Whole-Body Positron Emission Tomography with 18F-Fluorodeoxyglucose/Magnetic Resonance Imaging as a Screening Tool for the Detection of Malignant Transformation in Individuals with Neurofibromatosis Type 1.

Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in patients with neurofibromatosis type 1. They can result from premalignant neurofibromas, including neurofibromas with atypia and atypical neurofibromatous neoplasms of uncertain biologic potential. Some phenotypic characteristics have been described as associated with their development. The aim of this study was to outline our use of whole-body positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1, especially in the screening of asymptomatic individuals with a higher risk of developing an MPNST, and to study its impact on neurofibroma classification (malignant vs premalignant) and MPNST staging over time. Individuals with neurofibromatosis type 1 who underwent a positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging between 2017 and 2021 were included, analyzing separately the screened population. Maximum standard uptake value and diffusion-weighted imaging were assessed. Biopsy/surgery confirmed the diagnosis. In all, 345 positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging were performed in 241 patients, including 149 asymptomatic (62%) but at-risk patients. Eight MPNSTs in 8 screened individuals (5%), 6 neurofibromas with atypia in 4 individuals (3%), and 29 atypical neurofibromatous neoplasms of uncertain biologic potential in 23 individuals (15%) were diagnosed. Over time, the proportion of grade 3 MPNST and the malignant/premalignant ratio in screened individuals significantly decreased (P = .03 and P < .001, respectively). This study emphasizes the diagnostic and screening performances of whole-body positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1.

In-Hospital Clinical Features, Morbidity, and Mortality of Patients with Neurofibromatosis 1 in France: A Nationwide, Population-Based Retrospective Cohort Study.

Neurofibromatosis 1 (NF1) is a multisystem disease that can affect nearly every organ system. The aim of our study was to describe the in-hospital population with NF1 in France. We conducted a nationwide retrospective cohort study using the French hospital administrative database. A total of 11,425 patients with NF1 (53.4% female, 19,080 person years) were identified from January 2013 to December 2019. A total of 23% had at least one diagnosis of a comorbidity or NF1-associated complication or disease, and it was highest in the age group of 10-15 years. A total of 2,601 (22.8%) had a diagnosis of cancer. There were 366 (3.2%) in-hospital deaths, and we observed a standardized mortality ratio of 4.14 (95% confidence interval = 3.71-4.56), with a higher standardized mortality ratio in women and in the age group of 10-15 years. The standardized incident ratio (SIR) of cancer was 10.3 (95% confidence interval = 9.6-11.1). We observed high SIR values for cancer in childhood, with a decrease toward that of the general population by age 70 years. We observed high SIRs for NF1-associated cancers: CNS SIR of 195.4 (95% confidence interval = 172.2-220.9) and small intestine SIR of 102.9 (95% confidence interval = 71.7-143.2). The study provides a better understanding of the prognosis in people living with NF1.

A process modelling approach to assess the impact of teledermatology deployment onto the skin tumor care pathway.

BACKGROUND: Teledermatology was raised as a potential answer to increase access and decrease delay for skin cancer management. However, its influence on non-melanoma skin cancer (NMSC) care pathway has never been studied. OBJECTIVES: To compare conventional care pathway to teledermatology (TD) in NMSC care pathways using a process modelling approach. PATIENTS AND METHODS: A period study including three groups was conducted in a department of dermatology. During the first period from January till February 2013 a NMSC care pathway was mapped for a group a prior TD integration. During the second period from September 2016 till October 2018, the NMSC care pathway was determined for patients managed by a conventional care process and after TD diagnosis. Patients characteristics, type of tumors and processes were compared using time as a key performance indicator. Mean were reported with their ± SD. Linear regression was performed using time between multidisciplinary consultation and surgery as outcome adjusted on sex, age and cancer type. RESULTS: During the first period (prior to TD) 89 NMSC patients were managed (mean age = 76 yr old ± 13) during the second period, 36 patients NMSC were managed after TD, mean age of 89 years old ± 6 and 954 patients in a conventional process, mean age of 78 years old ±12. In comparison between the two periods patient's age, sex and cancer distribution significantly differed while the rate of surgery was not significantly different (p = 0.967). Linear multivariate regression using time between multidisciplinary consultation and surgery as outcome adjusted on sex age and cancer type displayed that during the second period patients in the TD group spent 17.6 days more [0.98,34.25] while patient in the conventional care process group had 9.8 days [1.85,17.74] more than patient in the study period 1, (p = 0.04, p = 0.02) without significant difference for age and sex (p = 0.29, p = 0.51). Patients with a SCC had a decreased time between multidisciplinary consultation and surgery of -12.97 days [-17.43, -8.5], p < 10-3. CONCLUSION: Interestingly, patients managed by TD were significantly older than those managed using a conventional care pathway. Unexpectedly their total time spent in the process was not shorter. The results of this analysis illustrated the interest of using process modelling approach to assess the impact of a healthcare innovation integration and to further rethink coordination and care pathways for NSMC post TD.

Phase II Study of Pembrolizumab As First-Line, Single-Drug Therapy for Patients With Unresectable Cutaneous Squamous Cell Carcinomas.

PURPOSE: To evaluate first-line pembrolizumab monotherapy efficacy and safety in patients with unresectable cutaneous squamous cell carcinomas (CSCCs). PATIENTS AND METHODS: Patients, predominantly men, with their CSSCs' immunohistochemically determined programmed cell death-ligand 1 (PD-L1) status determined (tumor proportion score threshold, 1%), received pembrolizumab (200 mg every 3 weeks). The primary endpoint was the 39-patient primary cohort's objective response rate at week 15 (ORRW15). Secondary objectives were best ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), safety, ORR according to PD-L1 status and health-related quality of life using Functional Assessment of Cancer Therapy-General (FACT-G) score. An 18-patient expansion cohort, recruited to power the study to evaluate the ORRW15 difference between PD-L1+ and PD-L1- patients, was assessed for ORR, disease control rate, and safety, but not survival. RESULTS: Median age of all patients was 79 years. The primary cohort's ORRW15 was 41% (95% CI, 26% to 58%), including 13 partial and 3 complete responses. Best responses were 8 partial and 8 complete responses. At a median follow-up of 22.4 months, respective median PFS, DOR, and OS were 6.7 months, not reached, and 25.3 months, respectively. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were grade ≥ 3. One death was related to rapid CSCC progression; another resulted from a fatal second aggressive head and neck squamous cell carcinoma diagnosed 15 weeks postinclusion. ORRW15 for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1- patients (17%; P = .02). Responders' W15 total FACT-G score had improved (P = .025) compared with nonresponders. CONCLUSION: First-line pembrolizumab monotherapy exhibited promising anti-CSCC activity, with durable responses and manageable safety. PD-L1 positivity appears to be predictive of pembrolizumab efficacy.

Population Pharmacokinetics/Pharmacodynamics of Dabrafenib Plus Trametinib in Patients with BRAF-Mutated Metastatic Melanoma.

Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure-response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances (p < 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng∙h/mL, respectively, p < 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUCOHD/AUCDAB ≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29-33.56); p = 0.023 and 10.61 (2.34-48.15), p = 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11-9.50); p = 0.032 and HR = 1.23 (1.35-10.39), p = 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUCOHD/AUCDAB deserves more investigation in a larger cohort of MM patients.

Correction: Breast cancer in neurofibromatosis 1: survival and risk of contralateral breast cancer in a five country cohort study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Breast cancer in neurofibromatosis 1: survival and risk of contralateral breast cancer in a five country cohort study.

PURPOSE: Neurofibromatosis 1 (NF1) is an autosomal dominant condition caused by pathogenic variants of the NF1 gene. A markedly increased risk of breast cancer is associated with NF1. We have determined the breast cancer survival and risk of contralateral breast cancer in NF1. METHODS: We included 142 women with NF1 and breast cancer from five cohorts in Europe and 335 women without NF1 screened for other familial breast cancers. Risk of contralateral breast cancer and death were assessed by Kaplan-Meier analysis with delayed entry. RESULTS: One hundred forty-two women with NF1 were diagnosed for breast cancer at a median age of 46.9 years (range 27.0-84.3 years) and then followed up for 1235 person-years (mean = 8.70 years). Twelve women had contralateral breast cancer with a rate of 10.5 per 1000 years. Cumulative risk for contralateral breast cancer was 26.5% in 20 years. Five and 10-year all-cause survival was 64.9% (95% confidence interval [CI] = 54.8-76.8) and 49.8% (95%CI = 39.3-63.0). Breast cancer-specific 10-year survival was 64.2% (95% CI = 53.5-77.0%) compared with 91.2% (95% CI = 87.3-95.2%) in the non-NF1 age-matched population at increased risk of breast cancer. CONCLUSION: Women with NF1 have a substantial contralateral breast cancer incidence and poor survival. Early start of breast cancer screening may be a way to improve the survival.

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease: A Nationwide, Multicenter Cohort Study.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune-related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer. METHODS: A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response. RESULTS: The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty-four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression-free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression-free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation. CONCLUSION: Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.

Incidence and Clinical Impact of Anti-TNFα Treatment of Severe Immune Checkpoint Inhibitor-induced Colitis in Advanced Melanoma: The Mecolit Survey.

Immune checkpoint inhibitors (ICI) significantly improve overall survival (OS) in patients with advanced melanoma, but immune-related colitis may occur and warrant anti-tumor necrosis factor α (TNFα) treatment in severe forms. A nationwide, multicenter retrospective survey was conducted to assess both, the real-life incidence of grade 3/4 ICI-induced colitis treated with anti-TNFα, in patients with advanced melanoma, and the consequence of this therapeutic strategy on disease outcome. All patients with advanced melanoma treated with anti-TNFα agents for severe ICI-related colitis in the participating centers were included. Relative incidence was calculated according to the total number of patients treated with ICI in network centers during the period of inclusion. The possible impact of anti-TNFα treatment on disease outcome was evaluated through comparison of objective response rate, progression-free survival, and OS with pivotal literature data. Twenty-seven patients from 13 tertiary referral centers were included. Overall, severe ICI-related colitis treated with anti-TNFα occurred in 1% of patients with advanced melanoma, mostly with ipilimumab. Infliximab was successfully used in all patients but 1, mostly after 1 infusion. OS and progression-free survival of 12 and 3 months, respectively, were observed in these patients, along with an objective response rate of 41% at 12 months. This survey shows a low real-life incidence of severe colitis requiring anti-TNFα. Response rates to immunotherapy and survival data do not appear to significantly differ from those observed in pivotal studies. Severe ICI-induced colitis requiring anti-TNFα treatment appears to be a rare event in advanced melanoma, and infliximab does not seem to adversely affect disease outcome.

Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation.

BACKGROUND: Neurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described. METHODS: Constitutional NF1 mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the NF1 Leiden Open Variation Database (n=3432). RESULTS: No cases were observed with whole or partial gene deletions (HR 0.10; 95% CI 0.006 to 1.63; p=0.014, Fisher's exact test). There were no gross relationships with mutation position. Forty-five (64.3%; HR 6.4-83) of the 70 different mutations were more frequent than expected (p<0.05), while 52 (74.3%; HR 5.3-83) were significant when adjusted for multiple comparisons (adjusted p≤0.125; Benjamini-Hochberg). Higher proportions of both nonsense and missense mutations were also observed (adjusted p=0.254; Benjamini-Hochberg). Ten of the 11 missense cases with known age of BC occurred at <50 years (p=0.041). Eighteen cases had BRCA1/2 testing, revealing one BRCA2 mutation. DISCUSSION: These data strongly support the hypothesis that certain constitutional mutation types, and indeed certain specific variants in NF1 confer different risks of BC. The lack of large deletions and excess of nonsenses and missenses is consistent with gain of function mutations conferring risk of BC, and also that neurofibromin may function as a dimer. The observation that somatic NF1 amplification can occur independently of ERBB2 amplification in sporadic BC supports this concept. A prospective clinical-molecular study of NF1-BC needs to be established to confirm and build on these findings, but regardless of NF1 mutation status patients with NF1-BC warrant testing of other BC-predisposing genes.

Ipilimumab for the treatment of advanced melanoma in six kidney transplant patients.

Immune checkpoint inhibitors are new therapeutic options for metastatic melanoma, but few data are available in organ transplant recipient populations. Six French patients, three men and three women, mean age 66 years (range 44-74), all kidney transplant recipients, received ipilimumab (CTLA-4 inhibitor) for metastatic melanoma. At diagnosis of advanced melanoma, immunosuppressive therapy had been minimized in all but one. Adverse effects included one case of grade 1 diarrhea and one of grade 1 pruritus. One patient had acute T cell-mediated rejection confirmed by histology after the first injection of ipilimumab. After a median follow-up of 4.5 (3-20) months, one patient achieved partial response, one had stable disease, and four had disease progression. All the patients died, five from melanoma, one from another cause. In this series and in the literature, ipilimumab proved to be safe and possibly active. The acute rejection we encountered was probably related to both a rapid, drastic reduction of immunosuppression and the use of ipilimumab. Our safety data on ipilimumab contrast with the organ transplant rejections already reported with PD-1 inhibitors. We consider that immunosuppression should not be minimized, as the impact on metastatic disease control is probably small.

Cyclosporine for Epidermal Necrolysis: Absence of Beneficial Effect in a Retrospective Cohort of 174 Patients-Exposed/Unexposed and Propensity Score-Matched Analyses.

Cyclosporine has shown promising results for mortality in patients with Stevens-Johnson syndrome/toxic epidermal necrolysis. However, available studies included only a small number of patients and did not include a validated and homogenous control group. We present the results from a retrospective monocentric study including 174 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis during 2005-2016. Among them, 95 received cyclosporine (3 mg/kg/day) plus supportive care, and 79 received supportive care only. Both a traditional exposed/unexposed method and a propensity score-matching method were used to compare the progression of skin detachment between day 0 and day 5, the proportion of patients with cutaneous re-epithelialization starting on day 5 or mucosal re-epithelialization on day 10, the duration of progression, and the number of deaths between the two groups. None of these outcomes significantly favored cyclosporine, either by the exposed/unexposed method or the propensity score method. Acute renal failure affected more patients receiving cyclosporine (P = 0.05). Overall, the results of this epidemiological study did not show a beneficial effect of cyclosporine in patients with Stevens-Johnson syndrome/toxic epidermal necrolysis. They are discordant with those previously published. The large number of patients and the use of a propensity score method provide valuable insights. The main limitation of the study is the lack of randomization.

Immediate hypersensitivity reaction to pegylated liposomal doxorubicin: management and outcome in four patients.

Hypersensitivity reactions (HSR) to pegylated liposomal doxorubicin (PLD; Caelyx®) have been reported, and symptoms usually resolve with drug withdrawal. However, the risk of relapse of severe HSR and prevention remain poorly described. To report the management and outcome in four patients with HSR due to PLD. Patient characteristics, premedication regimen, rate of infusion, time between onset and HSR, clinical manifestations, and management were documented. A first cycle of PLD was received for cutaneous T-cell lymphoma (n = 3) and Kaposi sarcoma (n = 1). The drug was diluted in 250 mL 5% glucose and administered over one hour (4.17 mL dilution/min, i.e. 0.6 mg PLD/min for 1.8 m2 body surface area [BSA]). Grade 3 HSR occurred in the first minutes in the four patients. Because of the absence of alternative treatment for the underlying disease, PLD was resumed. Premedication was reinforced with 300 mg oral ranitidine and 50 mg hydroxyzine the night before and the morning of infusion. The rate of infusion was 1 mL dilution/min (0.14 mg PLD/min for 1.8 m2 BSA) for the first 15 minutes. No HSR occurred in three patients. In contrast, severe symptoms appeared in the first seconds of resumption in one patient. To minimise HSR to PLD, an initial reduced rate of infusion of 0.1-0.2 mg of PLD/min is warranted. In the event of HSR, alternative therapy must be privileged, and if necessary, careful re-challenge with PLD may be attempted, however relapse of HSR may occur.

Metabolic Tumour Burden Measured by 18F-FDG PET/CT Predicts Malignant Transformation in Patients with Neurofibromatosis Type-1.

BACKGROUND: To investigate the diagnostic and prognostic performances of 18F-FDG PET/CT measures of metabolic tumour burden in patients with neurofibromatosis type-1 (NF1), suspect of malignant transformation. METHODS: This retrospective study included 49 patients (15-60 years old, 30 women) with a diagnosis of NF1, followed in our Reference Centre for Rare Neuromuscular Diseases, who presented clinical signs of tumour progression (pain, neurological deficit, tumour growth). Quantitative metabolic parameters were measured on 149 tumoral targets, using semi-automatic software and the best cut off values to predict transformation was assessed by Receiver Operating Characteristics (ROC) analysis. Prognostic value of PET/CT metabolic parameters was assessed by Kaplan-Meier estimates of overall survival. RESULTS: Lesions were histologically documented in 40 patients: a sarcomatous transformation was found in 16, a dysplastic neurofibroma (NF) in 7, and a benign NF in 17; in the remaining 9 patients, a minimal follow-up of 12 mo (median 59 mo) confirmed the absence of transformation. The optimal cut off values for detection of malignant transformation were, in decreasing order of area under the ROC curves, a tumour-to-liver (T/L) ratio >2.5, SUVmax > 4.5, total lesion glycolysis (TLG) > 377, total metabolic tumour volume (TMTV) > 88 cm3, and heterogeneity index (HIsuv) > 1.69. The best prognostic marker was the TLG: the 4-y estimates of survival were 97% [95% CI, 90% - 100%] in patients with TLG ≤ 377 vs. 27% [95% CI, 5% - 49%] in patients with TLG > 377 (P < 0.0001; χ2 27.85; hazard ratio 13.27 [95% CI, 3.72-47.35]). T/L ratio, SUVmax and TMTV demonstrated slightly lower performance to predict survival, with χ2 ranging 14.41-19.12. The HIsuv index was not predictive of survival. CONCLUSION: Our study demonstrates that TLG and TMTV, as PET/CT measures of metabolic tumour burden, may be used clinically to identify sarcomatous transformation in patients with NF1 and predict overall survival, with a higher specificity for the TLG. Conventional measures such as the SUVmax, and T/L ratio also demonstrate high prognostic value.

Factors associated with postoperative complications in elderly patients with skin cancer: A retrospective study of 241 patients.

OBJECTIVES: The increasing frequency of skin tumors and longer life expectancy of the general population are likely to increase the frequency of dermatological surgery among elderly patients. The purpose of this study is to assess the rate of postoperative complications related to dermatological surgery in elderly patients and highlight the factors associated with these complications. METHODS: We conducted a retrospective monocentric study of patients aged >75 years who presented at our multidisciplinary consultation specialized for skin tumors from January 2008 to December 2010. The clinical characteristics, demographic information, and cancer history of these patients were analyzed. Postoperative complications (dehiscence, infection, hematomas, and other sequelae) were identified to establish the postoperative complication rate and determine risk factors. RESULTS: We included 241 patients. Basal cell carcinoma, squamous cell carcinoma, and melanoma accounted for 46%, 25%, and 28% of tumors, respectively. Skin carcinomas were mainly located on the face (93% of basal cell carcinomas and 72% of squamous cell carcinomas), and melanomas were mainly located on the limbs (50%). The average number of comorbidities was 3.0±1.5. The average postoperative complication rate was 20%. Multivariate analysis identified three independent risk factors: male gender (p<0.033), histological type (squamous cell carcinoma and melanoma) (p<0.008), and insufficient surgical resection (p<0.004). CONCLUSION: This study highlighted a high rate of postoperative complications in this elderly population. Three significant postoperative risk factors were identified. They may be used to assess a patient's operational risk as well as geriatric assessment tools.