Totally minimally invasive laparoscopic robot-assisted Ivor Lewis esophagectomy: improved technique and outcomes over 200 cases.

Background: Surgical resection of esophageal and gastroesophageal junction cancers is a very complex procedure with step learning curve. New technologies have made minimally invasive surgery possible, but challenges still remain for wide spread adoption of these techniques. This article aims to describe the outcomes and salient technical points of a totally minimally invasive, laparoscopic, robot-assisted Ivor Lewis esophagectomy (LRAMIE). Methods: Retrospective observational cohort study performed at a specialty cancer center using a prospectively maintained institutional database. Patients undergoing LRAMIE (laparoscopic abdomen, robotic chest) from 2014-2023 were included. Patients undergoing transhiatal and three-field esophagectomy were excluded. Operative and postoperative outcomes were compared over the study period to identify potential associations between outcomes over time. Results: Two-hundred patients were identified who underwent LRAMIE. Median age was 65 years and most were male (87.5%). The open conversion rate was 1% (n=2), which occurred within the first 30 cases. Operative time and blood loss were improved at the 60-case mark (P<0.001). Anastomotic stricture rate improved after 50 cases, and leak rate improved after 80 cases. Postoperative length of stay improved at both 50 and 100 cases with a median LOS of 6 days after 100 cases. Rate of postoperative pneumonia, 30- and 90-day mortality were reduced after 100 cases, although not statistically significant for mortality due to too few events. Conclusions: Totally minimally invasive Ivor Lewis esophagectomy at a high-volume center is a safe procedure. Operative outcomes improved significantly after 50-80 cases, followed by improvement in anastomotic results and postoperative outcomes, with corresponding excellent oncologic outcomes.

Induction Fluorouracil-Based Chemotherapy and PET-Adapted Consolidation Chemoradiation with Esophagectomy for High-Risk Gastroesophageal Adenocarcinoma.

Background: Neoadjuvant chemoradiation with esophagectomy is standard management for locally advanced esophageal adenocarcinoma. Induction chemotherapy with a tailored approach to chemoradiation based on metabolic response to therapy on PET was explored as an alternative strategy in the CALGB 80803 trial. We sought to describe real-world institutional experience implementing this approach outside of a clinical trial. Methods: Patients who were treated with induction fluorouracil-leucovorin-oxaliplatin (FOLFOX) or fluorouracil-leucovorin-oxaliplatin-docetaxel (FLOT) with tailored chemoradiation based on PET response and subsequent esophagectomy were identified from a prospectively maintained database. Primary outcomes were pathologic complete response (pCR) and overall survival (OS) following completion of all therapy. Results: There were 35 patients who completed induction chemotherapy, chemoradiation, and esophagectomy. Thirty-three completed restaging PET following induction chemotherapy with metabolic response seen in 76% (n = 25/33). The pCR rate was 31% (n = 11/35) and the ypN0 rate was 71% (n = 25/35). Among the patients who demonstrated metabolic response to induction FOLFOX/FLOT and subsequently continued fluorouracil-based chemoradiation, the pCR rate was 39% (n = 9/23). The rate of pathologically negative lymph nodes in this group was high (n = 19/23, 83%) with 100% R0 resection rate (n = 23/23). With the median follow-up of 43 months, the median OS was not reached for this group and was significantly longer than the OS for the remainder of the cohort (p = 0.027, p = 0.046 adjusted for clinical stage). Conclusions: Induction FOLFOX/FLOT chemotherapy with evaluation of sensitivity via metabolic response and tailored chemoradiation seems to lead to high pCR and ypN0 rates in high-risk patients with adenocarcinoma of the esophagus and GE junction. This approach in clinical practice seems to recapitulate encouraging results in clinical trials.

Benchmarks and Geographic Differences in Gallbladder Cancer Surgery: An International Multicenter Study.

BACKGROUND: High-quality surgery plays a central role in the delivery of excellent oncologic care. Benchmark values indicate the best achievable results. We aimed to define benchmark values for gallbladder cancer (GBC) surgery across an international population. PATIENTS AND METHODS: This study included consecutive patients with GBC who underwent curative-intent surgery during 2000-2021 at 13 centers, across seven countries and four continents. Patients operated on at high-volume centers without the need for vascular and/or bile duct reconstruction and without significant comorbidities were chosen as the benchmark group. RESULTS: Of 906 patients who underwent curative-intent GBC surgery during the study period, 245 (27%) were included in the benchmark group. These were predominantly women (n = 174, 71%) and had a median age of 64 years (interquartile range 57-70 years). In the benchmark group, 50 patients (20%) experienced complications within 90 days after surgery, with 20 patients (8%) developing major complications (Clavien-Dindo grade ≥ IIIa). Median length of postoperative hospital stay was 6 days (interquartile range 4-8 days). Benchmark values included ≥ 4 lymph nodes retrieved, estimated intraoperative blood loss ≤ 350 mL, perioperative blood transfusion rate ≤ 13%, operative time ≤ 332 min, length of hospital stay ≤ 8 days, R1 margin rate ≤ 7%, complication rate ≤ 22%, and rate of grade ≥ IIIa complications ≤ 11%. CONCLUSIONS: Surgery for GBC remains associated with significant morbidity. The availability of benchmark values may facilitate comparisons in future analyses among GBC patients, GBC surgical approaches, and centers performing GBC surgery.

Tumor Regression Grade and Overall Survival following Gastrectomy with Preoperative Therapy for Gastric Cancer.

BACKGROUND: Pre-/perioperative chemotherapy is well-established for management of locoregional gastric cancer (LRGC). The American Joint Committee on Cancer advocates histopathologic assessment of tumor regression grade (TRG) but does not endorse a specific schema. We sought to examine the prognostic value of the recently revised National Comprehensive Cancer Network (NCCN) definition of TRG specifying TRG0 as no disease in primary tumor or lymph nodes. PATIENTS AND METHODS: Patients with clinical-stage T2+/N+/M0 LRGC receiving preoperative chemotherapy and curative-intent gastrectomy were identified (2000-2020). TRG using the current NCCN definition was retrospectively assigned. Factors associated with TRG were examined using ordinal logistic regression and overall survival (OS) was assessed using the Kaplan-Meier method and Cox regression. RESULTS: Among 117 patients, the most common chemotherapy regimen was epirubicin, cisplatin, plus fluorouracil or capecitabine (ECF/ECX) (n = 48, 41%), followed by folinic acid, fluorouracil, and oxaliplatin (FOLFOX) (n = 30, 26%), and fluorouracil, leucovorin, oxaliplatin, plus docetaxel (FLOT) (n = 13, 11%). TRG3 was the most common histopathologic response (n = 68, 58%), followed by TRG2 (n = 25, 21%), TRG1 (n = 18, 15%), and, lastly, TRG0 (n = 6, 5.1%). The only preoperative factor independently associated with lower TRG was gastroesophageal junction tumor location (OR 0.24, p = 0.012). Higher TRG was independently associated with worse OS in a stepwise fashion (HR 1.49, p = 0.026). Posttreatment pathologic lymph node status was the strongest prognostic factor (HR 1.93, p = 0.026). Independent prognostic value of TRG and ypT stage could not be shown due to substantial overlap. CONCLUSIONS: TRG using the contemporary NCCN definition is associated with OS in LRGC. TRG0 is uncommon but with excellent prognosis. ypN status is the strongest prognostic factor and the revised NCCN definition acknowledging this is appropriate.

Simultaneous Hepatic and Visceral Resection: Preoperative Risk Stratification and Implications on Return to Intended Oncologic Therapy.

PURPOSE: Sequence of therapies for synchronous liver metastasis (LM) is complex, with data supporting individualized approaches, although no guiding tools are currently available. We assessed the impact of simultaneous hepatic and visceral resections (SHVR) on textbook outcome (TO) and return to intended oncologic therapy (RIOT), and provide risk-stratification tools to guide individualized decision making and counseling. METHODS: Patients with synchronous LM undergoing hepatectomy ± SHVR were included (2015-2021). Primary and secondary outcomes were TO and RIOT (days), respectively. Using multivariable modeling, a risk score for TO was developed. Decision tree analysis using recursive partitioning was performed for hierarchical risk stratification. The associations between SHVR, TO, and RIOT were examined. RESULTS: Among 533 patients identified, 124 underwent SHVR. TO overall was 71.7%; 79.2% in the non-SHVR group and 46.8% in the SHVR group (p < 0.001). SHVR was the strongest predictor of non-TO (right colon/small bowel: odds ratio [OR] 4.63, 95% confidence interval [CI] 2.65-8.08; left colon/rectum: OR 6.09, 95% CI 2.59-14.3; stomach/pancreas: OR 6.69, 95% CI 1.46-30.7; multivisceral: OR 10.9, 95% CI 3.03-39.5). A composite score was developed yielding three risk strata for TO (score 0-2: 89% vs. score 3-5: 67% vs. score ≥ 6: 37%; p < 0.001). Decision tree analysis was congruent, identifying SHVR as the most important determinant of TO. In patients with colorectal LM, SHVR was associated with delayed time to RIOT (p = 0.004); the risk-stratification tool for TO was equally predictive of RIOT (p < 0.01). CONCLUSIONS: SHVR is associated with reduced likelihood of TO and in turn delayed RIOT. As SHVR is increasingly performed in order to consolidate cancer care, patient selection considering these different outcomes is critical.

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+.

Clockwise Anterior-to-Posterior-Double Isolation (CAP-DI) Approach for Portal Lymphadenectomy in Biliary Tract Cancer: Technique, Yield, and Outcomes.

Background: Portal lymphadenectomy (PLND) is the current standard for oncologic resection of biliary tract cancers (BTCs). However, published data show it is performed infrequently and often yields less than the recommended 6 lymph nodes. We sought to identify yield and outcomes using a Clockwise Anterior-to-Posterior technique with Double Isolation of critical structures (CAP-DI) for PLND. Methods: Consecutive patients undergoing complete PLND for BTCs using CAP-DI technique were identified (2015−2021). Lymph node (LN) yield and predictors of LN count were examined. Secondary outcomes included intraoperative and postoperative outcomes, which were compared to patients having hepatectomy without PLND. Results: In total, 534 patients were included; 71 with complete PLND (36 gallbladder cancers, 24 intrahepatic cholangiocarcinomas, 11 perihilar cholangiocarcinomas) and 463 in the control group. The median PLND yield was 5 (IQR 3−8; range 0−17) and 46% had at least 6 nodes retrieved. Older age was associated with lower likelihood of ≥6 node PLND yield (p = 0.032), which remained significant in bivariate analyses with other covariates (p < 0.05). After adjustment for operative factors, performance of complete PLND was independently associated with longer operative time (+46.4 min, p = 0.001), but no differences were observed in intraoperative or postoperative outcomes compared to the control group (p > 0.05). Conclusions: Yield following PLND frequently falls below the recommended minimum threshold of 6 nodes despite a standardized stepwise approach to complete clearance. Older age may be weakly associated with lower PLND yield. While all efforts should be made for complete node retrieval, failure to obtain 6 nodes may be an unrealistic metric of surgical quality.

Anatomic patterns of recurrence in biliary tract cancers: does primary tumor site matter?

Background: Recommendations for postoperative surveillance and adjuvant therapy following curative-intent resection for biliary tract cancers-including intrahepatic and extrahepatic cholangiocarcinoma (IHCCA and EHCCA) and primary gallbladder cancer (GBC)-are uniform across primary tumor site. However, these tumors may have distinct patterns of recurrence. Methods: A retrospective observational cohort study was performed at a specialty cancer center. Patients undergoing resection of IHCCA, EHCCA, and GBC were identified (2005-2020). Recurrence-free survival (RFS) was estimated using Kaplan-Meier and Cox proportional hazard methods. Anatomic patterns of initial site of recurrence were described and compared. Results: There were 142 patients included; 50 IHCCA, 32 EHCCA, and 60 GBC. Median RFS was 30.8 months, which was not significantly different between IHCCA, EHCCA, or GBC in univariate analysis or after adjustment. Nodal positivity was significantly associated with poor RFS (HR 3.92, P≤0.001). The most common initial site of recurrence overall was intrahepatic (n=49/64, 77%), in isolation (n=32) or synchronous with other site of recurrence (n=17). Significant differences in anatomic pattern of recurrence were observed (P=0.049) with IHCCAs more commonly recurring with simultaneous hepatic-pulmonary disease (n=5/22, 23%; EHCCA n=2/19, 10%; GBC n=1/23, 4%), GBC more commonly recurring within the porta (n=7/23, 30%; IHCCA n=0; EHCCA n=1/19, 5%), and EHCCA more commonly recurring within the peritoneum (n=5/19, 26%; IHCCA n=2/22, 9%, GBC n=2/23, 9%). Conclusions: Patterns of initial recurrence appear to differ between primary tumor site, likely reflecting underlying differences in anatomy and biology. These data could help inform future studies for adjuvant therapy as well as timing and anatomic focus for surveillance imaging.

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.

Predictors of False Negative Sentinel Lymph Node Biopsy in Clinically Localized Merkel Cell Carcinoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is routinely recommended for clinically localized Merkel cell carcinoma (MCC); however, predictors of false negative (FN) SLNB are undefined. METHODS: Patients from six centers undergoing wide excision and SLNB for stage I/II MCC (2005-2020) were identified and were classified as having either a true positive (TP), true negative (TN) or FN SLNB. Predictors of FN SLNB were identified and survival outcomes were estimated. RESULTS: Of 525 patients, 28 (5.4%), 329 (62.7%), and 168 (32%) were classified as FN, TN, and TP, respectively, giving an FN rate of 14.3% and negative predictive value of 92.2% for SLNB. Median follow-up for SLNB-negative patients was 27 months, and median time to nodal recurrence for FN patients was 7 months. Male sex (hazard ratio [HR] 3.15, p = 0.034) and lymphovascular invasion (LVI) (HR 2.22, p = 0.048) significantly correlated with FN, and increasing age trended toward significance (HR 1.04, p = 0.067). The 3-year regional nodal recurrence-free survival for males >75 years with LVI was 78.5% versus 97.4% for females ≤75 years without LVI (p = 0.009). Five-year disease-specific survival (90.9% TN vs. 51.3% FN, p < 0.001) and overall survival (69.9% TN vs. 48.1% FN, p = 0.035) were significantly worse for FN patients. CONCLUSION: Failure to detect regional nodal microscopic disease by SLNB is associated with worse survival in clinically localized MCC. Males, patients >75 years, and those with LVI may be at increased risk for FN SLNB. Consideration of increased nodal surveillance following negative SLNB in these high-risk patients may aid in early identification of regional nodal recurrences.

Survival Outcomes Following Lymph Node Biopsy in Thin Melanoma-A Propensity-Matched Analysis.

BACKGROUND: The use of sentinel lymph node biopsy in patients with T1 melanoma ≤ 1 mm has not been reported in a prospective clinical trial setting, so these clinical outcomes remain understudied. This study seeks to evaluate overall survival (OS) with and without lymph node biopsy (LNB) in patients with clinical T1N0M0 melanoma (0.5-1.0 mm). PATIENTS AND METHODS: Patients were identified using the National Cancer Data Base (2004-2012). After stratification into 0.5-0.7-mm and 0.8-1.0-mm groups, patients undergoing LNB were propensity score-matched 1:1 to patients not undergoing LNB. OS was compared using the Kaplan-Meier method and the stratified log-rank test. RESULTS: Resection was performed in 28,846 patients, and LNB in 14,028 (49%); 15,194 were included in propensity score-matched analysis. The LNB and no-LNB groups were well balanced on all studied covariates (standardized mean difference < 0.10). Among patients with tumors 0.5-0.7 mm, 5- and 10-year OS were 94.7% and 82.7%, respectively, for the LNB group compared with 94.3% and 84.4% for the no-LNB group (p = 0.35). Among patients with tumors 0.8-1.0 mm in thickness, 5- and 10-year OS were 93.9% and 81.6%, respectively, for the LNB group compared with 90.3% and 74.3% for the no-LNB group (p < 0.0001). CONCLUSIONS: There was no difference in OS by LNB status in patients with lesions 0.5-0.7 mm, consistently with recommendations against its routine use in this group. In lesions 0.8-1.0 mm, receipt of LNB was associated with a clinically small but significant improvement in OS. Further study is warranted to better understand this outcome difference.

The impact of surgery for metastatic pancreatic neuroendocrine tumor: a contemporary evaluation matching for chromogranin a level.

BACKGROUND: Studies supporting surgical management of metastatic pancreatic neuroendocrine tumor (PNET) are limited by selection bias. Chromogranin A (CgA) has been used as a biomarker for PNET and may reflect disease burden or biology. This study aimed to correlate CgA level with overall survival and to use it to match patients selected for different treatment approaches in an analysis of the impact of surgical management. METHODS: 1478 patients diagnosed with PNET in the National Cancer Database (2004-2014) were retrospectively identified, and logistic regression analyses were used to evaluate associations between the presence of metastatic disease and CgA level. After matching patients by CgA level and other factors predictive of surgical management, Kaplan-Meier survival analysis was performed. RESULTS: Median CgA level was significantly higher in metastatic versus localized PNET(169 ng/mL versus 66 ng/mL, p < 0.001). On multivariate logistic regression, CgA level was predictive of metastatic disease(OR 1.002, p < 0.001) and survival in metastatic and non-metastatic patients. After matching for CgA level, surgery was associated with improved overall survival. DISCUSSION: CgA level is predictive of the presence of distant metastatic disease and overall survival in PNET. When matched by CgA and other predictors of treatment approach, patients with metastatic PNET undergoing surgery have improved survival.

Grade is a Dominant Risk Factor for Metastasis in Patients with Rectal Neuroendocrine Tumors.

BACKGROUND: Small (< 2 cm) and diminutive (< 1 cm) rectal neuroendocrine tumors (RNETs) are often described as indolent lesions. A large single-center experience was reviewed to determine the incidence of metastasis and the risk factors for its occurrence. METHODS: Cases of RNET between 2010 and 2017 at a single institution were retrospectively reviewed. The rate of metastasis was determined, and outcomes were stratified by tumor size and grade. Uni- and multivariable predictors of metastasis were identified, and a classification and regression tree analysis was used to stratify the risk for distant metastasis. RESULTS: The study identified 98 patients with RNET. The median follow-up period was 28 months. Of the 98 patients, 79 had primary tumors smaller than 1 cm, 8 had tumors 1 to 2 cm in size, and 11 had tumors 2 cm in size or larger. In terms of grade, 86 patients had grade 1 (G1) tumors, 8 patients had grade 2 (G2) tumors, and 4 patients had grade 3 (G3) tumors. Twelve patients developed metastatic disease. Both size and grade were associated with distant metastasis in the uni- and multivariable analyses, but when stratified by grade, size was predictive of metastasis only for G1 tumors (p < 0.001). Among the 12 patients with metastatic disease, 3 (25%) had diminutive primary tumors, and 9 (75%) had primary tumors 2 cm in size or larger. Diminutive tumors that metastasized were all G2. CONCLUSIONS: Patients with diminutive and small RNETs are at risk for metastatic disease. Tumor grade is a dominant predictor of dissemination. More rigorous staging, closer surveillance, or more aggressive initial management may be warranted for patients with G2 tumors, irrespective of size.