Citations

Abstract Purpose: To evaluate the impact of trimodality treatment versus monotherapy or dual therapy for radiation-associated angiosarcoma of the breast (RAASB) after prior breast cancer treatment. Experimental Design: With Institutional Review Board approval, we identified patients diagnosed with RAASB and abstracted data on disease presentation, treatment, and oncologic outcomes. Trimodality therapy included (i) taxane induction, (ii) concurrent taxane/radiation, and then (iii) surgical resection with wide margins. Results: A total of 38 patients (median age 69 years) met inclusion criteria. Sixteen received trimodality therapy and 22 monotherapy/dual therapy. Skin involvement and disease extent were similar in both groups. All trimodality patients required reconstructive procedures for wound closure/coverage, compared with 48% of monotherapy/dual therapy patients (P < 0.001). Twelve of 16 (75%) patients receiving trimodality therapy had a pathologic complete response (pCR). With median follow-up of 5.6 years, none had local recurrence, 1 patient (6%) had distant recurrence, and no patients died. Among 22 patients in the monotherapy/dual therapy group, 10 (45%) had local recurrence, 8 (36%) had distant recurrence, and 7 (32%) died of disease. Trimodality therapy demonstrated significantly better 5-year recurrence-free survival [RFS; 93.8% vs. 42.9%; P = 0.004; HR, 7.6 (95% confidence interval, CI: 1.3–44.2)]. Combining all patients with RAASB regardless of treatment, local recurrence was associated with subsequent distant recurrence (HR, 9.0; P = 0.002); distant recurrence developed in 3 of 28 (11%) patients without local recurrence compared with 6 of 10 (60%) with local recurrence. The trimodality group had more surgical complications that required reoperation or prolonged healing. Conclusions: Trimodality therapy for RAASB was more toxic but is promising, with a high rate of pCR, durable local control, and improved RFS.

Accurate prediction of progression in subjects at risk of Alzheimer's disease is crucial for enrolling the right subjects in clinical trials. However, a prospective comparison of state-of-the-art algorithms for predicting disease onset and progression is currently lacking. We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of a 5-year future time period, of three key outcomes: clinical diagnosis, Alzheimer's Disease Assessment Scale Cognitive Subdomain (ADAS-Cog13), and total volume of the ventricles. The methods used by challenge participants included multivariate linear regression, machine learning methods such as support vector machines and deep neural networks, as well as disease progression models. No single submission was best at predicting all three outcomes. For clinical diagnosis and ventricle volume prediction, the best algorithms strongly outperform simple baselines in predictive ability. However, for ADAS-Cog13 no single submitted prediction method was significantly better than random guesswork. Two ensemble methods based on taking the mean and median over all predictions, obtained top scores on almost all tasks. Better than average performance at diagnosis prediction was generally associated with the additional inclusion of features from cerebrospinal fluid (CSF) samples and diffusion tensor imaging (DTI). On the other hand, better performance at ventricle volume prediction was associated with inclusion of summary statistics, such as the slope or maxima/minima of patient-specific biomarkers. On a limited, cross-sectional subset of the data emulating clinical trials, performance of the best algorithms at predicting clinical diagnosis decreased only slightly (2 percentage points) compared to the full longitudinal dataset. The submission system remains open via the website https://tadpole.grand-challenge.org, while TADPOLE SHARE (https://tadpole-share.github.io/) collates code for submissions. TADPOLE's unique results suggest that current prediction algorithms provide sufficient accuracy to exploit biomarkers related to clinical diagnosis and ventricle volume, for cohort refinement in clinical trials for Alzheimer's disease. However, results call into question the usage of cognitive test scores for patient selection and as a primary endpoint in clinical trials.

Clinical stage III melanoma, defined as resectable RECIST measurable nodal disease with or without in-transit metastases, represents approximately 15% of new melanoma diagnoses every year with additional cases presenting as recurrent nodal disease following previous treatment of a primary melanoma. The standard of care for patients with resectable clinical stage III melanoma is surgical resection, consisting of therapeutic lymph node dissection and/or resection of in-transit disease and consideration of adjuvant systemic therapy and occasionally adjuvant radiation. These patients have high rates of regional recurrence and progression to metastatic disease postsurgery, highlighting the need for better treatment options. With the success of immune checkpoint inhibitors in both the adjuvant and metastatic settings, the use of these agents in the neoadjuvant setting has been an emerging area of research interest. In this chapter, we will discuss the rationale for neoadjuvant immunotherapy; review impactful clinical trials; and define response monitoring, surgical considerations, emerging therapies, and unanswered questions for neoadjuvant therapy as a recent paradigm shift in the management of clinical stage III melanoma.

Abstract Background: Sentinel lymph node biopsy (SLNB) provides important staging and prognostic information that guides surveillance and adjuvant systemic therapy decisions for patients with cutaneous melanoma. At most centers, SLNB is indicated for patients with cutaneous melanoma with at least a 5% risk of having nodal metastases, typically melanomas ≥0.8 mm in thickness or selected thinner lesions with high-risk features such as elevated mitotic rate and/or ulceration. However, up to 85% of patients who undergo SLNB have a negative result. Currently, there is an unmet clinical need to better identify patients with a low risk of nodal metastasis who may safely forgo SLNB, but otherwise meet established criteria for undergoing SLNB. Previously, a model using primary tumor gene expression profile (GEP) data combined with clinicopathological features (CP) was developed to identify melanoma patients with a low risk of having a positive SLN. The model has been externally validated in multiple retrospective studies. The aim of the MERLIN_001 observational registry study is to prospectively validate the CP-GEP model in an independent multicenter cohort of primary cutaneous melanoma patients, who undergo lymphatic mapping and SLNB per current clinical guidelines. Methods: A total of 9 centers across the US are included in the study with planned enrollment of 2,340 patients, allowing for a loss of up to 30% due to screen failure, tissue loss, low RNA yield, no gene expression profile or failure to perform the planned SLNB. Patients with clinically node-negative cutaneous melanoma and planned SLNB using current guideline indications are eligible for the study and will be followed for five years. Both patients and investigators are blinded to the results (NCT04759781). FFPE material from the initial melanoma biopsy is collected and the GEP of the primary melanoma is assessed. Subsequently, CP-GEP probability scores are calculated and expressed as a binary classification (Low Risk or High Risk for nodal metastasis), which will be compared to SLNB pathology results. Performance metrics for CP-GEP will be evaluated and will include: SLNB Reduction Rate based on Negative Predictive Value, Positive Predictive Value, Sensitivity and Specificity, and the corresponding 95% confidence intervals. Finally, the performance of CP-GEP to stratify patients according to risk of recurrence (recurrence-free survival, distant metastasis-free survival, overall survival) will also be assessed, based on five-year outcomes data. Additional analyses will be performed using the data collected throughout the study. Enrollment of patients started in September 2021 and is ongoing. As of January 2023, 890 patients have been enrolled, representing 46% of the targeted number of patients with a successful SLNB and CP-GEP test result. Citation Format: Tina J. Hieken, Michael E. Egger, Christina V. Angeles, Erin E. Burke, Michael C. Lowe, John R. Hyngstrom, Georgia M. Beasley, Edmund K. Bartlett, Vernon K. Sondak. Merlin_001: a prospective registry study of a primary melanoma gene-signature to predict sentinel node (SN) status and determine its prognostic value for more accurate staging of SN-negative melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT053.

Abstract Purpose: Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking. Patients and Methods: We performed a single-arm, multicenter clinical trial using “flip dose” ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%–66%] and 37% (95% CI, 19%–55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%–95%) and 68% (95% CI, 46%–83%), respectively. Median RFS was 10.3 months (95% CI, 5.7–25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.

Spinal cord stimulation (SCS) has demonstrated effectiveness for neuropathic pain. Unfortunately, some patients report inadequate long-term pain relief. Patient selection is emphasized for this therapy; however, the prognostic capabilities and deployment strategies of existing selection techniques, including an SCS trial, have been questioned. After approval by the Board of Directors of the American Society of Regional Anesthesia and Pain Medicine, a steering committee was formed to develop evidence-based guidelines for patient selection and the role of an SCS trial. Representatives of professional organizations with clinical expertize were invited to participate as committee members. A comprehensive literature review was carried out by the steering committee, and the results organized into narrative reports, which were circulated to all the committee members. Individual statements and recommendations within each of seven sections were formulated by the steering committee and circulated to members for voting. We used a modified Delphi method wherein drafts were circulated to each member in a blinded fashion for voting. Comments were incorporated in the subsequent revisions, which were recirculated for voting to achieve consensus. Seven sections with a total of 39 recommendations were approved with 100% consensus from all the members. Sections included definitions and terminology of SCS trial; benefits of SCS trial; screening for psychosocial characteristics; patient perceptions on SCS therapy and the use of trial; other patient predictors of SCS therapy; conduct of SCS trials; and evaluation of SCS trials including minimum criteria for success. Recommendations included that SCS trial should be performed before a definitive SCS implant except in anginal pain (grade B). All patients must be screened with an objective validated instrument for psychosocial factors, and this must include depression (grade B). Despite some limitations, a trial helps patient selection and provides patients with an opportunity to experience the therapy. These recommendations are expected to guide practicing physicians and other stakeholders and should not be mistaken as practice standards. Physicians should continue to make their best judgment based on individual patient considerations and preferences.

Abstract Purpose: Triple-negative invasive lobular carcinoma (TN-ILC) of breast cancer is a rare disease and the clinical outcomes and prognostic factors are not well-defined. Methods: Women with stage I-III TN-ILC or triple-negative invasive ductal carcinoma (TN-IDC) of the breast undergoing mastectomy or breast-conserving surgery between 2010 and 2018 in the National Cancer Database were included. Kaplan-Meier curves and multivariate Cox proportional hazard regression were used to compare overall survival (OS) and evaluate prognostic factors. Multivariate logistic regression was performed to analyze the factors associated with pathological response to neoadjuvant chemotherapy. Results: The median age at diagnosis for women with TN-ILC was 67 years compared to 58 years in TN-IDC (p<0.001). There was no significant difference in the OS between TN-ILC and TN-IDC in multivariate analysis (HR 0.96, p=0.44). Black race and higher TNM stage were associated with worse OS, whereas receipt of chemotherapy or radiation was associated with better OS in TN-ILC. Among women with TN-ILC receiving neoadjuvant chemotherapy, the 5-year OS was 77.3% in women with a complete pathological response (pCR) compared to 39.8% in women without any response. The odds of achieving pCR following neoadjuvant chemotherapy were significantly lower in women with TN-ILC compared to TN-IDC (OR 0.53, p<0.001). Conclusion: Women with TN-ILC are older at diagnosis but have similar OS compared to TN-IDC after adjusting for tumor and demographic characteristics. Administration of chemotherapy was associated with improved OS in TN-ILC, but women with TN-ILC were less likely to achieve complete response to neoadjuvant therapy compared to TN-IDC.

AbstractAlthough decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including MT‐ATP6 mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3–5 μM; screening cutoff >5) and ultimately diagnosed with MT‐ATP6 mitochondrial disease. Follow‐up testing revealed a pattern of hypocitrullinemia together with elevated propionyl‐(C3) and 3‐hydroxyisovaleryl‐(C5‐OH) acylcarnitines, and a homoplasmic pathogenic variant in MT‐ATP6 in all cases. Single and multivariate analysis of NBS data from the 11 cases using Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu) demonstrated citrulline <1st percentile, C3 > 50th percentile, and C5‐OH >90th percentile when compared with reference data, as well as unequivocal separation from proximal UCD cases and false‐positive low citrulline cases using dual scatter plots. Five of the eight mothers were symptomatic at the time of their child(ren)'s diagnosis, and all mothers and maternal grandmothers evaluated molecularly and biochemically had a homoplasmic pathogenic variant in MT‐ATP6, low citrulline, elevated C3, and/or elevated C5‐OH. All molecularly confirmed individuals (n = 17) with either no symptoms (n = 12), migraines (n = 1), or a neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) phenotype (n = 3) were found to have an A or U mitochondrial haplogroup, while one child with infantile‐lethal Leigh syndrome had a B haplogroup.