Emapalumab as salvage therapy for adults with malignancy-associated hemophagocytic lymphohistiocytosis.

Not available.

Somatic mutations in FAS pathway increase hemophagocytic lymphohistiocytosis risk in T- and/or NK-cell lymphoma patients.

While significant progress has been made in understanding the genetic basis of primary hemophagocytic lymphohistiocytosis (HLH), the pathogenesis of secondary HLH, the more prevalent form, remains unclear. Among the various conditions giving rise to secondary HLH, HLH in lymphoma patients (HLH-L) accounts for a substantial proportion. In this study, we investigated the role of somatic mutations in the pathogenesis of HLH-L in a cohort of patients with T- and/or NK-cell lymphoma. We identified a 3-time higher frequency of mutations in FAS pathway in patients with HLH-L. Patients harbouring these mutations had a 5-time increased HLH-L risk. These mutations were independently associated with inferior outcome. Hence, our study demonstrates the association between somatic mutations in FAS pathway and HLH-L. Further studies are warranted on the mechanistic role of these mutations in HLH-L.

Development and Validation of a Mixed-Reality Simulator for Reducing Biopsy Core Deviation During Simulated Freehand Systematic Prostate Biopsy.

INTRODUCTION: We describe the development and validation of a mixed-reality prostate biopsy (PBx) simulator with built-in guidance aids and real-time 3-dimensional visualization. METHODS: We evaluated our simulator during one-on-one training sessions with urology residents and attendings from 2018 to 2022. Participants performed freehand, side-fire, double-sextant transrectal ultrasound-guided systematic prostate biopsy (sPBx). After a baseline assessment (first set of 12 biopsy cores), participants trained for 25 minutes with visualization and cognitive aids activated. Training was followed by an exit set of 12 biopsy cores without visualization or cognitive aids and afterward, subjective assessment by trainees of the simulator. Deviation is the shortest distance of the center of a core from its intended template location. RESULTS: Baseline deviations (mean ± SD) for residents (n = 24) and attendings (n = 4) were 13.4 ± 8.9 mm and 8.5 ± 3.6 mm ( P < 0.001), respectively. Posttraining deviations were 8.7 ± 6.6 mm and 7.6 ± 3.7 mm ( P = 0.271), respectively. Deviations between baseline and exit were decreased significantly for residents ( P < 0.001) but not for attendings ( P = 0.093). Overall feedback from participants was positive. Confidence in performing a PBx increased in novices after training ( P = 0.011) and did not change among attendings ( P = 0.180). CONCLUSIONS: A new PBx simulator can quantify and improve accuracy during simulated freehand sPBx while providing visualization and graphical feedback. Improved simulated sPBx accuracy could lead to more even distribution of biopsy cores within the prostate when performed in clinical settings, possibly reducing the high risk of missing an existing lesion and thus decreasing the time to initiating treatment, if indicated.

Retrospective characterization of nodal marginal zone lymphoma.

Nodal marginal zone lymphoma (NMZL) is a rare non-Hodgkin B-cell lymphoma that has historically been difficult to define, though is now formally recognized by the World Health Organization Classification. To better characterize the clinical outcomes of patients with NMZL, we reviewed a sequential cohort of 187 patients with NMZL to describe baseline characteristics, survival outcomes, and time-to-event data. Initial management strategies were classified into five categories: observation, radiation, anti-CD20 monoclonal antibody therapy, chemoimmunotherapy, or other. Baseline Follicular Lymphoma International Prognostic Index scores were calculated to evaluate prognosis. A total of 187 patients were analyzed. The five-year overall survival was 91% (95% confidence interval [CI], 87-95), with a median follow-up time of 71 months (range, 8-253) among survivors. A total of 139 patients received active treatment at any point, with a median follow-up time of 56 months (range, 13-253) among survivors who were never treated. The probability of remaining untreated at five years was 25% (95% CI, 19-33). For those initially observed, the median time to active treatment was 72 months (95% CI, 49-not reached). For those who received at least one active treatment, the cumulative incidence of receiving a second active treatment at 60 months was 37%. Transformation to large B-cell lymphoma was rare, with a cumulative incidence of 15% at 10 years. In summary, our series is a large cohort of uniformly diagnosed NMZL with detailed analyses of survival and time to event analyses. We showed that NMZL commonly presents as an indolent lymphoma for which initial observation is often a reasonable strategy.

TP53 mutations identify high-risk events for peripheral T-cell lymphoma treated with CHOP-based chemotherapy.

Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets next-generation sequencing panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with an increased risk of progression (by multivariate analysis) included advanced-stage disease and bone marrow involvement. The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations and TP53/17p deletions. PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5 months for PTCL with a TP53 mutation (n = 21) vs 10.5 months for PTCL without a TP53 mutation (n = 111). No TP53 aberrancy correlated with inferior overall survival (OS). Although rare (n = 9), CDKN2A-deleted PTCL correlated with inferior OS, with a median of 17.6 months vs 56.7 months for patients without CDKN2A deletions. This retrospective study suggests that patients with PTCL with TP53 mutations experience inferior PFS when treated with curative-intent chemotherapy, warranting prospective confirmation.

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome.

T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management. With the goal of improving patient outcomes and formulating a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy panel composed of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy. Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, explore its relationship with similar manifestations following CAR T cell infusions, and propose the term "immune effector cell-associated HLH-like syndrome (IEC-HS)" to describe this emergent toxicity. We also delineate a framework for identifying IEC-HS and put forward a grading schema that can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insight into potential treatment approaches and strategies to optimize supportive care and delineate alternate etiologies that should be considered in a patient presenting with IEC-HS. By collectively defining IEC-HS as a hyperinflammatory toxicity, we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides toward a more comprehensive assessment and treatment approach.

Current Treatment of Peripheral T-cell Lymphoma.

The peripheral T-cell lymphomas (PTCLs) are a notoriously diverse family of non-Hodgkin lymphomas with generally aggressive biology. Clinical management is challenging given a largely inadequate literature base comprised of few randomized trials and heterogeneous observational reports. Herein, we provide an account of our practice in the treatment of the 3 most common nodal PTCLs: PTCL, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma (ALCL). In the up-front setting, we employ anthracycline-based induction, with the incorporation of brentuximab vedotin for all those with ALCL and consideration in those with other CD30-expressing PTCLs based on improved progression-free and overall survival in the absence of additional toxicity in the ECHELON-2 trial. We strongly consider high-dose therapy with autologous stem cell rescue in first complete remission. In the relapsed or refractory (R/R) setting, we often look to clinical trials or choose from 4 FDA-approved single agents-belinostat, brentuximab vedotin, romidepsin, and pralatrexate-based on tumor phenotype and side-effect profiles. Our goal in the R/R setting is achievement of complete remission followed by allogeneic transplant with curative intent in appropriate candidates or long-term disease control in others. Numerous investigational agents are advancing through trials and have potential to alter standards of care in the near future.

Durable Response to Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, and Prednisone (BV-CHP) in a Patient with CD30-Positive PTCL Arising as a Post-Transplant Lymphoproliferative Disorder (PTLD).

T-cell PTLDs are lymphoid proliferations that develop in recipients of SOT or allogeneic HSCT. They carry an extremely poor prognosis with a reported median survival of only 6 months. The infrequency with which they are encountered makes treatment a challenge due to the lack of prospective trials to guide management. The significantly higher risk of morbidity and mortality in T-cell PTLD, compared to B-cell PTLD, underscores the challenge of treating these patients and the need for new therapeutic options. Brentuximab vedotin, an ADC targeting CD30, is FDA-approved in combination with CHP as front-line treatment for patients with CD30 expressing PTCL. Herein we report a case of CD30-positive T-cell PTLD that was successfully treated with BV-CHP, suggesting the added value of the addition of BV to chemotherapy, contributing to our patient's long and ongoing progression-free survival. To our knowledge, this is the first documented case of successful treatment using BV-CHP for a CD30-positive, EBV-negative, late T-cell PTLD.

Attitude is everything: keep probe pitch neutral during side-fire prostate biopsy. A simulator study.

OBJECTIVES: To develop and validate on a simulator a learnable technique to decrease deviation of biopsied cores from the template schema during freehand, side-fire systematic prostate biopsy (sPBx) with the goal of reducing prostate biopsy (PBx) false-negatives, thereby facilitating earlier sampling, diagnosis and treatment of clinically significant prostate cancer. PARTICIPANTS AND METHODS: Using a PBx simulator with real-time three-dimensional visualization, we devised a freehand, pitch-neutral (0°, horizontal plane), side-fire, transrectal ultrasonography (TRUS)-guided sPBx technique in the left lateral decubitus position. Thirty-four trainees on four Canadian and US urology programmes learned the technique on the same simulator, which recorded deviation from the intended template location in a double-sextant template as well as the TRUS probe pitch at the time of sampling. We defined deviation as the shortest distance in millimeters between a core centre and its intended template location, template deviation as the mean of all deviations in a template, and mastery as achieving a template deviation ≤5.0 mm. RESULTS: All results are reported as mean ± sd. The mean absolute pitch and template deviation before learning the technique (baseline) were 8.2 ± 4.1° and 8.0 ± 2.7 mm, respectively, and after mastering the technique decreased to 4.5 ± 2.7° (P = 0.001) and 4.5 ± 0.6 mm (P < 0.001). Template deviation was related to mean absolute pitch (P < 0.001) and increased by 0.5 mm on average with each 1° increase in mean absolute pitch. Participants achieved mastery after practising 3.9 ± 2.9 double-sextant sets. There was no difference in time to perform a double-sextant set at baseline (277 ± 102 s) and mastery (283 ± 101 s; P = 0.39). CONCLUSION: A pitch-neutral side-fire technique reduced template deviation during simulated freehand TRUS-guided sPBx, suggesting it may also reduce PBx false-negatives in patients in a future clinical trial. This pitch-neutral technique can be taught and learned; the University of Florida has been teaching it to all Urology residents for the last 2 years.

Clinical characteristics and outcomes of black patients with mycosis fungoides and Sézary syndrome: a subgroup analysis of the phase III MAVORIC trial.

Treatment-specific responses and comprehensive disease characteristics are limited in black patients with cutaneous T-cell lymphoma (CTCL). These shortcomings prompted us to perform a subgroup analysis of black patients enrolled in the MAVORIC trial - an international, randomized, phase 3 trial comparing mogamulizumab vs. vorinostat in relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS). Ten percent (N = 37) of the entire MAVORIC population (N = 372) identified as black. Significant clinical differences in black patients when compared to non-black patients included a younger median age at enrollment (53 vs. 66 years; p < 0.001), an increased frequency of MF as opposed to SS (73% vs. 52.8%; p < 0.001), and higher rates of earlier-stage disease (IB-IIA) at enrollment (37.8% vs. 21.2%; p = 0.022). Mogamulizumab offered similar response rates and progression-free survival in black patients (7.57 months) compared to the entire MAVORIC population (7.7 months) and was associated with a similar safety profile.

SMMARTS: An Open Architecture Development Platform for Modular, Mixed, and Augmented Reality Procedural and Interventional Simulators.

INTRODUCTION: Different simulators often share elements, resulting in different laboratories doing redundant work. This can lead to higher development and acquisition costs, proprietary, incompatible technology, lack of interoperability, and large inventories that reduce accessibility to the benefits of simulation. Simulation technology can become more affordable and scalable with open architecture and modular design. We describe the System of Modular Mixed and Augmented Reality Tracking Simulators (SMMARTS) open architecture, rapid development platform for designing and building modular procedural and guided-intervention simulators. METHODS: A modular stand provides mechanical indexing (registration) of a modular anatomical block representing the anatomy relevant to the simulated intervention. A software development kit (SDK) integrated with the hardware (stand and hand-held tracked tools such as a needle and ultrasound probe) facilitates software development. The SMMARTS SDK at https://github.com/UF-CSSALT/SMMARTS-SDK developed in Unity Technologies' Unity game engine includes Arduino microcontroller and NDI's 6 degrees of freedom tracking connectivity along with software tools such as a replayer, user interface templates, 3D visualization of the virtual counterparts of physical elements, scoring monitors, cognitive aids, common error messages, and Experience Application Programming Interface compatibility. RESULTS: We used SMMARTS to develop 9 different simulators internally (instructor-less central venous access currently deployed to Iraq, prostate biopsy, epidural loss-of-resistance, ventriculostomy, pterygopalatine fossa block, lumbar/chronic pain blocks, chest tube insertion) and externally (intravenous access). DISCUSSION: As a living tool, SMMARTS now has sufficient functionality and benefits that we can share it to help clinicians and engineers focus more on content specific to learning objectives rather than back-end tasks.

Extreme Peripheral Blood Plasmacytosis Mimicking Plasma Cell Leukemia as a Presenting Feature of Angioimmunoblastic T-Cell Lymphoma (AITL).

Angioimmunoblastic T-cell lymphoma (AITL) is one of four major subtypes of nodal peripheral T cell lymphoma, characterized by its cell of origin, the follicular helper T-cell (TFH). Patients typically present with prominent constitutional (B) symptoms, generalized lymphadenopathy, hepatosplenomegaly, cytopenias, and rash. Here we present a case of a 62-year-old male with progressive cervical adenopathy, fevers and weight loss presenting with extreme polyclonal plasmacytosis and high plasma EBV viral load. While the initial presentation appeared to mimic plasma cell leukemia or severe infection, lymph node biopsy and bone marrow biopsy confirmed a diagnosis of AITL. This case highlights the heterogeneity of the clinical presentation of AITL to enable physicians to more promptly recognize, diagnose and initiate treatment.

The spectrum of CD30+ T cell lymphoproliferative disorders in the skin.

Primary cutaneous CD30+ T cell lymphoproliferative disorders (pcCD30+ T cell LPDs) are a spectrum of pre-malignant to frankly neoplastic lymphoproliferations that comprise lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL), and borderline lesions. Although the atypical T cells that are the hallmark of these disorders share the expression of CD30, as the identifying marker, the clinical presentation, histological features and clinical course are vastly different. Furthermore, histopathologic features of pcCD30+ T cell LPDs may overlap with other cutaneous and systemic lymphomas. While most pcCD30+ T cell LPDs have an excellent prognosis, systemic lymphomas typically have a poorer outcome. CD30 has now been shown to be a reliable therapeutic target in pcCD30+ T cell LPDs. This review will emphasize the structure and function of CD30, along with the clinical and pathological spectrum of pcCD30+ T cell LPDs. It will also highlight other CD30+ lymphoproliferations that must be differentiated by careful clinical and pathological correlation.

Allogeneic hematopoietic stem cell transplantation in advanced stage mycosis fungoides and Sézary syndrome: a concise review.

Mycosis fungoides and Sézary syndrome encompass over 70% of all cases of cutaneous T-cell lymphoma (CTCL). While early stage disease has excellent long-term survival rates, advanced stage disease (IIB-IV) carries a poor prognosis with a median 5-year overall survival rate of approximately 50%. Early stage and advanced stage disease have different treatment algorithms with systemic therapy being indicated upfront in the later. The role of allogeneic hematopoietic stem cell transplant (HSCT) has gained considerable interest in recent years as a treatment option for CTCL given the increasingly promising long-term outcomes in an otherwise incurable disease. Herein, we provide a brief update on the current advances in HSCT followed by a concise review of the role of HSCT for CTCL. We conclude with our recommendations to approaching HSCT as a curative treatment option for CTCL.

Fatal Case of Primary Cutaneous Aggressive T-Cell Lymphoma Switching From a CD4+ to a CD8+ Phenotype: Progressive Disease With Bexarotene and Romidepsin Treatment.

A 77-year-old white male presented to the clinic with two isolated cutaneous tumors on his forehead. A cutaneous biopsy showed a focally folliculotropic CD4 cutaneous lymphoma. The tumors were irradiated with a complete response, and he was started on oral bexarotene. He experienced localized cutaneous relapse 3 months into treatment. These new tumors now revealed a surprisingly CD8 cytotoxic phenotype, but with the same clone. A systemic workup was negative. His regimen was switched to romidepsin, and he was treated with local radiation again. Another 3.5 months passed in remission until he developed widespread cutaneous tumors. Positron emission tomography/computed tomography revealed multifocal systemic disease involving his diaphragm, liver, distal duodenum, proximal jejunum, anterior chest wall including pectoral muscles, and lungs without significant adenopathy. He died a few days later. Given his full clinical and pathological course, he was given the diagnosis of an aggressive primary cutaneous T-cell lymphoma, unspecified.

Langerhans cell histiocytosis and Erdheim-Chester disease, both with cutaneous presentations, and papillary thyroid carcinoma all harboring the BRAF(V600E) mutation.

Langerhans cell histocytosis (LCH) and Erdheim-Chester disease are two rare histiocytic disorders. Their occurrence in the same patient is more infrequent, but has been described. We report a case of a 38-year-old woman who presented with a diagnosis of single system cutaneous LCH. Subsequently, she developed multiple papules on her extremities consistent with a non-LCH xanthogranuloma type lesion. BRAF(V600E) mutation immunostain, VE1 was positive in the skin lesion, which was confirmed by molecular polymerase chain reaction (PCR) studies, initiating a complete systemic workup for Erdheim-Chester disease. Systemic involvement was confirmed with bilateral sclerotic bone lesions and retroperitoneal and pelvic fibrosing disease. She was also found to have a BRAF(V600E) mutation positive papillary thyroid carcinoma. New suspicious cutaneous lesions presenting in patients with a history of LCH need to be biopsied. A BRAF(V600E) mutation in a non-LCH histiocytic lesion with a xanthogranuloma phenotype (CD163/CD68/CD14/fascin/Factor 13a) should prompt an Erdheim-Chester disease workup. This is a unique case of a woman with BRAF(V600E) mutation positive Erdheim-Chester disease and cutaneous LCH, while also being, to our knowledge, the first reported case in the English literature of it occurring in a patient with a BRAF(V600E) mutation positive papillary thyroid carcinoma.

Effects of pre-emptive morphine, ibuprofen or local anesthetic on fos expression in the spinal trigeminal nucleus following tooth pulp exposure in the rat.

In the present study, we used Fos expression as an index of nociceptive input to the spinal trigeminal nucleus after exposure of the coronal pulp tissue of maxillary right first molars and examined the effects of pretreatment with an opioid, a nonsteroidal anti-inflammatory drug or a local anesthetic before pulp exposure. Exposure of the tooth pulp produced a significant increase in Fos-like immunoreactivity in the superficial laminae of subnucleus caudalis; pretreatment with a control infiltration injection of saline directly above the maxillary molar 30 min before pulp exposure had no effect on Fos expression. Pretreatment with morphine 30 min before pulp exposure dose-dependently (2.5, 5, and 10 mg/kg subcutaneously) reduced Fos expression in subnucleus caudalis whereas pretreatment with ibuprofen (10-100 mg/kg subcutaneously) did not significantly affect Fos expression. Local anesthetic pretreatment was effective in reducing Fos expression only for the long acting bupivacaine; lidocaine without and with epinephrine (1:100,000) failed to significantly affect Fos expression. These results suggest that pre-emptive opioid treatment can decrease postoperative central nervous system changes associated with tooth pulp injury, and therefore, may decrease postoperative pain. Given the effects of local anesthetic on Fos expression, a combination of long acting local anesthetic with pre-emptive opioid would likely be most efficacious in decreasing postoperative dental pain.

The contribution of trabecular bone to the visibility of the lamina dura: an in vitro radiographic study.

OBJECTIVE: The objective of this study was to determine the degree to which trabecular bone contributes to the radiographic visibility of lamina dura. STUDY DESIGN: Segments of human cadaver mandible were obtained and split longitudinally. Two identical radiographs were made of each segment (1) before the removal of any additional bone and after (2) the removal of a small amount of the lamina dura at the apex of a tooth, (3) block removal of trabecular bone, and (4) smoothing of the endosteal surface of the external cortex. The radiographs were projected in random pairs for each sample. Six dentists judged whether a difference in the amount of lamina dura could be detected between 2 sets of radiographs. RESULTS: Chi-square analysis revealed a significant radiographic difference between radiographs made initially and after removal of the lamina dura and trabecular bone. CONCLUSIONS: Fewer than half of the changes of lamina dura loss alone could be detected radiographically by the observing dentists, whereas nearly all cases of the loss of periapical lamina dura in conjunction with loss of trabecular bone could be detected.