Identification of high-risk patients with a seven-biomarker prognostic signature for adjuvant treatment trial recruitment in American Joint Committee on Cancer v8 stage I-IIA cutaneous melanoma.

PURPOSE: Many patients with resected American Joint Committee on Cancer (AJCC) early-stage cutaneous melanoma nonetheless die of melanoma; additional risk stratification approaches are needed. PATIENTS AND METHODS: Using prospectively-collected whole-tissue sections, we assessed in consecutive stage I-IIA patients (N = 439), a previously-validated, immunohistochemistry-based, 7-biomarker signature to prognosticate disease-free survival (DFS), melanoma-specific survival (MSS; primary end-point) and overall survival (OS), independent of AJCC classification. RESULTS: Seven-marker signature testing designated 25.1% of patients (110/439) as high-risk (stage IA, 13.3% [43/323], IB, 53.2% [42/79], and IIA, 67.6% [25/37]). A Kaplan-Meier analysis demonstrated high-risk patients to have significantly worse DFS, MSS and OS versus low-risk counterparts (P < 0.001). In multivariable Cox regression modelling also including key clinicopathological/demographic factors, 7-marker signature data independently prognosticated the studied end-points. Models with the 7-marker signature risk category plus clinicopathological/demographic covariates substantially outperformed models with clinicopathological/demographic variables alone in predicting all studied outcomes (areas under the receiver operator characteristic curve 74.1% versus 68.4% for DFS, 81.5% versus 71.2% for MSS, 80.9% versus 73.0% for OS; absolute differences 5.7%, 10.3% and 7.9%, respectively, favouring 7-marker signature risk category-containing models). CONCLUSION: In patients with AJCC early-stage disease, the 7-marker signature reliably prognosticates melanoma-related outcomes, independent of AJCC classification, and provides a valuable complement to clinicopathological/demographic factors.

Characteristics and outcome of patients with small bowel adenocarcinoma (SBA).

BACKGROUND: Small bowel adenocarcinoma (SBA) remains a rare malignancy accounting for less than 5% of all the gastrointestinal tract cancers. However, only limited data and expert guidelines are available for this entity. As a result, treatment concepts are predominantly derived from colorectal cancer. METHODS: To substantiate data on the course of disease, diagnosis and treatment of SBA, we performed a population-based analysis from a Bavarian population of 2.2 million people. RESULTS: We identified 223 patients with SBA. Mean age at diagnosis was 67.8 years and patients were diagnosed rather late (34.5% UICC stage IV). Largest proportion of these patients were diagnosed with adenocarcinoma of the duodenum (132 patients, 59.2%) and most patients were diagnosed with late stage cancer, stage IV (70 patients, 31.4%). With respect to treatment, most patients underwent primary surgery (187 patients, 84.6%). Systemic therapy seemed to have an impact in UICC stage IV patients but not in UICC stage IIB or III. The 5-year survival rate was 29.0%. This was significantly less compared to colon cancer in the same cohort, which was 50.0%. Furthermore, median survival of patients with small bowel cancer was only 2.0 years (95% CI 1.4-2.5) compared to 4.9 years (95% CI 4.8-5.1) of patients with colon cancer. CONCLUSION: SBA showed a distinct epidemiology compared to colon cancer. Thus, data acquisition particularly on systemic treatment are paramount, with the objective to complement the available guidelines.

[Surgical treatment of adenocarcinoma of the esophagogastric junction type II : Comparison between transhiatal extended gastrectomy and thoracoabdominal esophagectomy]. / Chirurgische Therapie des Adenokarzinoms des ösophagogastralen Übergangs Typ II : Vergleich zwischen transhiatal erweiterter Gastrektomie und thorakoabdomineller Ösophagektomie.

BACKGROUND: The incidence of adenocarcinoma of the esophagogastric junction (AEG) has significantly increased. However, the best surgical treatment for AEG type II is still the subject of current research. The goal of this retrospective cohort study is to compare survival and recurrence rates in patients, who underwent either thoracoabdominal esophagectomy (TAE) or transhiatal extended gastrectomy (TEG). MATERIAL AND METHODS: The study is based on a cohort of 272 patients diagnosed with AEG type II between 2002 and 2020, recorded by a population-based clinical cancer registry. Of the included patients 63 underwent TAE and 209 TEG. In order to compare overall survival, recurrence rates, and recurrence free survival, we applied the Kaplan-Meier method, univariable and multivariable Cox regression. RESULTS: Our analysis showed no statistically significant difference concerning overall survival (p = 0.333). However a tendency towards higher survival rates after TAE for the period from 2016-2020 (p = 0,058) is possible. In contrast a significant difference concerning higher cumulative recurrence rates after TAE was found after Kaplan-Meier analysis (p = 0.049). This trend was not observed for the time after 2016 (p = 0.993), in which over 50% of TAE were performed. No differences were found regarding recurrence-free survival (p = 0.772). CONCLUSION: Our findings in a rather small cohort are concordant with most studies showing no differences or a trend towards better survival after TAE. Other studies found no significant difference regarding recurrence-free survival as well. In conclusion, no significant differences were found between TEG and TAE in surgical treatment of AEG type II.

Long-term outcome of patients with intermediate- and high-risk endometrial cancer after pelvic and paraaortic lymph node dissection: a comparison of laparoscopic vs. open procedure.

OBJECTIVE: The primary therapy for intermediate- and high-risk endometrial cancer includes pelvic and paraaortic lymph node evaluation. Laparoscopic surgery is an increasingly popular intervention due to decreased risk and better short-term morbidity; however, a recent study casts doubt on the benefit of this approach in terms of oncological safety. In this cancer registry study, we sought to evaluate the benefit of laparoscopy versus laparotomy and retrospectively compared overall survival, recurrence rates, and recurrence-free survival among patients with intermediate- and high-risk endometrial cancer who underwent either laparoscopic or open surgery. METHODS: This observational study included 419 patients who have been treated from 2011 to 2017. We employed Kaplan-Meier method, and univariable and multivariable Cox-regression to compare overall survival, recurrence rates, and recurrence-free survival in 110 patients, who underwent laparoscopic, with 309 patients, who underwent open surgery. To address the confounding bias in this retrospective study, we also performed a propensity score matching (PSM) analysis including 357 patients (laparoscopy: n = 107; open surgery: n = 250). RESULTS: We found a benefit for laparoscopic over open surgery in patients with intermediate- and high-risk endometrial cancer for overall survival in both univariable (p = 0.002; PSM: p = 0.016) and multivariable analyses (p = 0.019; PSM: p = 0.007). In contrast, there was no statistically significant difference between both patient groups regarding the cumulative recurrence rates. A univariable analysis identified a significant benefit for laparoscopy regarding recurrence-free survival (p = 0.003; PSM: p = 0.029) but a multivariable analysis failed to confirm this finding (p = 0.108; PSM: p = 0.118). CONCLUSIONS: Our study provides evidence that laparoscopic systematic lymphadenectomy does not present a lower oncological efficacy than open surgery in the treatment of patients with endometrial cancer.

Tissue microarray analysis of methylthioadenosine phosphorylase protein expression in melanocytic skin tumors.

BACKGROUND: Using tissue microarrays, we investigated whether methylthioadenosine phosphorylase (MTAP) protein expression is associated with clinicopathologic variables in benign and malignant melanocytic skin tumors. OBSERVATIONS: Cytoplasmic MTAP expression was detected in 227 (72.1%) of 315 informative cases. Expression was significantly reduced in primary malignant melanomas and in melanoma metastases compared with benign nevi (P<.001 for both). No difference was noted in MTAP expression between primary malignant melanomas and melanoma metastases. In primary malignant melanomas, a Ki67-labeling index less than 5% was associated with MTAP expression (P = .04), suggesting that loss of MTAP expression is associated with proliferation. No other variables had significant associations with MTAP expression. Lymph node metastases demonstrated significantly higher MTAP expression compared with skin metastases (P = .01). In the overall cohort, MTAP expression was not associated with prognosis. Among 26 patients with MTAP-positive melanomas and tumor recurrence, 18 patients who received interferon therapy had a significant benefit compared with 8 patients who did not receive interferon therapy (P = .009). This was not seen in the patients with MTAP-negative tumors. Conclusion Methylthioadenosine phosphorylase protein expression may be a predictive marker of interferon therapy resistance in patients with melanoma and disease progression.

A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.

BACKGROUND: Current staging methods such as tumor thickness, ulceration and invasion of the sentinel node are known to be prognostic parameters in patients with malignant melanoma (MM). However, predictive molecular marker profiles for risk stratification and therapy optimization are not yet available for routine clinical assessment. METHODS AND FINDINGS: Using tissue microarrays, we retrospectively analyzed samples from 364 patients with primary MM. We investigated a panel of 70 immunohistochemical (IHC) antibodies for cell cycle, apoptosis, DNA mismatch repair, differentiation, proliferation, cell adhesion, signaling and metabolism. A marker selection procedure based on univariate Cox regression and multiple testing correction was employed to correlate the IHC expression data with the clinical follow-up (overall and recurrence-free survival). The model was thoroughly evaluated with two different cross validation experiments, a permutation test and a multivariate Cox regression analysis. In addition, the predictive power of the identified marker signature was validated on a second independent external test cohort (n=225). A signature of seven biomarkers (Bax, Bcl-X, PTEN, COX-2, loss of ß-Catenin, loss of MTAP, and presence of CD20 positive B-lymphocytes) was found to be an independent negative predictor for overall and recurrence-free survival in patients with MM. The seven-marker signature could also predict a high risk of disease recurrence in patients with localized primary MM stage pT1-2 (tumor thickness ≤2.00 mm). In particular, three of these markers (MTAP, COX-2, Bcl-X) were shown to offer direct therapeutic implications. CONCLUSIONS: The seven-marker signature might serve as a prognostic tool enabling physicians to selectively triage, at the time of diagnosis, the subset of high recurrence risk stage I-II patients for adjuvant therapy. Selective treatment of those patients that are more likely to develop distant metastatic disease could potentially lower the burden of untreatable metastatic melanoma and revolutionize the therapeutic management of MM.

Histopathologic features and microsatellite instability of cancers of the papilla of vater and their precursor lesions.

The prevalence and development of microsatellite instability (MSI) and underlying mismatch repair (MMR) deficiency in the carcinogenesis of adenocarcinomas of the papilla of Vater and their precursor lesions are not well established. We analyzed 120 ampullary adenomas (31 pure adenomas and 89 carcinoma-associated adenomas) and 170 pure adenocarcinomas for MSI, immunohistochemical expression of MMR proteins and specific histopathologic features. The most common histologic subtype was intestinal (46.5%), followed by pancreatobiliary (23.5%), poorly differentiated adenocarcinomas (12.9%), intestinal-mucinous (8.2%), and invasive papillary carcinomas (5.3%). Eight of 89 adenomas (9%) and 15/144 carcinomas (10%) showed high microsatellite instability (MSI-H), 10/89 adenomas (11%) and 5/144 carcinomas (4%) showed low microsatellite instability (MSI-L), and 71/89 adenomas (80%) and 124/144 carcinomas (86%) were microsatellite stable (MSS). MSI analysis from carcinomas contiguous with an adenomatous component (n=54) exhibited concordant results in 6/8 (75%) MSI-H and 42/46 (91.3%) MSS tumors. Of 14 carcinomas with MSI-H, 7 showed loss of MLH1 and 5/6 (83%) MLH1 promoter methylation, and 2 carcinomas showed simultaneous loss of MSH2 and MSH6. Two carcinomas and 3 adenomas with MSI-H revealed exclusive loss of MSH6. MSI-H cancers were significantly associated with intestinal mucinous subtype (P<0.001), high tumor grade (P=0.003), expansive growth pattern (P=0.044), and marked lymphoid host response (P=0.004). Patients with MSI-H carcinoma had a significantly longer overall survival (P=0.0082) than those with MSI-L or MSS tumors. Our findings indicate that the MSI-phenotype is an early event, which develops at the stage of adenoma and is reliably detectable in the precursor lesion. The MMR deficient molecular pathway of carcinogenesis is associated with a histopathologic phenotype in ampullary cancer, similar to the one that has been well described in colon cancer.

Bone morphogenetic protein 7 (BMP7) expression is a potential novel prognostic marker for recurrence in patients with primary melanoma.

The purpose of this study was to investigate whether protein expression of bone morphogenetic protein 7 (BMP7) is associated with clinico-pathologic characteristics in benign and malignant melanocytic skin tumors. Tissue microarrays (TMAs) were used to analyze BMP7 expression and the Ki-67 labeling index immunohistochemically. Expression was scored semi quantitatively (0-2+). BMP7 protein expression of any intensity (1+-2+) was detected in 50.2% (153/305) of informative cases. In general, BMP7 expression was significantly induced in malignant melanomas (P< 0.001) and melanoma metastases (P< 0.001), compared to benign nevi. Additionally, expression of BMP7 in primary melanomas was associated with Ki-67 labeling index > 5% suggesting that induction of BMP7 expression is associated with proliferation (P=0.028). None of the other clinical and histological factors analyzed was significantly related to BMP7 expression. Interestingly, lymph node metastases demonstrated a significantly higher BMP7 expression compared to skin metastases (P<0.01). Strong BMP7 expression (score 2+) was significantly associated with shorter tumor recurrence (P< 0.05). In summary, induction of BMP7 expression is frequent in melanomas and may serve as a novel prognostic marker of progression in melanoma patients.

Nuclear Maspin expression is associated with response to adjuvant 5-fluorouracil based chemotherapy in patients with stage III colon cancer.

Maspin, a member of the Serpin protease inhibitor family, is overexpressed in poorly differentiated colorectal tumors and more frequently found in tumors with microsatellite instability. Immunohistochemical nuclear Maspin staining is predominantly seen in tumor cells at the invasion front of such cancers, suggesting that this molecule is associated with local tumor cell infiltration and aggressiveness. In a retrospective study, we studied nuclear Maspin expression as a potential prognostic tool in a total of 172 primary stage III colon cancers by immunohistochemistry. Of those 172 patients, 76 were treated by surgery only, and 96 patients received additional adjuvant 5-fluorouracil (5-FU) based chemotherapy. Nuclear Maspin expression was an independent adverse prognostic factor for overall survival in our patient cohort (hazard ratio 2.08; 95% CI, 1.13-3.81; p = 0.018). However, patients with primary tumors expressing Maspin in the nucleus showed a significant treatment benefit from 5-FU chemotherapy (hazard ratio 0.384; 95% CI, 0.188-0.784; p = 0.009) compared to adjuvantly treated patients whose tumors did not express this molecule. Nuclear Maspin expression is highly predictive of 5-FU chemotherapy response in patients with advanced stage colon cancer. Patients with negative immunohistochemical Maspin expression do not benefit from 5-FU treatment and may be candidates for an alternative (non-5-FU based) adjuvant therapy regime.