Treatment responsive acute GVHD after posttransplant cyclophosphamide-based prophylaxis: incidence and clinical outcomes.

BACKGROUND: Post-transplant cyclophosphamide (PTCy) following hematopoietic cell transplantation (HCT) has emerged as standard of care for graft-versus-host disease (GVHD) prevention in adult patients without increasing malignant relapse. We previously defined acute GVHD (aGVHD) treatment response categories as either corticosteroid-sensitive (SS), dependent (SD), or resistant (SR) based on response to first-line corticosteroids and reported their clinical outcomes following non-PTCy based prophylaxis. Over one-third of patients developed aGVHD requiring systemic therapy. Cases were predominantly SR with a 14% overall incidence of SR aGVHD. The incidence and clinical outcomes of these three distinct aGVHD treatment response groups following PTCy-based prophylaxis is not well described. OBJECTIVE: The objective of this retrospective, single-institution, cohort study was to assess the incidence and clinical outcomes of SS, SD, and SR aGVHD following HCT with PTCy-based prophylaxis using a prophylactic regimen of PTCy, tacrolimus, and mycophenolate mofetil (MMF). STUDY DESIGN: We included 196 consecutive (2017-2021) adult and pediatric patients receiving allogeneic HCT for malignant and non-malignant disorders at the University of Minnesota. Patients received PTCy on days +3 and +4 plus tacrolimus and mycophenolate mofetil prophylaxis. Bone marrow (BM) and peripheral blood stem cell (PBSC) graft sources and related and unrelated donors were included. Recipients received myeloablative (MAC) or reduced-intensity conditioning (RIC) regimens. RESULTS: In 196 allografts, 54 (28%) developed aGVHD before day +180 with median time to onset of 50 days (IQR 34-71 days). Of those, 32 patients (16% overall) developed maximum grade II-III aGVHD requiring systemic corticosteroids with the following response: 13 (41%) SS, 10 (31%) SD, and 9 (28%) SR. Overall incidence of SR aGVHD was 4.6%. Only 12 patients (6%) developed maximum grade III aGVHD while none had grade IV aGVHD. 2-year overall survival analyzed from 80 days after initiation of systemic treatment was similar in the SS and SD groups (77 and 75%, respectively), comparable to those without aGVHD (81%), but was lowest in the SR group (20%) with GVHD being the primary cause of death. Non-relapse mortality (NRM) was highest in the SR group. MN high risk and higher GVHD grade at onset were risk factors for developing SR aGVHD. CONCLUSIONS: Overall, we report a low incidence (16%) of aGVHD requiring systemic corticosteroids with PTCy-based prophylaxis. Acute GVHD cases were predominantly SS aGVHD with a lower incidence of SD and SR aGVHD. Our findings suggest that PTCy-based prophylaxis reduces rates of treatment resistant aGVHD. Patients with SR aGVHD had the worst clinical outcomes and poorest survival. Those with SS and SD aGVHD had similar clinical outcomes, both better than SR aGVHD.

Treatment-Sensitive and Treatment-Dependent Chronic Graft-versus-Host Disease Yield Superior Failure-Free and Overall Survival Compared to Treatment-Resistant Chronic Graft-versus-Host Disease.

Response to treatment of chronic graft-versus-host disease (cGVHD) may help predict prognosis and outcomes. We hypothesized that the response of cGVHD to treatment and the ability to taper immunosuppression define distinct treatment response categories that differ in terms of risk factors and prognosis. Our aim was to determine specific clinical characteristics and outcomes associated with 3 distinct cGVHD treatment response groups based on the response to and duration of immunosuppressive therapy (IST) as treatment-sensitive (TS), treatment-resistant (TR), and treatment-dependent (TD) cGVHD. This retrospective single-institution cohort study included 1142 consecutive adult and pediatric recipients of allogeneic hematopoietic cell transplantation (HCT) performed for malignant and nonmalignant disorders at the University of Minnesota between 2008 and 2016. All donor, graft, conditioning regimen, and GVHD prophylaxis strategies were included, but only patients who commenced systemic treatment within 30 days of cGVHD diagnosis were included. A total of 185 patients who developed cGVHD necessitating IST within 30 days of cGVHD diagnosis were included in this analysis. At 1 year after cGVHD onset, 13% of the patients were TS, 27% were TD, and 60% were TR (including 14% deceased), whereas at 2 years after cGVHD onset, 29% were TS, 5% were TD, and 66% were TR (including 22% deceased). In a landmark analysis starting at 1 year after cGVHD onset, 5-year failure-free survival (FFS) and overall survival (OS) were lowest in the TR group (FFS, 38%; OS, 70%), with comparable outcomes in the TD (74% and 82%, respectively) and TS (79% for both) groups. Compared to no cGVHD, TR cGVHD was associated with worse OS at 5 years after cGVHD (hazard ratio, 2.09 versus no cGVHD; 95% confidence interval, 1.3 to 3.3; P < .01). Our findings suggest that refining cGVHD classification into 3 treatment response states defines important predictors of early and late clinical outcomes and identifies patients needing more effective treatment.

Natural history of craniovertebral abnormalities in a single-center study in 54 patients with Hurler syndrome.

OBJECTIVE: Craniovertebral junction (CVJ) abnormalities are common and well documented in mucopolysaccharidosis type I-Hurler syndrome (MPS IH), often causing severe spinal canal narrowing. However, the requirement for surgical decompression and/or fusion is uncommon. Although hematopoietic cell transplant (HCT) has been shown to prolong the lives of patients with MPS IH, its effect in halting or reversing musculoskeletal abnormalities is less clear. Unfortunately, there are currently no universal guidelines for imaging or indication for surgical interventions in these patients. The goal of this study was to track the progression of the CVJ anatomy in patients with MPS IH following HCT, and to examine radiographic features in patients who needed surgical intervention. METHODS: Patients with MPS IH treated at the University of Minnesota with allogeneic HCT between 2008 and 2020 were retrospectively reviewed. Patients who underwent CVJ surgery were identified with chart review. All MPS IH cervical scans were examined, and the odontoid retroflexion angle, clivoaxial angle (CXA), canal width, and Grabb-Oakes distance (pB-C2) were measured yearly for up to 7 years after HCT. Longitudinal models based on the measurements were made. An intraclass correlation coefficient was used to measure interrater reliability. Nine children without MPS IH were examined for control CVJ measurements. RESULTS: A total of 253 cervical spine MRI scans were reviewed in 54 patients with MPS IH. Only 4 (7.4%) patients in the study cohort required surgery. Three of them had posterior fossa and C1 decompression, and 1 had a C1-2 fusion. There was no statistically significant difference in the spinal parameters that were examined between surgery and nonsurgery groups. Among the measurements, canal width and CXA varied drastically in patients with different neck positions. Odontoid retroflexion angle and CXA tended to decrease with age. Canal width and pB-C2 tended to increase with age. CONCLUSIONS: Based on the data, the authors observed an increase in canal width and pB-C2, whereas the CXA and odontoid retroflexion angle became more acute as the patients aged after HCT. The longitudinal models derived from these data mirrored the development in children without MPS IH. Spinal measurements obtained on MR images alone are not sufficient in identifying patients who require surgical intervention. Symptom monitoring and clinical examination, as well as pathological spinal cord changes on MRI, are more crucial in assessing the need for surgery than is obtaining serial imaging.

Impact of melphalan day -1 vs day -2 on outcomes after autologous stem cell transplant for multiple myeloma.

Background: Melphalan is the most common conditioning regimen used prior to autologous stem cell transplant (ASCT); however, there are varying data on optimal melphalan timing prior to transplant for best safety and efficacy. Historically, ASCT conditioning consisted of melphalan 200 mg/m2 on day 2 (D-2) (48 h prior to ASCT), but many institutions have since adopted a melphalan protocol with administration on day 1 (D-1) (24 h prior to SCT) or split dosing over the 2 days. The optimal timing of melphalan has yet to be determined. Methods: In this single-center retrospective study, we analyzed transplant outcomes for patients between March 2011 and September 2020 admitted for high-dose, single-agent melphalan 200 mg/m2 on D-1 vs. D-2. The primary outcomes were time to neutrophil and platelet engraftment. Secondary outcomes include incidence of hospital readmission within 30 days, 2-year progression-free survival, and 2-year overall survival. Results: A total of 366 patients were studied (D-2 n = 269 and D-1 n = 97). The incidence of high-risk cytogenetics was similar between the two groups (37% vs. 40%). Median days to absolute neutrophil count engraftment was similar at 11 days in the D-2 and D-1 cohort (n = 269, range 0-14, IQR 11-11 vs. n = 97, range 0-14, IQR 11-12). Median days to platelet engraftment >20,000/mcL was 18 days for D-2 melphalan (range: 0-28, IQR 17-20) versus 19 days for D-1 melphalan (range: 0-32, IQR 17-21). Overall survival at 2 years post-transplant was similar in both cohorts (94%; p = 0.76), and PFS was 70% in D-2 compared with 78% in D-1 (p = 0.15). In a multivariable model including age and performance status, hospital readmission within 30 days of transplant was higher in the D-1 cohort (odds ratio 1.9; p = 0.01). Conclusion: This study demonstrates similar neutrophil and platelet engraftment in D-1 and D-2 melphalan cohorts with similar 2-year PFS and OS. Either D-2 or D-1 melphalan dosing schedule is safe and effective.

Digital and manual interfollicular Ki-67 are associated with a progression-free survival in patients with low-grade follicular lymphoma.

OBJECTIVES: Novel histopathologic prognostic factors are needed to identify patients with follicular lymphoma (FL) at risk of inferior outcomes. Our primary objective was to evaluate the Ki-67 proliferative index in follicular and interfollicular areas in tissue biopsy specimens from patients with newly diagnosed FL and correlate with clinical outcomes. Our secondary objective was to correlate PD-L1 and LAG-3 with clinical outcomes. METHODS: Seventy cases of low-grade FL from the University of Minnesota were evaluated with Ki-67 immunohistochemical stain. Ki-67 expression as a continuous variable was interpreted digitally and manually in follicular and interfollicular areas. Progression-free survival (PFS) and overall survival (OS) were analyzed by Cox regression, and hazard ratios (HRs) per 10-point increase in Ki-67 were calculated. RESULTS: Progression-free survival at 4 years was 28% (95% CI, 19%-41%). Interfollicular, but not follicular, Ki-67 was associated with PFS by manual (HR, 1.33; P = .01) and digital (HR, 1.38; P = .02) analysis. Digital and manual Ki-67 were only moderately correlated but demonstrated similar effects on PFS. At 4 years, OS was 90% with no association with follicular or interfollicular Ki-67 proliferation. CONCLUSIONS: Higher interfollicular Ki-67 by either digital or manual analysis is associated with a poorer PFS in patients with low-grade FL. These results suggest further validation of this marker is warranted to improve pathologic risk stratification at FL diagnosis. PD-L1 and LAG-3 were not associated with PFS or OS.

Epilepsy in cardiofaciocutaneous syndrome: Clinical burden and response to anti-seizure medication.

Treatment-resistant epilepsy is among the most serious complications of cardiofaciocutaneous syndrome (CFCS), a rare disorder caused by germline variants in the RAS-MAPK signaling pathway. This study analyzed the clinical characteristics of epilepsy and response to anti-seizure medications (ASMs) in a multinational CFCS cohort. A caregiver survey provided data regarding seizure history, use of ASMs and other treatment approaches, adverse effects, caregiver perception of treatment response, and neurological disease burden impact among individuals with CFCS. Results from 138 survey responses were quantitatively analyzed in conjunction with molecular genetic results and neurological records. The disease burden impact of CFCS was higher among individuals with epilepsy (n = 74/138), especially those with more severe seizure presentation. Oxcarbazepine, a sodium-channel blocker, had the best seizure control profile with relatively infrequent adverse effects. The most commonly prescribed ASM, levetiracetam, demonstrated comparatively poor seizure control. ASM efficacy was generally similar for individuals with BRAF and MAP2K1 gene variants. The high proportion of patients with CFCS who experienced poor seizure control despite use of multiple ASMs highlights a substantial unmet treatment need. Prospective study of ASM efficacy and clinical trials of therapies to attenuate RAS-MAPK signaling may improve avenues for clinical management.

Comparison of peripheral leukocyte parameters in patients receiving conventionally and hypofractionated radiotherapy schemes for the treatment of newly diagnosed glioblastoma.

Introduction: Treatment for glioblastomas, aggressive and nearly uniformly fatal brain tumors, provide limited long-term success. Immunosuppression by myeloid cells in both the tumor microenvironment and systemic circulation are believed to contribute to this treatment resistance. Standard multi-modality therapy includes conventionally fractionated radiotherapy over 6 weeks; however, hypofractionated radiotherapy over 3 weeks or less may be appropriate for older patients or populations with poor performance status. Lymphocyte concentration changes have been reported in patients with glioblastoma; however, monocytes are likely a key cell type contributing to immunosuppression in glioblastoma. Peripheral monocyte concentration changes in patients receiving commonly employed radiation fractionation schemes are unknown. Methods: To determine the effect of conventionally fractionated and hypofractionated radiotherapy on complete blood cell leukocyte parameters, retrospective longitudinal concentrations were compared prior to, during, and following standard chemoradiation treatment. Results: This study is the first to report increased monocyte concentrations and decreased lymphocyte concentrations in patients treated with conventionally fractionated radiotherapy compared to hypofractionated radiotherapy. Discussion: Understanding the impact of fractionation on peripheral blood leukocytes is important to inform selection of dose fractionation schemes for patients receiving radiotherapy.

Malignant Melanoma in a Retrospective Cohort of Immunocompromised Patients: A Statistical and Pathologic Analysis.

BACKGROUND: Malignant melanoma is the leading cause of death due to cutaneous malignancy. Immunocompromised individuals have an elevated risk of developing melanoma. We aimed to provide histopathologic and statistical characterization of melanoma development in immunocompromised patients. METHODS: We reviewed our institution's databases to identify all patients with a confirmed history of immunosuppression who subsequently developed melanoma, focusing on diagnoses during the follow-up period of 2011-2019. A total of 93 patients with a combined 111 melanoma lesions were identified. RESULTS: Common causes of immunosuppression included transplantation and lymphoproliferative disorders. Superficial spreading and lentigo malignant melanoma were the most common malignant melanoma subtypes. Median Breslow depth was 0.7 mm, and the most common primary tumor stage was T1a. Our transplant sub-cohort had an overall melanoma incidence of 0.9 per 1000 person-years (95% CI 0.66 to 1.20) and a standardized incidence ratio (SIR) of 1.53 (95% CI 1.12 to 2.04) relative to a general population cohort from the Surveillance, Epidemiology, and End Results Program (SEER). CONCLUSIONS: We report histopathologic characteristics of immunocompromised patients developing melanoma at a large academic tertiary-care center. Differences in age, sex, time since transplantation, and transplant type may play a significant role in melanoma SIR in this patient demographic.

Receptor for hyaluronan-mediated motility (RHAMM) defines an invasive niche associated with tumor progression and predicts poor outcomes in breast cancer patients.

Breast cancer invasion and metastasis result from a complex interplay between tumor cells and the tumor microenvironment (TME). Key oncogenic changes in the TME include aberrant synthesis, processing, and signaling of hyaluronan (HA). Hyaluronan-mediated motility receptor (RHAMM, CD168; HMMR) is an HA receptor enabling tumor cells to sense and respond to this aberrant TME during breast cancer progression. Previous studies have associated RHAMM expression with breast tumor progression; however, cause and effect mechanisms are incompletely established. Focused gene expression analysis of an internal breast cancer patient cohort confirmed that increased RHAMM expression correlates with aggressive clinicopathological features. To probe mechanisms, we developed a novel 27-gene RHAMM-related signature (RRS) by intersecting differentially expressed genes in lymph node (LN)-positive patient cases with the transcriptome of a RHAMM-dependent model of cell transformation, which we validated in an independent cohort. We demonstrate that the RRS predicts for poor survival and is enriched for cell cycle and TME-interaction pathways. Further analyses using CRISPR/Cas9-generated RHAMM-/- breast cancer cells provided direct evidence that RHAMM promotes invasion in vitro and in vivo. Immunohistochemistry studies highlighted heterogeneous RHAMM protein expression, and spatial transcriptomics associated the RRS with RHAMM-high microanatomic foci. We conclude that RHAMM upregulation leads to the formation of 'invasive niches', which are enriched in RRS-related pathways that drive invasion and could be targeted to limit invasive progression and improve patient outcomes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Chronic GVHD after steroid-sensitive, -dependent, and -refractory acute GVHD: incidence and clinical outcomes.

Chronic graft-versus-host disease (cGVHD) is a major limitation to the long-term success of allogeneic hematopoietic cell transplantation (HCT). Our prior study of acute GVHD (aGVHD) defined distinct treatment-response groups based on the response to first-line corticosteroids: steroid-sensitive (SS), steroid-resistant (SR), and steroid-dependent (SD) aGVHDs. We conducted a retrospective, single-institution, cohort study to assess the incidence, risk factors, and clinical outcomes of patients with cGVHD after a previous diagnosis of SS, SD, or SR aGVHD, compared with those with no history of aGVHD. Among 784 consecutive adult and pediatric recipients of HCT for hematologic malignancies between 2008 and 2016, 347 (44%) developed aGVHD, with 13% SS, 12% SD, and 19% SR aGVHD. The 3-year cumulative incidence of cGVHD was 25%. Among those with cGVHD, 39% had no prior aGVHD diagnosis, whereas among those with a prior aGVHD diagnosis, 16% had SS, 24% had SD, and 21% had SR aGVHD. Mild or moderate cGVHD was highest among those with preceding SD aGVHD, whereas severe cGVHD was most frequent among those with previous SR aGVHD. We identified SD and SR aGVHDs as significant independent risk factors for the development of cGVHD after allogeneic HCT, whereas SS aGVHD was not a risk factor. Our study demonstrates that cGVHD after SD aGVHD did not have an intermediate prognosis between SR and SS groups as hypothesized; rather, cGVHD after both SD and SR aGVHD have similar prognoses. Our findings suggest that previous aGVHD response states are important predictors of cGVHD severity and outcomes.

A Multicenter Phase 2 Clinical Trial of 10-Day Decitabine, Dose-Escalated Donor Lymphocyte Infusion, and Ruxolitinib for Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Cell Transplantation.

Post-transplantation relapse of acute myeloid leukemia and myelodysplastic syndromes has a poor prognosis. Donor lymphocyte infusion (DLI) is one treatment approach. However, efficacy is limited, and toxicity, mostly in the form of acute graft-versus-host disease (GVHD), is frequent. We tested a novel approach using 10-day decitabine, dose-escalated DLI, and ruxolitinib in a multicenter phase 2 trial aimed at increasing the efficacy of DLI and reducing its toxicity. Up to four 28-day cycles were administered. The primary endpoint was 6-month overall survival (OS). Of the 14 patients who started cycle 1, 13 received 1 DLI, 6 received 2 DLIs, and 1 received 3 4 DLIs. A preplanned interim analysis after enrolling 14 patients suggested futility, and the trial was closed to accrual. The final analysis showed a 6-month OS of 36% (95% confidence interval [CI], 18 to 72), a 1-year progression-free survival of 7% (95% CI, 1% to 47%), a 6-month cumulative incidence of grade II-IV acute GVHD of 57% (95% CI, 26% to 80%), and a 1-year nonrelapse mortality of 14% (95% CI, 2% to 38%). The combined modality treatment studied in this trial was ineffective and did not reduce DLI toxicity.

Nonlinear association between body mass index and overall survival in advanced NSCLC patients treated with immune checkpoint blockade.

BACKGROUND: We investigated the association of body mass index (BMI) modeled as a continuous variable with survival outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI). METHODS: We performed a single-institution retrospective analysis of consecutively diagnosed locally advanced or metastatic NSCLC patients treated with single-agent ICI in the first line or recurrent setting. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and objective response rate (ORR). BMI was modeled using a four-knot restricted cubic spline. Multiple Cox regression was used for survival analysis. RESULTS: Two hundred patients were included (female 54%; never smoker 12%). Adenocarcinoma was the most common histology (61%). Median age was 67 years, median BMI was 25.9 kg/m2, and 65% of patients had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. On multivariable analysis, only BMI and ECOG PS were independently associated with OS (p < 0.01). Mortality risk decreased as the BMI increased from 20 to 30 kg/m2 (HR 0.49, 95% CI 0.28-0.84); however, it was reversed as the BMI surpassed ~ 30 kg/m2. Compared to ECOG PS ≥ 2, patients with ECOG PS of 0-1 had a longer OS (HR 0.42, 95% CI 0.28-0.63). Similar trends were observed with PFS and ORR, but the strength of the association was weaker. CONCLUSION: We observed a nonlinear association between BMI and OS following treatment with ICI in advanced NSCLC. Risk of death increases at both extremes of BMI with a nadir that exists around 30 kg/m2.

Effect of restricting menthol flavored cigarettes or E-cigarettes on smoking behavior in menthol smokers.

Bans of menthol characterizing flavor in tobacco products have been enacted in some localities and proposed in the United States for cigarettes. To gather data regarding how restrictions for menthol in cigarettes and e-cigarettes may affect current menthol cigarette smokers, 37 African American menthol smokers participated in a pilot study in which they were asked to abstain (n = 18) or not abstain from menthol cigarettes (n = 19) for 8-weeks. All participants received menthol flavored e-cigarettes for 4 weeks and tobacco flavored e-cigarettes for 4 weeks in random order. Number of cigarettes smoked per day (estimated mean ratio [EMR] = 0.31; 95% CI: 0.13, 0.72) and exhaled CO concentrations (EMR = 0.61; 95% CI: 0.43, 0.88) were lower in the menthol cigarette abstainer group compared to the menthol cigarette non-abstainer group. Those in the menthol cigarette abstainer group reported higher scores on motivation to quit (p = 0.03) and perceived effectiveness of quitting skills (p = 0.02). There were no substantial effects seen in amount smoked or exhaled CO based on flavor of e-cigarettes provided. Higher e-cigarette use (based on reported puffs per day) was reported in the menthol cigarette abstainer (vs. non-abstainer) group (p < 0.01) and also during the 4-week period when provided with menthol (vs. tobacco) e-cigarettes (p < 0.01). These data suggest that the potential of e-cigarettes to reduce tobacco related harm may be enhanced if combined with a ban on menthol flavor in combustible cigarettes. Larger studies are needed to determine the effect of limiting menthol in e-cigarettes on smoking behavior among current menthol smokers.

Impact of pectoralis muscle loss on cardiac outcome and survival in Cancer patients who received anthracycline based chemotherapy: retrospective study.

INTRODUCTION: The impact of pectoralis muscle mass index (PMI) on cardiac events is not well studied in cancer patients, especially in those who have received chemotherapy with high potential cardiac toxicity such as anthracyclines. METHODS: Individuals aged ≥18 years with a diagnosis of breast cancer, sarcoma, or lymphoma who received anthracycline-based chemotherapy at the University of Minnesota MHealth Fairview between 2009 and 2014. Eligible patients had to have two CT scans: a baseline CT scan within 6 months prior to chemotherapy and a follow-up CT scan within 2 years after treatment. The PMI was calculated as the right pectoralis muscle area indexed to height squared. Multivariable linear regression was used to analyze factors associated with PMI at follow-up, overall mortality, and major cardiac events (MACE). RESULTS: A total of 474 patients (breast cancer 192; lymphoma 184; sarcoma 98) participated with a median age of 61 years at the time of baseline CT scan; 161 (34%) were male. Almost all patients received anthracyclines except 12% who received trastuzumab only. The median baseline PMI was 5.8 cm2/m2 (4.9, 7.7) which decreased 10.5% after chemotherapy, to 5.2 cm2/m2 (4.4, 6.4). Baseline PMI was not significantly associated with OS, but we detected lower risks of MACE with larger PMI at baseline. Greater baseline PMI was associated with greater follow-up PMI, but also with greater relative PMI loss. Female gender, older age, and history of smoking were also associated with greater PMI losses. CONCLUSION: Greater pre-treatment pectoralis muscle index in patients treated with anthracyclines have a lower risk of MACE. Early identification of sarcopenia using PMI could trigger proactive engagement for intervention and risk-stratified therapies.

Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study.

PURPOSE: Dysregulation of RAS or its major effector pathway is the molecular mechanism of RASopathies, a group of multisystemic congenital disorders. Neurologic complications are especially challenging in the management of the rare RASopathy cardiofaciocutaneous (CFC) syndrome. This study evaluated clinical neurologic and neurodevelopmental features and their associations with CFC syndrome gene variants. METHODS: A multinational cohort of 138 individuals with CFC syndrome (BRAF = 90, MAP2K1 = 36, MAP2K2 = 10, KRAS = 2) was recruited. Neurologic presentation was captured via clinician review of medical records and caregiver-completed electronic surveys. Validated measures of seizure severity, adaptive function, and gross motor function were obtained. RESULTS: The overall frequency of intellectual disability and seizures was 82% and 55%, respectively. The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants. A disproportionate incidence of severe, treatment-resistant seizures was observed in patients with variants in the catalytic protein kinase domain of BRAF and at the common p.Y130 site of MAP2K1. Neurodevelopmental outcomes were associated with genotype as well as seizure severity. CONCLUSION: Molecular genetic testing can aid in prediction of epilepsy and neurodevelopmental phenotypes in CFC syndrome. Study results identified potential CFC syndrome-associated variants in the development of relevant animal models for neurologic, neurocognitive, and motor function impairment.

Five-Year Cumulative Incidence of Axillary Web Syndrome and Comparison in Upper Extremity Movement, Function, Pain, and Lymphedema in Survivors of Breast Cancer With and Without Axillary Web Syndrome.

OBJECTIVE: To determine the cumulative incidence and natural history of axillary web syndrome (AWS) and its related postoperative risk for physical impairments in a cohort of women followed for 5 years post breast cancer surgery. DESIGN: Prospective, longitudinal study. SETTING: Academic health center. PARTICIPANTS: Women (N=36) with and without AWS after breast cancer surgery with sentinel node biopsy or axillary lymph node dissection. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were assessed for AWS, shoulder goniometric flexion and abduction range of motion, function (Disability of the Arm, Shoulder, and Hand), lymphedema (bioimpedance spectroscopy, girth measures, tissue dielectric constant), and pain (visual analog scale) at 2, 4, 12, and 78 weeks and 5 years after breast cancer surgery. Analysis of variance compared range of motion, function, lymphedema, and pain in women identified with AWS with those without AWS across visits. Univariate logistic regression assessed if AWS was a risk factor for physical impairment at 5 years. RESULTS: The cumulative incidence of AWS was 57%. Fifty percent (14/28) of the women who completed all study visits had signs of AWS at 5 years. Abduction active range of motion was significantly lower in women with AWS at 2 and 4 weeks post surgery. AWS was identified as a risk factor for reduced shoulder motion at 5 years. Regardless of AWS, 75% of the women experienced 1 or more upper extremity physical impairments at 5 years, which is an increase from 66% at 78 weeks in the same cohort. CONCLUSIONS: AWS is associated with reduced shoulder range of motion in the early postoperative time period, can persist for 5 years after breast cancer surgery, and increases the risk of long-term reduced shoulder range of motion. Long-term physical issues are apparent after breast cancer surgery regardless of AWS.

Effect on Tobacco Use and Subjective Measures of Including E-cigarettes in a Simulated Ban of Menthol in Combustible Cigarettes.

INTRODUCTION: Bans of menthol characterizing flavor in tobacco products have been proposed; however, there is limited data regarding the impact on current menthol cigarette smokers of including e-cigarettes in such bans. METHODS: In this six-week pilot study, 47 menthol smokers were randomized to receive all tobacco products from an experimental marketplace simulating either no menthol ban, a menthol ban for cigarettes but not e-cigarettes, or a ban for both ("total menthol ban"). RESULTS: At the first visit, all but one participant selected cigarettes with e-cigarettes selected by 38%, 69%, and 40% of participants in the no ban, menthol cigarette ban, and total menthol ban groups, respectively. Over the study period, the total menthol ban group smoked more than the menthol cigarette ban group (estimated mean ratio [EMR] in cigarettes per day = 1.38; 95% CI: 1.1, 1.75; p = .006). Compared to the no ban condition, the menthol cigarette ban group smoked slightly fewer (EMR = 0.87; 95% CI: .68, 1.11) and the total menthol ban group smoked slightly more (EMR = 1.20; 95% CI: 1.00, 1.45) although neither difference reached statistical significance. In both menthol ban conditions, ratings were lower (vs. no ban) on several measures of craving and cigarette effects and liking. CONCLUSIONS: Menthol bans that include e-cigarettes may result in different patterns of tobacco use than if only combustible cigarettes are included, although e-cigarettes were not extensively used in any group. Larger studies are needed to determine policies most likely to provide the largest public health benefit. IMPLICATIONS: Bans of menthol characterizing flavor have been proposed, however, the effects on menthol cigarette smokers of including e-cigarettes in such bans are not clear. This study found that smokers randomized to a simulated ban on menthol in both cigarettes and e-cigarettes smoked more cigarettes per day over the 6-week study period than those randomized to a simulated ban on menthol in only cigarettes suggesting that smoking patterns among current menthol smokers differ depending on which products are included in a menthol ban. Larger studies are needed to determine the policies most likely to provide the largest public health benefit.

Graded Prognostic Assessment (GPA) for Patients With Lung Cancer and Brain Metastases: Initial Report of the Small Cell Lung Cancer GPA and Update of the Non-Small Cell Lung Cancer GPA Including the Effect of Programmed Death Ligand 1 and Other Prognostic Factors.

PURPOSE: Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly. METHODS AND MATERIALS: A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA. RESULTS: Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P < .01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies. CONCLUSIONS: Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.

Social behavior in RASopathies and idiopathic autism.

BACKGROUND: RASopathies are genetic syndromes that result from pathogenic variants in the RAS-MAPK cellular signaling pathway. These syndromes, which include neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, and Costello syndrome, are associated with a complex array of medical and behavioral health complications. Despite a heightened risk for social challenges and autism spectrum disorder (ASD), few studies have compared different aspects of social behavior across these conditions. It is also unknown whether the underlying neuropsychological characteristics that contribute to social competence and socially empathetic ("prosocial") behaviors differ in children with RASopathies as compared to children with nonsyndromic (i.e., idiopathic) ASD. METHODS: In this cross-sectional, survey-based investigation, caregivers of preschool and school-aged children with RASopathies (n = 202) or with idiopathic ASD (n = 109) provided demographic, medical, and developmental information about their child, including psychiatric comorbidities. For children who were able to communicate verbally, caregivers also completed standardized rating scales to assess social competence and empathetic behavior as well as symptoms of hyperactivity/inattention and emotional problems. RESULTS: As compared to children with idiopathic ASD, children with RASopathies were rated as demonstrating more resilience in the domain of empathy relative to their overall social competence. Similarities and differences emerged in the psychological factors that predicted social behavior in these two groups. Stronger communication skills and fewer hyperactive-impulsive behaviors were associated with increased empathy and social competence for both groups. Greater emotional challenges were associated with lower social competence for children with RASopathies and stronger empathy for children with idiopathic ASD. Among children with RASopathy and a co-occurring ASD diagnosis, socially empathetic behaviors were observed more often as compared to children with idiopathic ASD. CONCLUSIONS: Findings suggest that the development of social behavior among children with RASopathies involves a distinct pattern of strengths and weaknesses as compared to a behaviorally defined disorder (idiopathic ASD). Identification of areas of resilience as well as behavioral and social challenges will support more targeted intervention.

Sentinel lymph node tumour burden using digital cell count estimation predicts outcomes in melanoma.

BACKGROUND AND AIMS: Cutaneous melanoma often metastasises in primis to sentinel lymph nodes (SLNs). Currently, there is no standardized method of characterizing the micrometastatic tumour burden in SLN biopsies for melanoma. Different criteria have been developed to evaluate SLN biopsies, yet none consider the number of cells identified. Here, we used software analysis to digitally quantify metastatic tumour burden within SLNs and correlated these data with clinicopathological and prognostic information. METHODS AND RESULTS: We identified 246 cases of SLN biopsies, including 63 positive (26%) and183 (74%) negative for metastatic melanoma. Digital cell counting was performed within the greatest metastatic focus and the entire metastatic tumour burden within the same SLN. Increasing cell count in the largest metastatic deposit correlated with the previously described Rotterdam [Spearman's r = 0.91; 95% confidence interval (CI) = 0.84, 0.94], Starz (Spearman's r = 0.78; 95% CI = 0.68, 0.87) and Dewar criteria (P < 0.01), validating our method of using cell count to define SLN tumour burden. Additionally, increasing cell count was associated with decreased metastasis-free survival (hazard ratio = 2.29; 95% CI = 1.22, 4.31). CONCLUSION: These data support the use of computerized cell count analysis for prognostication of outcomes in patients undergoing SLN biopsy.