the phosphorylation and translocation of GLUT1. At the same time, cycling between gross glycogenesis and glycogenolysis is also substantially increased, while the net flux favors sustained or increased glycogen storage. The shift in nutrient utilization impacts neutrophil functions in a function-specific manner. The activation of oxidative burst specifically depends on the utilization of extracellular glucose rather than glycogen. In contrast, the release of neutrophil traps can be flexibly supported by either glucose or glycogen. Neutrophil migration and fungal control is promoted by the shift away from glycogen utilization. Together, these results quantitatively characterize fundamental features of neutrophil metabolism and elucidate how metabolic remodeling shapes neutrophil functions upon activation.

Germline APC Alterations May Predispose to Testicular Sex Cord-Stromal Tumors.

Sertoli cell tumor is a type of testicular sex cord-stromal tumor (TSCST) typically driven by gain-of-function CTNNB1 variants. Recently, molecular studies have identified TSCSTs (including Sertoli cell tumors) with loss-of-function APC variants, raising the possibility that germline APC alterations may predispose to TSCSTs. In this study, we evaluated 4 TSCSTs from 4 individual patients, including 3 APC -mutant neoplasms identified in prior studies (1 in a patient with familial adenomatous polyposis [FAP] and 2 in patients with unknown syndromic status) and 1 tumor of unknown mutational status diagnosed in a patient with known FAP. Three neoplasms were typical Sertoli cell tumors, and 1 was a malignant unclassified TSCT. All neoplasms exhibited diffuse nuclear beta-catenin expression. Non-neoplastic tissue could be obtained for DNA sequencing in the 3 Sertoli cell tumors. Comparative assessment of non-neoplastic and lesional tissue in these cases suggested that germline APC variants with subsequent inactivation of the gene (loss of heterozygosity) were the likely oncogenic driver of these Sertoli cell tumors. In the malignant unclassified TSCSTs, APC inactivation was also interpreted as the most likely driver event, and the germline origin of the variant was inferred using a recently published method. The results of this study suggest that pathogenic germline APC alterations (eg, FAP and variants thereof) may predispose to TSCSTs.

Infantile Sinonasal Myxoma Is Clinically and Genetically Distinct From Other Myxomas of the Craniofacial Bones and From Desmoid Fibromatosis.

Sinonasal myxomas are rare benign tumors of the maxillary bone and sinus. There is published evidence that sinonasal myxomas occurring in children up to 3 years of age ("infantile sinonasal myxomas") are clinically distinctive and harbor Wnt signaling pathway alterations. Here, we characterized 16 infantile sinonasal myxomas and compared them to 19 maxillary myxomas and 11 mandibular myxomas in older patients. Clinical follow-up was available for 21 patients (46%) overall (median: 2.6 y; range: 4 mo to 21 y), including 10 of 16 infantile sinonasal myxomas (62%). None of the 8 resected infantile sinonasal myxomas recurred, despite positive margins in 6 of them. One incompletely resected infantile sinonasal myxoma underwent partial regression without additional treatment. In contrast, 4 of the 11 other myxomas with follow-up recurred (36%), including one that recurred twice. Imaging studies demonstrated all infantile sinonasal myxomas to be expansile lesions arising from the anterior maxillary bone adjacent to the nasal aperture, with peripheral reactive bone formation. Histologically, infantile sinonasal myxomas showed short, intersecting fascicles of bland fibroblastic cells with prominent stromal vessels. Examples with collagenous stroma showed some morphologic overlap with desmoid fibromatosis, although none showed infiltrative growth into adjacent soft tissue. Immunohistochemistry demonstrated nuclear ß-catenin expression in 14 of 15 infantile sinonasal myxomas (93%), in contrast to 4 of 26 other myxomas of craniofacial bones (15%). Smooth muscle actin was expressed in only 1 of 11 infantile sinonasal myxomas (9%). Next-generation sequencing was successfully performed on 10 infantile sinonasal myxomas and 7 other myxomas. Infantile sinonasal myxomas harbored CTNNB1 point mutations in 4 cases (D32Y, G34E, G34R, and I35S), and none harbored alterations to the phosphorylation sites T41 and S45 that are altered in 99% of CTNNB1 -mutant desmoid fibromatoses. Three tumors showed alterations consistent with biallelic APC inactivation. Three infantile sinonasal myxomas that showed strong nuclear ß-catenin expression were negative for CTNNB1 and APC alterations. Sequencing was negative for CTNNB1 or APC alterations in all 7 myxomas of craniofacial bones in older patients. Four of these myxomas in older patients (57%) showed copy number alterations, and all lacked known driving alterations. These findings support the notion that infantile sinonasal myxomas are clinically and genetically distinctive, and we propose the use of the diagnostic term "infantile sinonasal myxoma" to distinguish this tumor type from other myxomas of the craniofacial bones. Infantile sinonasal myxoma should be distinguished from desmoid fibromatosis because of its unique clinical presentation, more indolent clinical behavior, different morphology, different immunohistochemical profile, and different genetics. Given its indolent behavior even when marginally excised, infantile sinonasal myxoma can be managed with conservative surgery.

PEComa of the Adrenal Gland: A Clinicopathologic Series of 7 Cases.

PEComas are a family of mesenchymal neoplasms composed of histologically distinctive perivascular epithelioid cells which demonstrate myomelanocytic differentiation. PEComas of the adrenal gland are very rare and can represent a considerable diagnostic challenge given their morphologic overlap with more common adrenal cortical neoplasms. We present the clinicopathologic features of 7 primary adrenal PEComas. The cohort comprised 5 male and 2 female patients with a median age of 63 years (range: 31 to 71 y). One patient had Birt-Hogg-Dubé syndrome and another had Lynch syndrome; however, none had a history of tuberous sclerosis complex. Histologically, tumors showed nested and/or sheet-like growth and epithelioid cytomorphology with pale-to-eosinophilic granular cytoplasm. Two tumors had an admixed spindle cell component. There was a median of 4 mitoses per 10 HPFs (range: 0 to 8). Necrosis was present in 4 tumors and lymphovascular invasion in 1. Four tumors were classified as malignant. By immunohistochemistry, tumors were positive for HMB-45 (3/7), MITF (3/3), Melan-A (3/7), smooth muscle actin (5/7), desmin (5/7), and caldesmon (1/1). Two tumors were positive for TFE3 (2/4). Inhibin and SF1 were negative in all tumors assessed (0/6). Of 3 patients with available clinical follow-up information, 1 patient developed locally recurrent and metastatic disease (at 18 mo) and was alive with persistent disease at the last follow-up. Two patients had no recurrent or metastatic disease at the last follow-up (60 and 25 mo). Although PEComas of the adrenal gland are rare, pathologists need to be alert to this entity in the differential diagnosis of primary adrenocortical neoplasms. In suspected cases, the judicious use of melanocytic and smooth muscle markers, in addition to TFE3 and markers of adrenocortical differentiation (such as SF1 and inhibin) can assist in diagnosis. As in PEComas arising at other visceral sites, an association with tuberous sclerosis complex seems to be uncommon.

Malignant Proliferating Pilar Tumor: Clinicopathologic, Immunohistochemical, and Molecular Study of 17 Cases.

Proliferating pilar tumors are rare neoplasms that differentiate toward the outer sheath near the isthmus and can rarely undergo malignant transformation. We performed histopathologic evaluation on 26 benign proliferating pilar tumor (BPPT) and 17 malignant proliferating pilar tumor (MPPT). Ki-67 and p53 immunostains were performed on 13 BPPT and 10 MPPT. Six MPPT cases were successfully analyzed by a next-generation sequencing platform which surveyed exonic DNA sequences of 447 cancer genes and 191 regions across 60 genes for rearrangement detection. Patient demographics and clinical characteristics were similar between the BPPT and MPPT groups. Follow-up data of 16 of 17 MPPT (median, 25 mo) showed metastasis in 1 MPPT. The histologic features associated with MPPT include size >2.5 cm, adjacent desmoplastic stroma, small nests or cords of atypical epithelium in surrounding stroma, irregular infiltration or borders, abnormal keratinization, large hyperchromatic nuclei, prominent nucleoli, severe cytologic atypia, nuclear pleomorphism, necrosis, and increased mitotic figures. MPPT harbors copy number gains of 15q and losses of 6p and 6q, findings previously reported in BPPT. However, MPPT harbors frequent TP53 mutations as molecular markers of progression. Different from cutaneous squamous cell carcinoma, MPPT more frequently demonstrates low tumor mutational burden and typically lacks a UV signature, suggestive of a different etiologic pathway than squamous cell carcinoma. In summary, with a median follow-up of 25 months, this study shows that MPPT is a biologically indolent carcinoma with rare metastasis. Molecular analyses suggest a non-UV-related pathogenesis with frequent TP53 aberration.