Clinical and Pathologic Response to Neoadjuvant Immunotherapy in DNA Mismatch Repair Protein-Deficient Gastroesophageal Cancers.

BACKGROUND: Mismatch repair deficient (dMMR) gastroesophageal cancers (GEC) are a distinct subgroup. Among patients with locally advanced disease, previous trial data suggest a good response to neoadjuvant immune checkpoint inhibitors (nICI). PATIENTS AND METHODS: Since 2019, our institution has routinely performed MMR testing for new GEC cases. Patients diagnosed with GEC (2019-2024) were included in the study. Quantitative data are described as the median and interquartile range (IQR); qualitative data are described as quantities and percentages. RESULTS: A total of 24 patients with dMMR GEC were identified following implementation of routine immunohistochemical testing; 14 were potentially resectable with a median follow-up of 14 months (IQR 8-27). All patients underwent pre-treatment positron emission tomography (PET; median SUV 20.9). Among the 14 potentially resectable patients, 4 underwent immediate surgery, 10 were treated with nICI, and 5 underwent surgical resection to date. All regimens included PD-1 inhibitors, with 70% receiving pembrolizumab. Re-staging PET was performed in five patients; the median post-nICI SUV was 5.1 (range 4.7-6.3). All resected specimens had gross ulceration after nICI, but 60% (N = 3) had a pathologic complete response (pCR) following nICI; one patient had a near-complete response (nCR) and one patient had a partial response (pPR). Reduction in SUV was 75% and 82% in the pCR patients, 25% in the nCR patient, and 43% in the pPR patient. CONCLUSIONS: dMMR GECs are responsive to nICI in this limited experience, mirroring early clinical trial data. Given persistent metabolic activity and visible ulceration despite pCR, studies should continue to optimize tools for estimating post-nICI pCR in these patients.

Clinical Characteristics and Special Considerations in the Management of Rare Melanoma Subtypes.

Rare histologic subtypes of melanoma, including acral, mucosal, uveal, and desmoplastic melanomas, only make up 5% of all diagnosed melanomas and are often underrepresented in large, randomized trials. Recent advancements in systemic therapy have shown marked improvement in pathologic response rates, improving progression-free and overall survival among cutaneous melanoma patients, but there are limited data to demonstrate improved survival among rarer subtypes of melanoma. Acral melanoma has a poor response to immunotherapy and is associated with worse survival. Mucosal melanoma has a large variability in its presentation, a poor prognosis, and a low mutational burden. Uveal melanoma is associated with a high rate of liver metastasis; recent adoption of infusion and perfusion therapies has demonstrated improved survival among these patients. Desmoplastic melanoma, a high-risk cutaneous melanoma, is associated with high locoregional recurrence rates and mutational burden, suggesting this melanoma may have enhanced response to immunotherapy. While these variants of melanoma represent distinct disease entities, this review highlights the clinicopathologic characteristics and treatment recommendations for each of these rare melanomas and highlights the utility of modern therapies for each of them.

Intralesional and Infusional Updates for Metastatic Melanoma.

Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional therapies, more options are available for use. Isolated limb infusion (ILI) was first introduced in the 1990s for the management of advanced melanoma, followed by the utilization of isolated extremity perfusion (ILP). Following this, intralesional oncolytic viruses, xanthene dyes, and cytokines were introduced for the management of in-transit metastases as well as unresectable, advanced melanoma. In 2015, the Food and Drug Administration (FDA) approved the first oncolytic intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of advanced melanoma. Additionally, immune checkpoint inhibition has demonstrated efficacy in the management of advanced melanomas, and this improvement in outcomes has been extrapolated to aid in the management of in-transit metastatic disease. Finally, percutaneous hepatic perfusion (PHP), also approved by the FDA, has been reported to have a significant impact on the treatment of hepatic disease in uveal melanoma. While some of these treatments have less utility due to inferior outcomes as well as higher toxicity profiles, there are selective patient profiles for which these therapies carry a role. This review highlights intralesional and infusional therapies for the management of metastatic melanoma.

Sentinel lymph node biopsy in patients with T1a cutaneous malignant melanoma: A multicenter cohort study.

BACKGROUND: Sentinel lymph node biopsy is not routinely recommended for T1a cutaneous melanoma due to the overall low risk of positivity. Prognostic factors for positive sentinel lymph node (SLN+) in this population are poorly characterized. OBJECTIVE: To determine factors associated with SLN+ in patients with T1a melanoma. METHODS: Patients with pathologic T1a (<0.80 mm, nonulcerated) cutaneous melanoma from 5 high-volume melanoma centers from 2001 to 2020 who underwent wide local excision with sentinel lymph node biopsy were included in the study. Patient and tumor characteristics associated with SLN+ were analyzed by univariate and multivariable logistic regression analyses. Age was dichotomized into ≤42 (25% quartile cutoff) and >42 years. RESULTS: Of the 965 patients identified, the overall SLN+ was 4.4% (N = 43). Factors associated with SLN+ were age ≤42 years (7.5% vs 3.7%; odds ratio [OR], 2.14; P = .03), head/neck primary tumor location (9.2% vs 4%; OR, 2.75; P = .04), lymphovascular invasion (21.4% vs 4.2%; OR, 5.64; P = .01), and ≥2 mitoses/mm2 (8.2% vs 3.4%; OR, 2.31; P = .03). Patients <42 years with ≥2 mitoses/mm2 (N = 38) had a SLN+ rate of 18.4%. LIMITATIONS: Retrospective study. CONCLUSION: SLN+ is low in patients with T1a melanomas, but younger age, lymphovascular invasion, mitogenicity, and head/neck primary site appear to confer a higher risk of SLN+.

Impact of the affordable care act's medicaid expansion on presentation stage and perioperative outcomes of colorectal cancer.

BACKGROUND AND OBJECTIVES: Medicaid expansion has improved healthcare coverage and preventive health service use. To what extent this has resulted in earlier stage colorectal cancer diagnoses and impacted perioperative outcomes is unclear. METHODS: This was a retrospective difference-in-difference study using the National Cancer Database on adults (40-64) with Medicaid or no insurance, diagnosed with colorectal adenocarcinomas before (2010-2013) and after (2015-2018) expansion. The primary outcome was early-stage (American Joint Committee on Cancer Stage 0-1) diagnosis. The secondary outcomes were rate of local excision, emergency surgery, postoperative length of stay, rates of minimally invasive surgery, postoperative mortality, and overall survival (OS). RESULTS: Medicaid expansion was associated with an increase in early-stage diagnoses for patients with colorectal cancers (odds ratio [OR]: 1.28, 95% confidence interval [CI]: 1.15-1.43), an increase in local excision (OR: 1.39, 95% CI: 1.13-1.69), and a decreased rate of emergent surgery (OR: 0.85, 95% CI: 0.75-0.97) and 90-day mortality (OR: 0.75, 95% CI: 0.59-0.97). Additionally, patients in expansion states postexpansion had an improved 5-year OS (hazard ratio: 0.88, 95% CI: 0.83-0.94). CONCLUSIONS: Insurance coverage expansion may be particularly important for optimizing stage of diagnosis, subsequent survival, and perioperative outcomes for socioeconomically vulnerable patients.

An Internally Validated Prognostic Risk-Score Model for Disease-Specific Survival in Clinical Stage I and II Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy for which factors predictive of disease-specific survival (DSS) are poorly defined. METHODS: Patients from six centers (2005-2020) with clinical stage I-II MCC who underwent sentinel lymph node (SLN) biopsy were included. Factors associated with DSS were identified using competing-risks regression analysis. Risk-score modeling was established using competing-risks regression on a training dataset and internally validated by point assignment to variables. RESULTS: Of 604 patients, 474 (78.5%) and 128 (21.2%) patients had clinical stage I and II disease, respectively, and 189 (31.3%) had SLN metastases. The 5-year DSS rate was 81.8% with a median follow-up of 31 months. Prognostic factors associated with worse DSS included increasing age (hazard ratio [HR] 1.03, p = 0.046), male sex (HR 3.21, p = 0.021), immune compromise (HR 2.46, p = 0.013), presence of microsatellites (HR 2.65, p = 0.041), and regional nodal involvement (1 node: HR 2.48, p = 0.039; ≥2 nodes: HR 2.95, p = 0.026). An internally validated, risk-score model incorporating all of these factors was developed with good performance (AUC 0.738). Patients with ≤ 4.00 and > 4.00 points had 5-year DSS rates of 89.4% and 67.2%, respectively. Five-year DSS for pathologic stage I/II patients with > 4.00 points (n = 49) was 79.8% and for pathologic stage III patients with ≤ 4.00 points (n = 62) was 90.3%. CONCLUSIONS: A risk-score model, including patient and tumor factors, based on DSS improves prognostic assessment of patients with clinically localized MCC. This may inform surveillance strategies and patient selection for adjuvant therapy trials.

Validated Risk-Score Model Predicting Lymph Node Metastases in Patients with Non-Functional Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: The incidence of, and factors associated with, lymph node metastasis (LN+) in non-functional gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are not well characterized. METHODS: Patients were identified from the 2010-2015 National Cancer Database who underwent surgical resection with lymphadenectomy for clinical stage I-III non-functional GEP NETs. Among a randomly selected training subset of 75% of the study population, variables associated with LN+ were identified using multivariable logistic regression analysis, and these variables were used to create a risk-score model for LN+, which was internally validated among the remaining 25% of the cohort. RESULTS: Of 12,228 patients evaluated, 6,902 (56.4%) had LN+. Among the training set, variables associated with LN+ included age (70 years of age or older: odds ratio [OR] 1.12, 95% CI 1.00-1.24; ref: less than 70 years), tumor location (stomach: OR 3.72, 95% CI 2.94-4.71; small intestine: OR 19.60, 95% CI 17.31-22.19; ref: pancreas), tumor grade (moderately differentiated: OR 1.47, 95% CI 1.30-1.67; poorly differentiated/anaplastic: OR 1.53, 95% CI 1.21-1.95; ref: well-differentiated), tumor size (2-4 cm: OR 2.40, 95% CI 2.13-2.70; >4 cm: OR 5.25, 95% CI 4.47-6.17; ref: <2 cm), and lymphovascular invasion (OR 5.62, 95% CI 5.08-6.21; ref: no lymphovascular invasion). After internal validation, a risk-score model for LN+ using these variables was developed composed of low- (N = 2,779), intermediate- (N = 2,598), high- (N = 3,433), and very-high-risk (N = 3,418) groups; within each group the rate of LN+ was 8.7%, 48.6%, 64.9%, and 92.8%, respectively. CONCLUSIONS: This developed risk-score model, including both patient and tumor variables, can be used to calculate the risk for LN metastases in patients with GEP NETs.

Pathologic Factors Associated with Low Risk of Lymph Node Metastasis in Nonmucinous Adenocarcinoma of the Appendix.

BACKGROUND: Right hemicolectomy (RHC) for nodal staging is recommended for nonmucinous adenocarcinoma of the appendix (NMACA), but it is unclear whether a subgroup of patients at low risk for lymph node (LN) metastasis exists who may be managed with a less extensive resection. PATIENTS AND METHODS: Patients with NMACA without distant metastases who underwent margin negative resection via either RHC or appendectomy/partial colectomy (A/PC) were evaluated from the National Cancer Database (2004-2016). Patients at low risk for LN metastasis were identified. Multivariable survival analysis was performed, and 5-year overall survival (OS) was estimated. RESULTS: Of the 2487 patients included, 652 [26.2%; 95% confidence interval (CI) 24.5-28.0%] had LN metastases. T4 T stage [odds ratio (OR) 4.2, p = 0.032], poorly/undifferentiated histology (OR 2.2, p = 0.004), and lymphovascular invasion (LVI) (OR 4.4, p < 0.001) were associated with LN positivity. One hundred and thirteen patients (4.5%) had tumors at low risk for LN metastasis (T1 T stage, well/moderately differentiated tumors without LVI), and the rate of LN metastasis for this group was 1.8% (95% CI 0.5-6.2%). Conversely, the LN metastasis rate among the 2374 non-low-risk patients was 27.4% (95% CI 25.6-29.2%). Performance of A/PC instead of RHC was associated with a survival disadvantage among all patients (hazards ratio 1.5, p = 0.049), but among the low-risk cohort, 5-year OS did not differ based on resection type (88.3% A/PC versus 92.7% RHC, p = 0.305). CONCLUSIONS: Although relatively uncommon, early, pathologically favorable NMACA is associated with a very low risk of LN metastasis. These select patients may be managed with a less extensive resection without compromising oncologic outcomes.

Predictive risk-score model for selection of patients with high-risk stage II colon cancer for adjuvant systemic therapy.

BACKGROUND: Adjuvant systemic therapy is selectively considered for high-risk stage II colon cancer, but which patients benefit most from adjuvant systemic therapy is unclear. METHODS: Patients who underwent resection of stage II colon cancer were identified from the National Cancer Database (2010-2016). Risk-factors for decreased overall survival on multivariable analysis were used to establish a predictive risk-score model for all-cause mortality. After propensity matching within each risk group, 5-year overall survival was estimated based on receipt of adjuvant systemic therapy. RESULTS: Of the 15,241 patients evaluated, 2,857 (18.8%) received adjuvant systemic therapy. Risk factors for decreased overall survival included age >75 (hazard ratio 3.3, P < .001), male sex (hazard ratio 1.2, P < .001), White/Black race (hazard ratio 1.4, P = .020), preoperative carcinoembryonic antigen >3.5 ng/mL (hazard ratio 1.6, P < .001), T4a T-stage (hazard ratio 2.0, P < .001), T4b T-stage (hazard ratio 2.4, P < .001), lymphovascular invasion (hazard ratio 1.2, P = .003), perineural invasion (hazard ratio 1.3, P = .003), and non-R0 proximal/distal resection margins (hazard ratio 1.7, P < .001). An internally validated risk-score model using these factors was developed composed of low-risk (n = 8,489), moderate-risk (n = 4,623), and high-risk (n = 2,129) groups; within each group, 19.9%, 15.7%, and 20.8% of patients, respectively, received adjuvant systemic therapy. After propensity matching, adjuvant systemic therapy was not associated with improved 5-year overall survival for low-risk patients (89.8% vs 88.3%, P = .280), but was for moderate-risk (80.5% vs 70.8%, P < .001), and high-risk (65.2% vs 45.7%, P < .001) patients. CONCLUSION: A predictive risk-score model incorporating patient and tumor factors identifies a high-risk cohort of stage II colon cancer patients who may benefit from adjuvant systemic therapy, although the minority of these patients appear to be receiving treatment.

The impact of hospital volume on racial disparities in resected rectal cancer.

BACKGROUND: Although high volume centers (HVC) equate to improved outcomes in rectal cancer, the impact of surgical volume related to race is less defined. METHODS: Patients who underwent surgical resection for stage I-III rectal adenocarcinoma were divided into cohorts based on race and hospital surgical volume. Outcomes were analyzed following 1:1 propensity-score matching using logistic, Poisson, and Cox regression analyses with marginal effects. RESULTS: Fifty-four thousand one hundred and eighty-four (91.5%) non-Black and 5043 (8.5%) Black patients underwent resection of rectal cancer. Following 1:1 matching of non-Black (N = 5026) and Black patients, 5-year overall survival (OS) of Black patients was worse (72% vs. 74.4%, average marginal effects [AME] 0.66, p = 0.04) than non-Black patients. When compared to non-Black patients managed at HVCs, Black patients had worse OS (70.1% vs. 74.7%, AME 1.55, p = 0.03), but this difference was not significant when comparing OS between non-Black and Black patients managed at HVCs (72.3% vs. 74.7%, AME 0.62, p = 0.06). Length of stay was longer among Black and HVC patients across all cohorts. There was no difference across cohorts in 90-day mortality. CONCLUSIONS: Although racial disparities exist in rectal cancer, this disparity appears to be ameliorated when patients are managed at HVCs.

Lymph Node Evaluation after Neoadjuvant Chemotherapy for Patients with Gastric Cancer.

BACKGROUND: Adequate lymphadenectomy with at least 16 nodes retrieved at the time of gastrectomy is a quality measure recommended to ensure adequate staging. The minimum nodal retrieval recommended after receipt of neoadjuvant chemotherapy (NACT) is less defined. METHODS: Patients with clinical stages 1 to 3 gastric adenocarcinoma who received NACT and surgical resection were identified from the 2004-2015 National Cancer Database. The optimal nodal harvest number was calculated with Cox spline regression modeling. Cohorts with a nodal harvest higher or lower than this number were 1:1 propensity score-matched. Overall survival (OS) was analyzed using Kaplan-Meier survival estimates. RESULTS: Among 4337 patients receiving NACT, the optimal minimal nodal harvest at gastrectomy was 23 nodes. Compared with the patients who had fewer than 23 nodes retrieved, the patients with at least 23 nodes examined (n = 1073, 24.7%) were more likely to be female (26.1% vs 22%; p = 0.006) and non-white (29.3% vs 18.5%; p < 0.0001), to have a Charlson-Deyo score of 0 (71.5% vs 66.8%; p = 0.005), and to have undergone resection at an academic facility (67.9% vs 51.5%; p < 0.0001). The patients with at least 23 nodes examined had higher proportions of high-grade tumor (62% vs 57.4%; p = 0.030), pT3 or pT4 tumor (56.3% vs 48.7%; p < 0.0001), body tumor (21.3% vs 12.5%; p < 0.0001), or antrum/pylorus tumor (15.3% vs 11.4%; p < 0.0001). The patients with at least 23 nodes were more likely to have lymph node metastases identified (61% vs 51%; p < 0.0001). After matching, the patients with at least 23 nodes (n = 990) demonstrated an improved 5-year OS (57.9% vs 49%; p = 0.001). CONCLUSIONS: The extent of lymphadenectomy during gastrectomy for gastric adenocarcinoma should not be reduced after NACT because adequate lymph node retrieval remains important for prognostication.

Neoadjuvant radiation for cutaneous and soft tissue angiosarcoma.

BACKGROUND AND OBJECTIVES: Neoadjuvant radiation (NRT) is frequently utilized in soft tissue sarcomas to increase local control. Its utility in cutaneous and soft tissue angiosarcoma remains poorly defined. METHODS: This retrospective cohort study was performed using the National Cancer Database (2004-2016) evaluating patients with clinically localized, surgically resected angiosarcomas. Factors associated with receipt of NRT in the overall cohort and margin positivity in treatment naïve patients were identified by univariate and multivariable logistic regression analyses. Survival was assessed using Kaplan-Meier analysis. RESULTS: Of 597 patients, 27 (4.5%) received NRT. Increasing age (odds ratio [OR] 0.95, p = 0.025), tumor size more than or equal to 5 cm (OR 3.16, p = 0.02), and extremity tumor location (OR 3.99, p = 0.04) were associated with receipt of NRT. All patients who received NRT achieved an R0 resection (p = 0.03) compared with 17.9% of patients without NRT. Factors associated with risk of margin positivity included tumor size more than or equal to 5 cm (OR 1.85, p = 0.01), and head/neck location (OR 2.24, p = 0.006). NRT was not significantly associated with improved survival (p = 0.21). CONCLUSIONS: NRT improves rates of R0 resection but is infrequently utilized in cutaneous and soft tissue angiosarcoma. Increased usage of NRT, particularly for patients with lesions more than or equal to 5 cm, or head and neck location, may help achieve complete resections.

Optimizing Detection of Lymphatic Invasion in Primary Cutaneous Melanoma With the Use of D2-40 and a Paired Melanocytic Marker.

ABSTRACT: Dual immunohistochemical (IHC) staining with D2-40 and S100 improves detection of lymphatic invasion (LI) in primary cutaneous melanoma. However, limited data exist evaluating this technique using other melanocytic markers, and thus, the optimal marker for detection of LI is unestablished. To address this knowledge gap, a case-control study was performed comparing melanoma specimens from 22 patients with known lymphatic spread (LS) with a control group of 11 patients without LS. Specimens underwent dual IHC staining with D2-40 and MART-1, SOX-10, and S100 to evaluate for LI. Receiver operating characteristic analysis was used to estimate each stain's accuracy for detection of LI. The LS group was more likely to be ≥65 years (P = 0.04), have a tumor thickness of ≥1 mm (P < 0.01), and have ulcerated tumors (P = 0.02). Detection of LI with D2-40/MART-1 significantly correlated with LS (P = 0.03), and the D2-40/MART-1 stain was most accurate for LI based on receiver operating characteristic curve analysis (area under the curve [AUC] 0.705) in comparison with D2-40/SOX-10 (AUC 0.575) and D2-40/S100 (AUC 0.633). These findings suggest that MART-1 may be the optimal melanocytic marker to combine with D2-40 for detection of LI in melanoma. Further studies are needed to determine the utility of routinely performing these stains for histopathologic analysis of melanoma.