Regulatory Foxp3+ T cells are a critical cell population that suppresses T cell activation in response to microbial and viral pathogens. We identify a cell-intrinsic mechanism by which effector CD4+ T cells overcome the suppressive effects of Treg cells in the context of three distinct infections, Toxoplasma gondii, Listeria monocytogenes, and vaccinia virus. The acute responses to the parasitic, bacterial, and viral pathogens resulted in a transient reduction in frequency and absolute number of Treg cells. The infection-induced partial loss of Treg cells was essential for the initiation of potent Th1 responses and for host protection against the pathogens. The observed disappearance of Treg cells was a result of insufficiency in IL-2 caused by the expansion of pathogen-specific CD4+ T cells with a limited capacity of IL-2 production. Exogenous IL-2 treatment during the parasitic, bacterial, and viral infections completely prevented the loss of Treg cells, but restoration of Treg cells resulted in a greatly enhanced susceptibility to the pathogens. These results demonstrate that the transient reduction in Treg cells induced by pathogens via IL-2 deprivation is essential for optimal T cell responses and for host resistance to microbial and viral pathogens.

Inflammatory myofibroblastic tumor (IMT) is a distinctive fibroblastic and myofibroblastic spindle cell neoplasm with an accompanying inflammatory cell infiltrate and frequent receptor tyrosine kinase activation at the molecular level. The tumor may recur and rarely metastasizes. IMT is rare in the head and neck region, and limited information is available about its clinicopathologic and molecular characteristics in these subsites. Therefore, we analyzed a cohort of head and neck IMTs through a multi-institutional approach. Fourteen cases were included in the provisional cohort, but 1 was excluded after molecular analysis prompted reclassification. Patients in the final cohort included 7 males and 6 females, with a mean age of 26.5 years. Tumors were located in the larynx (n=7), oral cavity (n=3), pharynx (n=2), and mastoid (n=1). Histologically, all tumors showed neoplastic spindle cells in storiform to fascicular patterns with associated chronic inflammation, but the morphologic spectrum was wide, as is characteristic of IMT in other sites. An underlying fusion gene event was identified in 92% (n=11/12) of cases and an additional case was ALK-positive by IHC but could not be evaluated molecularly. ALK represented the driver in all but 1 case. Rearrangement of ALK, fused with the TIMP3 gene (n=6) was most commonly detected, followed by 1 case each of the following fusion gene partnerships: TPM3-ALK, KIF5B-ALK, CARS-ALK, THBS1-ALK, and a novel alteration, SLC12A2-ROS1. The excluded case was reclassified as spindle cell rhabdomyosarcoma after detection of a FUS-TFCP2 rearrangement and retrospective immunohistochemical confirmation of rhabdomyoblastic differentiation, illustrating an important diagnostic pitfall. Two IMT patients received targeted therapy with crizotinib, with a demonstrated radiographic response. One tumor recurred but none metastasized. These results add to the growing body of evidence that kinase fusions can be identified in the majority of IMTs and that molecular analysis can lead to increased diagnostic accuracy and broadened therapeutic options for patients.

ImportanceLarynx cancer is associated with considerable morbidity for patients and has a high mortality rate. Historical analyses showed that the incidence of larynx cancer was decreasing but the mortality was not similarly improving.ObjectiveTo assess whether incidence and mortality trends in larynx cancer in the US have improved.Design, Setting, and ParticipantsThis cohort study used population-based data from the Surveillance, Epidemiology, and End Results Program database for patients older than 18 years who were diagnosed with laryngeal cancer between January 1, 1986, and December 31, 2018. Data were analyzed from May 1, 2021, to May 31, 2022.Main Outcomes and MeasuresThe main outcomes were incidence and mortality of larynx cancer by sex, subsite, and patterns of surgical treatment.ResultsAmong 40 850 US patients with larynx cancer diagnosed from 1986 to 2018 (80.4% male), the incidence of larynx cancer decreased 55% from 5.00 per 100 000 people (95% CI, 4.70-5.32 per 100 000 people) to 2.26 per 100 000 people (95% CI, 2.11-2.42 per 100 000 people). During the same period, mortality decreased only 43% from 1.59 per 100 000 people (95% CI, 1.53-1.64 per 100 000 people) to 0.89 per 100 000 people (95% CI, 0.86-0.92 per 100 000 people). This corresponds to a 25% relative increase in case-fatality rate. Examination by stage showed a decrease in the incidence of localized disease at diagnosis of 40% from 2.65 per 100 000 people (95% CI, 2.44-2.89 per 100 000 people) to 1.60 per 100 000 people (95% CI, 1.45-1.76 per 100 000 people) from 1986 to 2002 and of 45% from 2.15 per 100 000 people (95% CI, 1.98-2.34 per 100 000 people) to 1.19 per 100 000 people (95% CI, 1.08-1.31 per 100 000 people) from 2005 to 2018. Distribution of larynx cancer by subsite remained stable, with most cases affecting the glottis. The proportion of patients receiving surgery as their first course of treatment decreased regardless of stage at presentation.Conclusions and RelevanceIn this cohort study, between 1986 and 2018, the incidence of larynx cancer decreased in the US, primarily because of the decrease in the incidence of localized disease. Mortality did not decrease similarly, resulting in an increased case-fatality rate overall. Encouraging earlier referrals for cancer concern, focusing resources where larynx cancer rates remain highest, renewing attention to research on new biologic causes of different tumor biologic characteristics, and conducting trials to directly compare treatments may help reverse this trend.

Background: Primary Ewing’s sarcoma (ES) is typically seen within the long bones, vertebrae, or pelvis. Uncommonly, it can be found within the cranium among the rarest locations for primary ES are the skull base, in particular, the petroclival bone. Case Description: The patient is a 68-year-old female with past medical history of Stage III breast cancer who presented with severe retro-orbital headache and diplopia due to a cranial nerve VI palsy. Magnetic resonance imaging (MRI) revealed a mass at the left petroclival bone with extension into the adjacent left petrous apex and into the posterior aspect of the left cavernous sinus proximal to the carotid artery. The patient subsequently underwent an endoscopic transsphenoidal biopsy. Pathological and molecular analysis supported a diagnosis of ES. The patient then underwent neoadjuvant chemotherapy and radiotherapy. At 12 month-follow-up, her petroclival ES demonstrated significant interval decrease in size on MRI surveillance imaging. Conclusions: This is the third case of primary ES of the petroclival bone to be reported in the literature. In this patient, management consisted of surgical incisional biopsy followed by adjuvant radiation and chemotherapy. Knowledge and awareness of this type of tumor is important for the skull base surgeon.

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