Mohs micrographic surgery in the surgical treatment paradigm of melanoma in situ and invasive melanoma: A clinical review of treatment efficacy and ongoing controversies.

Mohs Micrographic Surgery (MMS) for treatment of melanoma offers several advantages over wide local excision (WLE), including complete histologic margin evaluation, same-day resection and closure, and sparing of healthy tissue in critical anatomic sites. Recently, a large volume of clinical data demonstrating efficacy in MMS treatment of melanoma was published, leading to emerging patient safety considerations of incurred treatment costs, risk of tumor upstaging, and failure of care coordination for sentinel lymph node biopsy (SLNB). MMS offers a safe, effective, and value-based treatment for both melanoma in situ (MIS) and invasive melanoma (IM), particularly with immunohistochemistry use on frozen sections. Compared to wide local excision, MMS treatment demonstrates similar or improved outcomes for local tumor recurrence, melanoma-specific survival, and overall survival at long-term follow-up. Tumor upstaging risk is low, and if present, alteration to clinical management is minimal. Discussion of SLNB for eligible head and neck IM cases should be done prior to MMS. Though challenging, successful multidisciplinary coordination of SLNB with MMS has been demonstrated. Herein, we provide a detailed clinical review of evidence for MMS treatment of cutaneous melanoma and offer recommendations to address current controversies surrounding the evolving paradigm of surgical management for both MIS and invasive melanoma (IM).

Subungual melanoma with cartilaginous differentiation: Molecular insights.

Melanoma's rare capacity to undergo heterologous differentiation can create significant diagnostic challenges. The molecular mechanisms underlying this phenomenon are not well understood. We present an unusual case of subungual melanoma exhibiting extensive cartilaginous differentiation and provide insights into its molecular and cytogenomic features. Histopathologically, the tumor was predominantly composed of nodules of malignant cartilage in association with a smaller population of nested epithelioid to rhabdoid cells. Immunohistochemically, the tumor cells in both components were positive for S100, SOX10, and PRAME, and were negative for Melan-A and HMB-45. Molecular analysis by whole exome DNA sequence did not detect any pathogenic variants in genes commonly implicated in melanoma. Additional analysis by SNP chromosomal microarray revealed a complex genome characterized by numerous chromosomal losses and gains, including a homozygous deletion of the CDKN2A locus and a heterozygous deletion of the locus containing EXT2, a tumor suppressor implicated in hereditary multiple osteochondromas and secondary chondrosarcomas. This case underscores the importance of recognizing cartilaginous differentiation as a rare manifestation of melanoma, particularly at subungual sites, and suggests that at least some of these melanomas may be driven by non-canonical molecular pathways.

Severe acute radiation dermatitis after palbociclib therapy in the setting of palliative radiotherapy.

INTRODUCTION: Cyclin-dependent-kinase 4/6(CDK4/6) inhibitors are widely used as a first-line systemic treatment for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer. Although many patients with metastatic breast cancer require palliative radiotherapy (RT), there are limited data on the safety of combining a CDK4/6 inhibitor with palliative RT. CASE REPORT: Presented is a case of acute high-grade radiation dermatitis with low-dose palliative RT following administration of palbociclib. A 49-year-old woman with newly diagnosed hormone receptor-positive invasive ductal carcinoma of the left breast presented with lytic bone lesions in the left femur and lumbar spine. The patient initiated treatment with goserelin, tamoxifen, and palbociclib. She underwent prophylactic surgical fixation of the left femur and received post-operative RT encompassing the entire surgical nail (30 Gy/10 fractions) and palliative RT to the lumbar spine for pain relief (20 Gy/5 fractions). During cycle 4, palbociclib was stopped 3 days prior to the start of RT to reduce the risk of toxicity risk. However, 16 days after starting RT, she developed painful erythematous papules and bullae with moist desquamation on the left groin and lumbar spine. MANAGEMENT & OUTCOME: Her symptoms were managed with topical Aquaphor-lidocaine, silver sulfadiazine, and aluminum acetate soaks. Dermatitis subsided to dry desquamation within 2 weeks. The patient denied late toxicity at 11 months follow-up. DISCUSSION: Larger retrospective or prospective studies are needed to further elucidate the safety of combined CDK4/6 inhibitors and RT. In the meantime, special precautions are warranted in patients receiving combined therapy.

Electronic medical record documentation of germline genetic evaluations in patients with ovarian cancer.

Germline genetic evaluation is indicated for all patients with epithelial ovarian cancer (EOC). For testing to have clinical utility, results must be documented within the electronic medical record (EMR) and accessible to providers at the point of care, which can be challenging in the context of current EMR limitations and genetic testing processes. We examined the receipt of genetics services and EMR capture of genetic testing results in patients with EOC. We conducted a retrospective chart review to examine germline genetic evaluations among patients with EOC seen by a gynecologic or medical oncologist at the University of Pennsylvania in 2016. EMRs were reviewed to determine: (1) if patients were referred for genetic evaluation; (2) if genetic testing was performed; (3) if results were documented in office notes, scanned third-party test reports, and/or the EMR problem list; (4) if provider notes correctly listed the variant classification. Overall, 413 (62%) of patients had documented genetic testing. Genetic testing was documented in almost all provider notes (96%) and the majority of scanned EMR reports (64%). Pathogenic variants were found in 119 (29%) individuals; the majority (70%) had genetic testing documented within EMR problem lists. Provider notes were highly accurate in describing variant classification. In this study, genetic testing was performed and documented in the EMR for most EOC patients. Approximately one-third of those tested did not have scanned test reports specifying variant found, limiting the utility of test results for cascade testing and therapeutic decisions.

Promoting Publications Through Plastic Surgery Journal Instagram Accounts: Is It Worth It?

PURPOSE: Journals are increasingly using social media to increase article engagement. We aim to determine the impact of Instagram promotion on, and identify social media tools that effectively enhance, plastic surgery article engagement and impact. METHODS: Instagram accounts for Plastic and Reconstructive Surgery , Annals of Plastic Surgery , Aesthetic Surgery Journal , and Aesthetic Plastic Surgery were reviewed for posts published by February 8, 2022. Open access journal articles were excluded. Post caption word count and number of likes, tagged accounts, and hashtags were recorded. Inclusion of videos, article links, or author introductions was noted. All articles from journal issues published between the dates of the first and last posts promoting articles were reviewed. Altmetric data approximated article engagement. Citation numbers from the National Institutes of Health iCite tool approximated impact. Differences in engagement and impact of articles with and without Instagram promotion were compared by Mann-Whitney U tests. Univariate and multivariable regressions identified factors predictive of more engagement (Altmetric Attention Score, ≥5) and citations (≥7). RESULTS: A total of 5037 articles were included, with 675 (13.4%) promoted on Instagram. Of posts featuring articles, 274 (40.6%) included videos, 469 (69.5%) included article links, and 123 included (18.2%) author introductions. Promoted articles had higher median Altmetric Attention Scores and citations ( P < 0.001). On multivariable analysis, using more hashtags predicted higher article Altmetric Attention Scores (odds ratio [OR], 1.85; P = 0.002) and more citations (OR, 1.90; P < 0.001). Including article links (OR, 3.52; P < 0.001) and tagging more accounts (OR, 1.64; P = 0.022) predicted higher Altmetric Attention Scores. Including author introductions negatively predicted Altmetric Attention Scores (OR, 0.46; P < 0.001) and citations (OR, 0.65; P = 0.047). Caption word count had no significant impact on article engagement or impact. CONCLUSIONS: Instagram promotion increases plastic surgery article engagement and impact. Journals should use more hashtags, tag more accounts, and include manuscript links to increase article metrics. We recommend that authors promote on journal social media to maximize article reach, engagement, and citations, which positively impacts research productivity with minimal additional effort in designing Instagram content.

The prevalence of abnormal spirometry in children with CHD.

BACKGROUND: The burden of pulmonary disease in children with CHD remains under-recognised. Studies have examined children with single ventricle and two ventricle heart disease and documented a decreased forced vital capacity. Our study sought to further explore the pulmonary function of children with CHD. METHODS: A retrospective review was performed of spirometry in CHD patients over a 3-year period. Spirometry data were corrected for size, age, and gender and analysed using z-scores. RESULTS: The spirometry of 260 patients was analysed. About 31% had single ventricle (n = 80, 13.6 years (interquartile range 11.5-16.8)) and 69% had two ventricle circulation (n = 180, 14.4 years (interquartile range 12.0-17.3)). Single ventricle patients were found to have a lower median forced vital capacity z-score compared to two ventricle patients (p = 0.0133). The prevalence of an abnormal forced vital capacity was 41% in single ventricle patients and 29% in two ventricle patients. Two ventricle patients with tetralogy of Fallot and truncus arteriosus had similar low forced vital capacity comparable to single ventricle patients. The number of cardiac surgeries predicted an abnormal forced vital capacity in two ventricle patients except tetralogy of Fallot patients. CONCLUSION: Pulmonary morbidity in patients with CHD is common with a decreased forced vital capacity noted in single ventricle and two ventricle patients. Forced vital capacity is lower in patients with single ventricle circulation; however, two ventricle patients with tetralogy of Fallot or truncus arteriosus have similar lung function in comparison to the single ventricle group. The number of surgical interventions was predictive of forced vital capacity z-score in some but not all two ventricle patients and not predictive in single ventricle patients suggesting a multifactorial to pulmonary disease in children with CHD.

Progressive vasoconstriction with sequential thermal stimulation indicates vascular dysautonomia in sickle cell disease.

Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.

Assessing the use of methotrexate as an alternate therapy for pemphigus vulgaris and pemphigus foliaceus.

Methotrexate is historically recognized as an effective treatment of pemphigus but its utility as a single or alternate steroid-sparing agent was not recognized in recent consensus recommendations in pemphigus management. We aimed to evaluate the efficacy and safety of a treatment course for pemphigus that involves methotrexate as a single or steroid-sparing agent. In a retrospective cohort study, we examined patients with pemphigus vulgaris or pemphigus foliaceus who were on ≥3 months of methotrexate therapy. Efficacy and safety were evaluated by established pemphigus disease endpoints. Of the 34 patients who met inclusion criteria, 25 (73.5%) were on glucocorticoids at time of methotrexate initiation (median follow-up: 5.4 years; median time on methotrexate: 3.7 years). An appreciable proportion achieved disease control (91.2%), with some achieving clinical remission off all systemic therapies (23.5%). For patients on glucocorticoids, median time to control was 42 days, median time to minimal steroid dose tapering (5 mg prednisone) was 161 days, and median time to complete steroid tapering was 308 days. For patients on methotrexate as a single agent, median time to control was 119 days. Among all patients, relapse commonly occurred (88.2%). At last follow-up, 26.5% were managed on topical therapies alone and 11.8% required systemic steroid therapy. Methotrexate was largely tolerated with a low incidence of adverse events leading to treatment discontinuation (2.9%). Methotrexate has the potential to be an effective and well-tolerated option for patients and may be considered for use as an alternate single or steroid-sparing agent for pemphigus.

Reduced Forced Vital Capacity and the Number of Chest Wall Surgeries are Associated with Decreased Exercise Capacity in Children with Congenital Heart Disease.

Low forced vital capacity (FVC) is associated with decreased exercise capacity in CHD. Multiple prior cardiac surgeries have been associated with low FVC. We seek to understand the relationship between low FVC, number of cardiac surgeries and cardiopulmonary response leading to decreased exercise capacity. Retrospective chart review of demographics, surgical history and exercise testing including spirometry was performed in patients with CHD. Single ventricle patients were excluded. Low FVC was defined as a Z-score below the lower limit of normal. Exercise parameters were expressed as a percent of predicted. There were 93 patients with 2 ventricle CHD identified over 34 months with cardiopulmonary exercise testing. The FVC Z-score directly correlated with peak V̇O2% (R2 = 0.07, p < 0.05), and the O2 pulse% (R2 = 0.25, p < 0.0001). The VE/VCO2 was inversely related to the FVC Z-score (R2 = 0.11, p < 0.01). Patients with minimum three prior surgeries had decreased peak VO2% (63.7 vs. 72.8, p < 0.05), decreased peak O2 pulse% (80.8 vs. 97.9, p < 0.01) and a lower mean FVC Z-score (- 1.9 vs - 0.38, p < 0.01). The FVC Z-score and number of surgeries both predicted peak V̇O2% in multivariate analysis. Our study demonstrated that low FVC and three or more prior cardiac surgeries were associated with lower exercise capacity and lower stroke volume response. More cardiac surgeries were also associated with low FVC. However, both low FVC and the number of surgeries were independent predictors of exercise capacity.

Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer.

OBJECTIVE: Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort. METHODS: A Simon 2-stage design was utilized. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1-7 and olaparib 300 mg orally twice daily, days 1-28 of a 28-day cycle until toxicity or progression. Primary endpoints were toxicity and efficacy including objective response rate (ORR) by RECIST. Secondary endpoint was progression-free survival (PFS). The null hypothesis (≤5% ORR) would be rejected if there were ≥ 1 responses in 12 patients. RESULTS: Fourteen PARPi-naïve patients were evaluable for toxicity; 12 were evaluable for response. Three had BRCA1 mutations (1 germline, 2 somatic). Adverse events possibly related to treatment were primarily grade (G) 1/2. G3 toxicities included nausea (14.3%), fatigue (7.1%), anorexia (7.1%), and anemia (7.1%). No objective responses occurred. Best response was stable disease in 9 patients and progressive disease in three. Five patients had a ≥ 20% to <30% reduction in disease burden, including 3 with BRCA1 mutations. Three of 11 patients (27%; 2 with BRCA1 mutations) evaluable by Gynecologic Cancer Intergroup criteria had >50% CA-125 decline, including 2 with CA-125 normalization. Median PFS was 4.2 months overall (90% CI:3.5-8.2) and 8.2 months (3.6 months-not determined) for patients with BRCA1 mutations. CONCLUSIONS: Olaparib plus ceralasertib is well-tolerated. No objective responses occurred, though a signal of activity was seen particularly in disease associated with BRCA1. Further evaluation of this combination should include alternate dosing strategies in genomically-selected populations.

Loss of alpha-globin genes in human subjects is associated with improved nitric oxide-mediated vascular perfusion.

Alpha thalassemia is a hemoglobinopathy due to decreased production of the α-globin protein from loss of up to four α-globin genes, with one or two missing in the trait phenotype. Individuals with sickle cell disease who co-inherit the loss of one or two α-globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α-globin gene deletions affect sickle red cell deformability, the α-globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction. Decreased production of α-globin due to α-thalassemia trait may thereby limit nitric oxide scavenging and promote vasodilation. To evaluate this potential mechanism, we performed flow-mediated dilation and microvascular post-occlusive reactive hyperemia in 27 human subjects (15 missing one or two α-globin genes and 12 healthy controls). Flow-mediated dilation was significantly higher in subjects with α-trait after controlling for age (P = .0357), but microvascular perfusion was not different between groups. As none of the subjects had anemia or hemolysis, the improvement in vascular function could be attributed to the difference in α-globin gene status. This may explain the beneficial effect of α-globin gene loss in sickle cell disease and suggests that α-globin gene status may play a role in other vascular diseases.

Tricuspid regurgitant jet velocity and myocardial tissue Doppler parameters predict mortality in a cohort of patients with sickle cell disease spanning from pediatric to adult age groups - revisiting this controversial concept after 16 years of additional evidence.

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young adult mortality in SCD. To better understand the clinical importance of multi-level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S') and diastole (E'), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty-eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional-hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end-organ failure. On Cox proportional-hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S' results in a 91% increase, and 1 cm/s decrease in E' results in a 43% increase in mortality. While excluding cardiac parameters, higher plasma free hemoglobin was significantly associated with risk of mortality (p=.049). In conclusion, elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers.

Cosmetic procedure use as a type of substance-related disorder.

BACKGROUND: A role for addiction psychiatry in aesthetic treatment-seeking behavior has been evidenced for ultraviolet light tanning. OBJECTIVE: We aim to demonstrate an initial proof of concept for the presence of addictive behaviors in cosmetic procedure use. METHODS: Adults visiting a cosmetic dermatology practice with history of at least 1 cosmetic procedure and consideration of at least 1 cosmetic procedure in the past 12 months were included. Two previously validated instruments in the detection of alcohol use disorder, the Cut Down, Annoyed, Guilty, Eye-Opener (CAGE) questionnaire, and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria were modified to evaluate participants for a substance-related disorder (SRD) in cosmetic procedures. RESULTS: Of 153 adults, 34 (22.2%) met modified CAGE criteria, and 40 (26.1%) met modified DSM-V criteria. Results from both instruments were significantly associated (P < .0002). Significant differences in consideration and use of cosmetic treatments were found in SRD positive versus negative groups (P < .0001 and P = .009, respectively). LIMITATIONS: Preliminary criteria for SRD in cosmetic procedure use in this study has not yet been validated. CONCLUSIONS: A type of SRD involving cosmetic procedures may exist, and qualifying individuals may have increased cosmetic treatment use. Future efforts to rigorously validate an instrument for SRD detection in cosmetic procedures use are warranted for future research and clinical application.

Preventing complications in dermatologic surgery: Presurgical concerns.

Cutaneous surgery has become critical to comprehensive dermatologic care, and dermatologists must therefore be equipped to manage the risks associated with surgical procedures. Complications may occur at any point along the continuum of care, and therefore assessing, managing, and preventing risk from beginning to end becomes essential. This review focuses on preventing surgical complications pre- and postoperatively as well as during the surgical procedure.

Preventing and managing complications in dermatologic surgery: Procedural and postsurgical concerns.

The second article in this continuing medical education series reviews the evidence regarding the intraoperative and postoperative risks for patients and health care workers. We share the most up-to-date recommendations for risk management and postoperative complication management to ensure optimal surgical efficacy and patient safety.

Observer-Reported Outcomes and Cosmetic Procedures: A Systematic Review.

BACKGROUND: Cosmetic procedures have demonstrated beneficial effects on physical appearance based on anatomic markers as well as patient-perceived self-image and quality of life. Recent studies of observer-reported outcomes (OROs) suggest an additional benefit from aesthetic interventions. OBJECTIVE: The authors aimed to review the evidence of OROs from cosmetic procedures performed on the head and neck. PATIENTS, METHODS AND MATERIALS: PubMed, Embase, and Cochrane Library databases were searched for relevant studies, yielding 24 included original investigations. RESULTS: These studies captured 686 total patients, 8,257 observer evaluations, and a variety of interventions including face-lifts, blepharoplasty, rhinoplasty, and minimally invasive treatments including botulinum toxins and hyaluronic acid fillers. Forty-one distinct reported OROs were grouped into 12 descriptive domains. Domains were further grouped into 3 higher-order categories: aesthetics and wellness, social capacities, and skills and competencies. Improved perception after cosmetic intervention is most reproducibly demonstrated for the following ORO domains: age, attractiveness, sociability, relationship success, and occupational and financial competency. CONCLUSION: The synthesized findings imply a tertiary layer of benefit for cosmetic intervention beyond anatomical and patient-centered outcomes through enhanced perceptions of others. These findings may inform the pre-procedure risk-benefit discussion with patients of cosmetic medicine and drive future research into longitudinal outcomes.

Dermatologists' Perceptions and Confidence in Cosmetic Care for Male Patients.

BACKGROUND: Despite a growing interest in nonsurgical cosmetic procedures in men, the utilization of aesthetic treatments remains comparatively low, suggesting the presence of barriers to care. OBJECTIVE: To describe barriers to cosmetic intervention for male patients from the perspective of dermatologists. MATERIALS AND METHODS: An anonymous, online survey was distributed through a listserv made available by the American Academy of Dermatology. RESULTS: Dermatologist respondents perceived a low utilization of cosmetic services in male patients (5%) and a lack of opportunity (72.3%) to provide such services. Respondents also perceived a lack of sufficient education/training (40.9%), experience (20.5%), and a lack of evidence in the field (20.5%) for dermatologists as potential barriers to cosmetic care for male patients. Presence of targeted messaging and in-office educational materials for male patients was found to be associated with increased utilization of cosmetic treatments by male patients (p = .012, p = .012, respectively). Dermatologists reported strong confidence in delivering various noninvasive cosmetic treatments to male patients. CONCLUSION: Despite dermatologists' reported confidence in performing cosmetic procedures in men, many perceive insufficient education/training and experience with this population which may create barriers to cosmetic care for male patients. Increasing educational materials and targeted messaging to male patients may decrease barriers for patients to receive desired cosmetic care.

Application of Panel-Based Tests for Inherited Risk of Cancer.

Next-generation or massively parallel sequencing has transformed the landscape of genetic testing for cancer susceptibility. Panel-based genetic tests evaluate multiple genes simultaneously and rapidly. Because these tests are frequently offered in clinical settings, understanding their clinical validity and utility is critical. When evaluating the inherited risk of breast and ovarian cancers, panel-based tests provide incremental benefit compared with BRCA1/2 genetic testing. For inherited risk of other cancers, such as colon cancer and pheochromocytoma-paraganglioma, the clinical utility and yield of panel-based testing are higher; in fact, simultaneous evaluation of multiple genes has been the historical standard for these diseases. Evaluating inherited risk with panel-based testing has recently entered clinical practice for prostate and pancreatic cancers, with potential therapeutic implications. The resulting variants of uncertain significance and mutations with unclear actionability pose challenges to service providers and patients, underscoring the importance of genetic counseling and data-sharing initiatives. This review explores the evolving merits, challenges, and nuances of panel-based testing for cancer susceptibility.

Frequency of radiation-induced malignancies post-adjuvant radiotherapy for breast cancer in patients with Li-Fraumeni syndrome.

PURPOSE: Women with Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome caused by germline mutations in TP53, have an over 50% risk of developing breast cancer by age 70. Patients with LFS are at risk for radiation-induced malignancies; however, only small case series have prior investigated radiation risks in the treatment of breast cancer. We therefore aimed to investigate the risk of malignancy in breast cancer patients with LFS following adjuvant radiotherapy. METHODS: A single-institution retrospective chart review was conducted for female breast cancer patients with confirmed germline TP53 mutation. The frequency of radiation-induced malignancies in LFS patients was compared to non-LFS breast cancer cases reported in the Penn Medicine Cancer Registry via statistical analyses. RESULTS: We identified 51 female LFS breast cancer patients with 74 primary diagnoses. Fifty-seven% had a history of breast cancer only, and 25% had breast cancer as their presenting diagnosis of LFS. LFS-associated breast cancers were predominantly invasive ductal carcinoma (48%) and HER2+ (58%). Twenty patients underwent adjuvant radiotherapy with a median follow-up of 12.5 (2-20) years. Of 18 patients who received radiation in a curative setting, one (6%) patient developed thyroid cancer, and one (6%) patient developed sarcoma in the radiation field. This risk for radiation-induced malignancy associated with LFS was higher for both sarcoma and thyroid cancer in comparison with the control cohort. CONCLUSIONS: We found a lower risk of radiation-induced secondary malignancies in LFS breast cancer patients than previously reported in the literature (33% risk of radiation-induced sarcoma). These findings suggest that LFS may not be an absolute contraindication for radiotherapy in breast cancer. The potential risk for locoregional recurrence without radiotherapy must be weighed against the long-term risk for radiation-induced malignancies in consideration of adjuvant radiotherapy for LFS breast cancer patients.