Toxicities from BRAF and MEK Inhibitors: Strategies to Maximize Therapeutic Success.

PURPOSE OF REVIEW: This report highlights several of the recent therapeutic advancements in the treatment of BRAF-mutant tumors, discusses the most common adverse events observed with BRAF-targeted agents, and suggests strategies to manage and mitigate treatment-related toxicities. RECENT FINDINGS: BRAF and MEK inhibitors represent a significant advancement in the treatment of BRAF-mutated malignancies with data across tumor types demonstrating the anti-tumor efficacy of dual MAPK inhibition. Although these agents have a reasonable toxicity profile, variable side effects across organ systems can develop. The discovery of activating BRAF mutations and subsequent development of BRAF and MEK inhibitors has transformed the treatment algorithms of BRAF-mutant malignancies. With increased application of these targeted regimens, identification and prompt management of their unique adverse events are crucial.

Tofacitinib is Effective in Treating Refractory Immune Checkpoint Inhibitor Hepatitis.

Immune checkpoint inhibitors (ICI) have improved metastatic melanoma outcomes; however, toxicities, such as hepatitis, can be dose-limiting or even fatal.1 Systemic glucocorticoids and antimetabolite immunosuppressive medications remain the mainstay of treatment for ICI-hepatitis, but options for patients refractory to these therapies are limited.2 Herein we present 3 cases of glucocorticoid-refractory ICI-hepatitis treated with tofacitinib, an inhibitor of Janus kinase (JAK) 1 and 3. These patients represent consecutive patients referred to the Massachusetts General Hospital Severe Immunotherapy Complications service who were determined by our experts to have treatment failure with systemic glucocorticoid and antimetabolite combination therapy between August 2022 and September 2023.3 These were the only 3 patients managed by the Severe Immunotherapy Complications service who were treated with tofacitinib for ICI-hepatitis during that time.

Skin Cancer Incidence in Organ Transplant Recipients Referred for Benign Skin Conditions.

BACKGROUND: Solid organ transplant recipients (SOTRs) are at ∼100-fold increased risk for developing skin cancers compared with the general population, with increased morbidity and mortality. These patients are closely followed by dermatology; however, it is unclear how referral reasons from nondermatologic providers affect care in these patients. OBJECTIVE: This study examines the reason SOTRs are referred to dermatologic care by nondermatologic providers as a potential predictor of nonmelanoma skin cancer (NMSC) outcomes. MATERIALS AND METHODS: A retrospective case-control study was conducted with the records of 353 adult SOTRs referred to a specialized transplant dermatology clinic within an academic tertiary care center between 2007 and mid-2012. RESULTS: Eighty-one patients were diagnosed with 491 total premalignant and malignant skin lesions. A considerable proportion of patients diagnosed with NMSC were referred for benign skin conditions such as rash or acne. CONCLUSION: These results indicate that some SOTRs referred to dermatology for benign skin disorders are incidentally diagnosed with cutaneous malignancies; this is concerning given that referrals for benign skin conditions may delay appropriate care for cutaneous malignancies and preventative care. Better risk stratification, improved interdisciplinary collaboration, and prompt referrals for dermatologic care are needed in the care of SOTRs.

Relapse risk factors for patients with comorbid affective disorders and substance abuse disorders from an intensive treatment unit.

BACKGROUND AND OBJECTIVES: The prevalence of substance use disorders (SUD), particularly involving opiates and benzodiazepines, has increased to the detriment of public health and the economy. Here, we evaluate relapse factors among the high-risk demographic of patients with SUD and comorbid affective disorders. METHODS: A retrospective chart review of 76 patients discharged after detoxification and simultaneous psychiatric care for concomitant affective disorders and SUDs. Relapse was assessed by two independent evaluators via postdischarge chart review, which included state-wide healthcare utilization, by patient, through healthcare information exchange systems. A Cox Hazards analysis was performed to characterize relapse risk factors. RESULTS: Benzodiazepine use, admission through the emergency department (ED) rather than direct admission, frequent ED use in the preceding year, and history of prior attendance at multiple detoxification programs were risk factors for shortened time-to-relapse. Polysubstance use and intravenous drug use prolonged time to relapse. DISCUSSION AND CONCLUSIONS: Notable findings include the significant relapse risk associated with benzodiazepine abuse and frequent prior ED utilization. These risk factors could reflect a number of underlying mediators for relapse, including anxiety, disease burden, and malingering. Additionally, this study recapitulates the observation in other patient populations that the majority of health resource utilization is attributed to a small population of patients. SCIENTIFIC SIGNIFICANCE: This study is the first to identify relapse predictors among dual-diagnosis affective disorder and SUD patients in survival analysis, and replicates the alarming and largely unknown effect that benzodiazepines have on increasing relapse risk.

Topical arginase inhibition decreases growth of cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinomas (cSCC) are among the most commonly diagnosed malignancies, causing significant morbidity and mortality. Tumor-associated macrophage (TAM) expression of arginase is implicated in tumor progression, and therapeutic use of arginase inhibitors has been studied in various cancers. However, investigating potential cSCC immunotherapies including arginase inhibition in pre-clinical models is hampered by the lack of appropriate tumor models in immunocompetent mice. PDV is a cSCC cell line derived from chemical carcinogenesis of mouse keratinocytes. PDVC57 cells were derived from a PDV tumor in C57BL/6 (B6) mice. Unlike PDV, PDVC57 tumors grow consistently in B6 mice, and have increased TAMs, decreased dendritic and T cell intra-tumor infiltration. Arginase inhibition in cSCC tumors using Nω-hydroxy-nor-arginine (nor-NOHA) reduced tumor growth in B6 mice but not immunodeficient Rag1-deficient mice. nor-NOHA administration increased dendritic and T cell tumor-infiltration and PD-1 expression. The combination of nor-NOHA and anti-PD-1 therapy with nivolumab enhanced anti-PD-1 therapeutic efficacy. This study demonstrates the therapeutic potential of transcutaneous arginase inhibition in cSCC. A competent immune microenvironment is required for tumor growth inhibition using this arginase inhibitor. Synergistic co-inhibition of tumor growth in these results, supports further examination of transcutaneous arginase inhibition as a therapeutic modality for cSCC.

Aligning SARS-CoV-2 indicators via an epidemic model: application to hospital admissions and RNA detection in sewage sludge.

Ascertaining the state of coronavirus outbreaks is crucial for public health decision-making. Absent repeated representative viral test samples in the population, public health officials and researchers alike have relied on lagging indicators of infection to make inferences about the direction of the outbreak and attendant policy decisions. Recently researchers have shown that SARS-CoV-2 RNA can be detected in municipal sewage sludge with measured RNA concentrations rising and falling suggestively in the shape of an epidemic curve while providing an earlier signal of infection than hospital admissions data. The present paper presents a SARS-CoV-2 epidemic model to serve as a basis for estimating the incidence of infection, and shows mathematically how modeled transmission dynamics translate into infection indicators by incorporating probability distributions for indicator-specific time lags from infection. Hospital admissions and SARS-CoV-2 RNA in municipal sewage sludge are simultaneously modeled via maximum likelihood scaling to the underlying transmission model. The results demonstrate that both data series plausibly follow from the transmission model specified and provide a 95% confidence interval estimate of the reproductive number R0 ≈ 2.4 ± 0.2. Sensitivity analysis accounting for alternative lag distributions from infection until hospitalization and sludge RNA concentration respectively suggests that the detection of viral RNA in sewage sludge leads hospital admissions by 3 to 5 days on average. The analysis suggests that stay-at-home restrictions plausibly removed 89% of the population from the risk of infection with the remaining 11% exposed to an unmitigated outbreak that infected 9.3% of the total population.

Measurement of SARS-CoV-2 RNA in wastewater tracks community infection dynamics.

We measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA concentrations in primary sewage sludge in the New Haven, Connecticut, USA, metropolitan area during the Coronavirus Disease 2019 (COVID-19) outbreak in Spring 2020. SARS-CoV-2 RNA was detected throughout the more than 10-week study and, when adjusted for time lags, tracked the rise and fall of cases seen in SARS-CoV-2 clinical test results and local COVID-19 hospital admissions. Relative to these indicators, SARS-CoV-2 RNA concentrations in sludge were 0-2 d ahead of SARS-CoV-2 positive test results by date of specimen collection, 0-2 d ahead of the percentage of positive tests by date of specimen collection, 1-4 d ahead of local hospital admissions and 6-8 d ahead of SARS-CoV-2 positive test results by reporting date. Our data show the utility of viral RNA monitoring in municipal wastewater for SARS-CoV-2 infection surveillance at a population-wide level. In communities facing a delay between specimen collection and the reporting of test results, immediate wastewater results can provide considerable advance notice of infection dynamics.

Transient Sox9 Expression Facilitates Resistance to Androgen-Targeted Therapy in Prostate Cancer.

PURPOSE: Patients with metastatic prostate cancer are increasingly presenting with treatment-resistant, androgen receptor-negative/low (AR-/Low) tumors, with or without neuroendocrine characteristics, in processes attributed to tumor cell plasticity. This plasticity has been modeled by Rb1/p53 knockdown/knockout and is accompanied by overexpression of the pluripotency factor, Sox2. Here, we explore the role of the developmental transcription factor Sox9 in the process of prostate cancer therapy response and tumor progression. EXPERIMENTAL DESIGN: Unique prostate cancer cell models that capture AR-/Low stem cell-like intermediates were analyzed for features of plasticity and the functional role of Sox9. Human prostate cancer xenografts and tissue microarrays were evaluated for temporal alterations in Sox9 expression. The role of NF-κB pathway activity in Sox9 overexpression was explored. RESULTS: Prostate cancer stem cell-like intermediates have reduced Rb1 and p53 protein expression and overexpress Sox2 as well as Sox9. Sox9 was required for spheroid growth, and overexpression increased invasiveness and neural features of prostate cancer cells. Sox9 was transiently upregulated in castration-induced progression of prostate cancer xenografts and was specifically overexpressed in neoadjuvant hormone therapy (NHT)-treated patient tumors. High Sox9 expression in NHT-treated patients predicts biochemical recurrence. Finally, we link Sox9 induction to NF-κB dimer activation in prostate cancer cells. CONCLUSIONS: Developmentally reprogrammed prostate cancer cell models recapitulate features of clinically advanced prostate tumors, including downregulated Rb1/p53 and overexpression of Sox2 with Sox9. Sox9 is a marker of a transitional state that identifies prostate cancer cells under the stress of therapeutic assault and facilitates progression to therapy resistance. Its expression may index the relative activity of the NF-κB pathway.

DUSP22-IRF4 rearrangement in AIDS-associated ALK-negative anaplastic large cell lymphoma.

Patients with AIDS have increased risk of developing lymphomas, such as anaplastic large cell lymphoma (ALCL), which generally carry a poor prognosis. The DUSP-IRF4 genetic rearrangement in ALCL confers a favourable prognosis in HIV-negative patients; it is unknown how this interacts clinically with HIV/AIDS. A man aged 53 years presented with subcutaneous nodules on the scalp and axillae, and diffuse lymphadenopathy. Biopsy of subcutaneous nodule and lymph node showed large atypical anaplastic lymphocytes which were CD30+ and anaplastic lymphoma kinase-negative, consistent with primary systemic ALCL. In addition, he was found to be HIV-positive and diagnosed with AIDS. Genetic testing of the tissue revealed a DUSP22-IRF4 rearrangement. Complete remission was achieved with HyperCVAD and subsequent brentuximab vedotin monotherapy. We report a case of AIDS-associated primary systemic ALCL with a DUSP22-IRF4 rearrangement. AIDS-associated ALCL is an aggressive lymphoma, with a poor prognosis. However, the presence of the genetic rearrangement, previously unseen in this disease, drastically altered the disease course. This case highlights the value of genetic testing and identifies DUSP22-IRF4-associated ALCL in the setting of HIV-associated lymphoproliferative disorders.

Human keratinocyte carcinomas have distinct differences in their tumor-associated macrophages.

Cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) have different clinical behaviors, despite both being keratinocyte carcinomas mainly caused by ultraviolet radiation. Whether these distinct features are associated with tumor-associated macrophages (TAMs) is largely unknown. The main goal of this study was to conduct a comprehensive analysis of density and polarization states of TAMs in SCCs versus BCCs. The role of lactic acid in TAM polarization in SCC versus BCC was examined. We found that SCCs have a higher density of CD68 + TAMs compared to BCCs. TAMs in SCCs express higher levels of TAM-associated markers (arginase-1, MMP9, CD40 and CD127) than those in BCCs. Interestingly, differential expression of TAM-associated markers between SCCs and BCCs was reproduced in human monocytic THP-1 cells stimulated with SCC- or BCC-conditioned media. Analysis of soluble factor(s) in these tumors further revealed that SCCs have a significantly higher concentration of lactic acid than BCCs, and lactic acid was sufficient to upregulate TAM markers. Our results demonstrate that TAMs in SCCs versus BCCs differ in density and polarization states, which can be determined by soluble factors including tumor-derived lactic acid. These differences in TAMs may contribute to the distinct clinical behaviors of SCCs versus BCCs. This work was supported by grants from the National Institutes of Health and the Doris Duke Charitable Foundation. RESEARCH IN CONTEXT: Few studies have studied tumor-associated macrophages in the context of SCC versus BCC. It has been demonstrated that macrophages mobilize to the epidermis after being exposed to ultraviolet-B radiation and produce interleukin-10 (IL-10). It has also been shown that the production of IL-10 results in the evasion of T cell-mediated immunity in BCCs and SCCs. However, the relationship between TAMs and the clinical behaviors of SCCs and BCCs remains largely unclear. Our study shows that despite their similar origins, human cutaneous SCCs and BCCs are considerably different in their TAMs. To our knowledge, these results provide the first evidence of differential TAM density and polarization in SCCs versus BCCs, which may contribute to their characteristic clinical behaviors. Future studies are necessary to elucidate the mechanisms by which TAMs influence these cancers with the goal of developing therapies tailored to each type of malignancy.

Prediction Accuracy of Common Prognostic Scoring Systems for Metastatic Spine Disease: Results of a Prospective International Multicentre Study of 1469 Patients.

STUDY DESIGN: A prospective multicenter cohort study. OBJECTIVE: To assess the clinical accuracy of six commonly cited prognostic scoring systems for patients with spinal metastases. SUMMARY OF BACKGROUND DATA: There are presently several available methods for the estimation of prognosis in metastatic spinal disease, but none are universally accepted by surgeons for clinical use. These scoring systems have not been rigorously tested and validated in large datasets to see if they are reliable enough to inform day-to-day patient management decisions. We tested these scoring systems in a large cohort of patients. A total of 1469 patients were recruited into a secure internet database, and prospectively collected data were analyzed to assess the accuracy of published prognostic scoring systems. METHODS: We assessed six prognostic scoring systems, described by the first authors Tomita, Tokuhashi, Bauer, van der Linden, Rades, and Bollen. Kaplan-Meier survival estimates were created for different patient subgroups as described in the original publications. Harrell's C-statistic was calculated for the survival estimates, to assess the concordance between estimated and actual survival. RESULTS: All the prognostic scoring systems tested were able to categorize patients into separate prognostic groups with different overall survivals. However none of the scores were able to achieve "good concordance" as assessed by Harrell's C-statistic. The score of Bollen and colleagues was found to be the most accurate, with a Harrell's C-statistic of 0.66. CONCLUSION: No prognostic scoring system was found to have a good predictive value. The scores of Bollen and Tomita were the most effective with Harrell's C-statistic of 0.66 and 0.65, respectively. Prognostic scoring systems are calculated using data from previous years, and are subject to inaccuracies as treatments advance in the interim. We suggest that other methods of assessing prognosis should be explored, such as prognostic risk calculation. LEVEL OF EVIDENCE: 3.

The Effect of Insurance Type on Patient Access to Ankle Fracture Care Under the Affordable Care Act.

The purpose of this study is to assess the effect of insurance type (Medicaid, Medicare, private insurance) on the ability for patients with operative ankle fractures to access orthopedic traumatologists. The research team called 245 board-certified orthopedic surgeons specializing in orthopedic trauma within 8 representative states. The caller requested an appointment for their fictitious mother in order to be evaluated for an ankle fracture which was previously evaluated by her primary care physician and believed to require surgery. Each office was called 3 times to assess the response for each insurance type. For each call, information was documented regarding whether the patient was able to receive an appointment and the barriers the patient confronted to receive an appointment. Overall, 35.7% of offices scheduled an appointment for a patient with Medicaid, in comparison to 81.4%and 88.6% for Medicare and BlueCross, respectively (P < .0001). Medicaid patients confronted more barriers for receiving appointments. There was no statistically significant difference in access for Medicaid patients in states that had expanded Medicaid eligibility vs states that had not expanded Medicaid. Medicaid reimbursement for open reduction and internal fixation of an ankle fracture did not significantly correlate with appointment success rates or wait times. Despite the passage of the Affordable Care Act, patients with Medicaid have reduced access to orthopedic surgeons and more complex barriers to receiving appointments. A more robust strategy for increasing care-access for patients with Medicaid would be more equitable.

Metastatic Spine Tumor Epidemiology: Comparison of Trends in Surgery Across Two Decades and Three Continents.

BACKGROUND: Indications for surgery for symptomatic spinal metastases have become better defined in recent years, and suitable outcome measures have been established against a changing backdrop of patient characteristics, tumor behavior, and oncologic treatments. Nonetheless, variations still exist in the local management of patients with spinal metastases. In this study, we aimed to review global trends and habits in the surgical treatment of symptomatic spinal metastases, and to examine how these have changed over the last 25 years. METHODS: In this cohort study of consecutive patients undergoing surgery for symptomatic spinal metastases, data were collected using a secure Internet database from 22 centers across 3 continents. All patients were invited to participate in the study, except those unable or unwilling to give consent. RESULTS: There was a higher incidence of colonic, liver, and lung carcinoma metastases in Asian countries, and more frequent presentation of breast, prostate, melanoma metastases in the West. Trends in surgical technique were broadly similar across the centers. Overall survival rates after surgery were 53% at 1 year, 31% at 2 years, and 10% at 5 years after surgery (standard error 0.013 for all). Survival improved over successive time periods, with longer survival in patients who underwent surgery in 2011-2016 compared with those who underwent surgery in earlier time periods. CONCLUSIONS: Surgical habits have been fairly consistent among countries worldwide and over time. However, patient survival has improved in later years, perhaps due to medical advances in the treatment of cancer, improved patient selection, and operating earlier in the course of disease.

The Use of Soft Tissue Expanders Prior to Total Ankle Arthroplasty.

Soft tissue coverage and tension-free closure can often be challenging in patients with ankle arthropathy being considered for total ankle arthroplasty. We present 2 patients with severe posttraumatic ankle arthropathy who underwent placement of a soft tissue expander to assist with soft tissue coverage prior to total ankle arthroplasty. LEVELS OF EVIDENCE: Level IV.

Traumatic Testicular Dislocation Associated with Lateral Compression Pelvic Ring Injury and T-Shaped Acetabulum Fracture.

We report a case of a unilateral testicular dislocation to the superficial inguinal region associated with a lateral compression type pelvic ring injury (OTA classification 61-C3.3a2, b2, c3) and left T-shaped acetabulum fracture (OTA classification 62-B2) in a 44-year-old male who was in a motorcycle accident. The testicular dislocation was noted during the emergency department primary survey, and its location and viability were verified with ultrasound. The testicle was isolated during surgical stabilization of the left acetabulum through a Pfannenstiel incision and modified-Stoppa approach and returned through the inguinal canal to the scrotum. In follow-up, the patient did not suffer urologic or sexual dysfunction. All motorcycle collision patients presenting with pelvic ring injuries or acetabulum fractures should be worked up for possible testicular dislocation with a scrotal exam. Advanced imaging and a urologic consult may be necessary to detect and treat these injuries.

Prospective, multicenter study of postoperative deep-vein thrombosis in patients with haemophilia undergoing major orthopaedic surgery.

Perioperative clotting factor replacement is administered to reverse the inherent haemostatic defect in persons with haemophilia (PWH), potentially increasing their risk for developing venous thromboembolism (VTE) postoperatively. It was our objective to determine the prevalence of VTE in PWH undergoing total hip or knee arthroplasty (THA, TKA). Patients with haemophilia A or B who underwent THA or TKA were enrolled in this prospective, multicentre observational cohort study. Lower extremity venous duplex ultrasound was performed prior to surgery and 4-6 weeks after surgery. Eleven centres enrolled 51 subjects, 46 of whom completed the study. Six subjects (13.0 %) were treated with bypass agents perioperatively; the remaining 40 subjects received factor VIII or IX replacement. Intermittent pneumatic compression devices were utilised postoperatively in 23 subjects (50 %), and four subjects (8.7 %) also received low-molecular-weight heparin prophylaxis. One subject (2.2 %) with moderate haemophilia A was diagnosed with symptomatic distal deep-vein thrombosis (DVT) on day 6 following TKA. One subject (2.2 %) with severe haemophilia A was diagnosed with pulmonary embolism on day 9 following bilateral TKA. No subjects had asymptomatic DVT. Eighteen subjects (39.1 %) had major bleeding, and three subjects (6.5 %) experienced minor bleeding. The observed prevalence of ultrasound-detectable, asymptomatic DVT in PWH following TKA or THA in this study was low, but the incidence of symptomatic VTE (4.3 %, 95 % CI, 0.5-14.8 %) appeared similar to the estimated incidence in the general population without thromboprophylaxis.