Predictor Of Worse Recurrence-free Survival Research Articles

Unsatisfactory Long-term Results of Liver Transplant in Patients With Intrahepatic Cholangiocarcinoma

BackgroundCholangiocarcinoma is the primary liver tumor forming from the biliary epithelium. Two major subtypes of this disease are distinguished because of the initial location: the extra- and intrahepatic form. The latter disease is currently a controversial indication for liver transplant (LT). The aim of this study was to evaluate the outcomes of LT of patients with intrahepatic cholangiocarcinoma. MethodsBased on postoperative histopathologic examination of the explanted liver, 8 patients with intrahepatic cholangiocarcinoma were identified from all LT recipients in the period between 1994 and 2019 and included in this retrospective cohort study. Four of the patients received transplants with a preoperative diagnosis of hepatocellular carcinoma; the remaining tumors were incidental findings. Patient survival was the primary outcome measure. ResultsSix recipients had solitary lesion with a maximum tumor diameter of 6 cm. The median carbohydrate antigen 19-9 concentration prior to LT was 52.3 U/mL. The overall survival was 75.0%, 37.5%, and 25% after the first, third, and fifth year, respectively, with a median survival of 18 months. Age (P = .758), carbohydrate antigen 19-9 (P = .282), largest tumor size (P = .862), and the sum of the number of lesions and diameter of the largest tumor (P = .530) were not significantly associated with overall survival. Recurrence-free survival was 71.4% after 1 year and 28.6% after 3 and 5 years. Correspondingly, no significant predictors of worse recurrence-free survival were found. ConclusionsIntrahepatic cholangiocarcinoma remains associated with a very high risk of recurrence and dismal survival after LT irrespective of macroscopic disease burden.

Abstract 2413: Genomewide expression profiling identifies a novel gene-expression signature for recurrence prediction in patients with early-onset colorectal cancer (EOCRC)

Abstract Purpose: Although the incidence of CRC has declined over the last decade, recent evidence indicates that the incidence of early onset CRC (EOCRC; patients younger than age 50) is actually on the rise. The disease presentation in patients with EOCRC is quite distinct, with often the disease diagnosis at more advanced stages, poorer histological grade, and higher local recurrence rates, compared to late onset CRC (LOCRC). Hence, availability of biomarkers that can predict recurrence in high-risk EOCRC patients is much needed as it will lead to improved prognosis, and tailoring personalized treatment regimens in this population. Herein, we have conducted a genomewide biomarker discovery approach, followed by robust bioinformatic analysis to establish a novel gene-based recurrence prediction classifier in patients with EOCRC. Methods: We undertook a comprehensive and systematic biomarker discovery effort by first analyzing six independent, genomewide expression datasets (GSE14333, GSE17538, GSE3311, GSE37892, GSE39084 and GSE39582) of EOCRC patients to identify (discovery dataset; n=81) and validate (validation dataset; n=75) a gene signature for predicting recurrence in EOCRC. Subsequently, the robustness of this signature was analytically evaluated in an in-house clinical training cohort (n=54). Using recursive feature elimination approach based on random forest classification, the signature was further refined and the gene signature was validated in another independent clinical cohort (n=54). Results: We initially identified a 25-gene signature from a total of 3591 mRNAs, which showed significant potential for predicting recurrence free survival (RFS) in both the in-silico discovery (HR, 32.83, 95% confidential interval (CI), 10.73 - 100.51, P<0.001) and validation datasets in the discovery phase (HR, 4.11, 95% CI, 1.77 - 9.56, P <0.001). Subsequently, based on our clinical training cohort, we developed a reduced and optimized 5-gene signature, which demonstrated robust prognostic power in both the clinical training cohort (HR, 3.67; 95% CI, 1.48-9.52; P=0.003) and an independent validation cohort (HR, 7.53; 95% CI, 1.73-51.3; P=0.007). In univariate and multivariate cox regression analysis, our 5-gene signature emerged as an independent predictor of worse RFS. Furthermore, a combination signature comprising of lymph node metastasis and our 5-gene signature demonstrated an even superior predictive performance compared to individual factors in both cohorts (training cohort: HR 4.56; 95% CI, 0.65-0.88; validation cohort: HR 8.25, 0.86; 95% CI, 0.74-0.94). Conclusion: Our novel 5-gene signature provides a robust prognostic tool for patients with EOCRC; which can be clinically transformative in guiding post-surgical decision-making to improve survival and management of young patients suffering from this malignancy. Citation Format: Kensuke Yamamura, Lina Zhu, Raju Kandimalla, Takatoshi Matsuyama, Yusuke Kinugasa, Francesc Balaguer, Hideo Baba, Xin Wang, Ajay Goel. Genomewide expression profiling identifies a novel gene-expression signature for recurrence prediction in patients with early-onset colorectal cancer (EOCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2413.

Prognostic value of PD-L1 expression for surgically treated localized renal cell carcinoma: implications for risk stratification and adjuvant therapies.

Background:We aimed to evaluate the prognostic role of programmed-death receptor ligand (PD-L1) in a multinational cohort of patients with localized renal cell carcinoma (RCC).Methods:Formalin-fixed paraffin-embedded blocks of 1017 patients from the Latin American Renal Cancer Group were analyzed. Tissue microarrays were immunostained for PD-L1 using a commercially available monoclonal antibody. Expression of PD-L1 in ⩾5% tumor cells was considered positive. PD-1 expression in immune cells was also assessed. All cases were reviewed twice based on antibody expression and compared with a positive control. Cox proportional hazard regression models were used to identify predictors of recurrence-free survival (RFS) and overall survival (OS).Results:A total of 738 cases with complete follow up met criteria. Median age was 57 [interquartile range (IQR): 49–64] years, and median follow up was 34 (IQR: 15–62.9) months. Median tumor size was 5 cm (IQR: 3.0–7.5 cm). Approximately 8.2% and 7.6% of tumors were PD-L1 and programmed cell-death 1 (PD-1) positive, respectively. PD-L1 and PD-1 positivity were significantly associated with higher tumor stage (both p < 0.001), and presence of tumor necrosis and lymphovascular multivariable analyses; PD-L1 positivity was found as a predictor of worse RFS [hazard ratio (HR) = 2.08, p = 0.05] and OS (HR = 2.61, p = 0.02).Conclusions:PD-L1 positivity was significantly associated with worse outcomes for patients with localized RCC at intermediate follow up. This marker may help stratify patients for stricter surveillance after surgical treatment and provide a basis for checkpoint-inhibitor therapy in the adjuvant setting.

Association between Ki-67 expression and clinical outcomes among patients with clinically node-negative, thick primary melanoma who underwent nodal staging.

Patients with thick primary melanomas (≥4 mm) have highly variable survival outcomes. Cell proliferation marker Ki-67 has been identified as promising biomarker in thick melanoma but has not been evaluated since the wide spread adoption of sentinel lymph node biopsy. We revisit its prognostic relevance in the sentinel node era. We studied patients with thick (≥4 mm) primary melanoma prospectively enrolled in a clinicopathological biospecimen database from 2002 to 2015, and evaluated the prognostic value of Ki-67 expression while controlling for features included in the existing staging criteria. We analyzed 68 patients who underwent lymph node sampling and who had an available tumor for Ki-67 immunohistochemical (IHC) staining. The median tumor thickness was 6.0 mm; the median follow-up was 2.6 years. In multivariable analysis including nodal status and primary tumor ulceration, Ki-67 expression was an independent predictor of worse recurrence-free survival (HR 2.19, P = 0.024) and overall survival (HR 2.49, P = 0.028). Natural log-transformed tumor thickness (ln [thickness]) was also significantly associated with worse OS (HR 2.39, P = 0.010). We identify Ki-67 and ln (thickness) as potential biomarkers for patients with thick melanoma who have undergone nodal staging. If validated in additional studies, these biomarkers could be integrated into the staging criteria to improve risk-stratification.

Recurrence After Liver Transplantation for Hepatocellular Carcinoma

We sought to develop a "Model Of Recurrence After Liver transplant" (MORAL) for hepatocellular carcinoma (HCC). The Milan criteria are used to allocate livers to patients with HCC requiring liver transplantation (LT) but do not include objective measures of tumor biology. Biological markers including the neutrophil-lymphocyte ratio (NLR) and alpha-fetoprotein (AFP) have been associated with recurrence risk. Prospective cohort study of adults undergoing LT for HCC between January 2001 and December 2012. A total of 339 patients were included. On multivariable Cox regression analysis, 3 preoperatively available factors were independent predictors of worse recurrence-free survival (RFS), namely, an NLR ≥ 5 (P < 0.0001, hazard ratio, HR: 6.2), AFP > 200 (P < 0.0001, HR: 3.8), and Size >3 cm (P < 0.001, HR: 3.2). The Pre-MORAL score was constructed from the hazard ratios and assigning patients points in an additive fashion, with a minimum of 0 points (no factors) and a maximum of 13 points (all 3 factors). The highest risk patients in the Pre-MORAL had a 5-year RFS of 17.9% compared with 98.6% for the low risk group (P < 0.0001). The post-MORAL was constructed similarly using the 4 postoperatively available independent predictors of worse RFS, grade 4 HCC's (P < 0.0001, HR: 5.6), vascular invasion (P = 0.019, HR: 2.0), size >3 cm (P < 0.0001, HR: 3.2) and number >3 (P = 0.048, HR: 1.8). The pre- and post-MORAL were superior to Milan at predicting recurrence with c-statistics of 0.82 and 0.87, compared with 0.63, respectively. We then combined the scores to produce a combo-MORAL, with a c-statistic of 0.91 for predicting recurrence. The MORAL score provides a simple, highly accurate tool for predicting recurrence and risk-stratification pre- and postoperatively.

Preoperative Systemic Inflammation and Complications Affect Long-term Gallbladder Carcinoma Outcomes Following Surgery with Curative Intent.

Gallbladder carcinoma (GBCA) has extremely poor outcomes. We aimed to investigate clinicopathological prognostic variables, including the modified Glasgow prognostic score (mGPS), for patients with resected GBCA. This retrospective study included 54 patients with GBCA resected between 1996 and 2014. Univariate and multivariate analyses were performed to identify prognostic factors associated with overall and recurrence-free survival. Curative resection (R0) was achieved in 43 patients (79.6%). The median patient age was 74 years (range=25-99 years), and the majority (n=33, 61.1%) were women. Incidental GBCA was detected in 18 patients (33.3%). The overall and recurrence-free survival rates were 63.3% and 55.8% at 3 years and 58.4% and 51.3% at 5 years, respectively. In multivariate analysis, postoperative intra-abdominal complications (p=0.015), non-curative resection (p=0.008), worse histological type (p=0.003), and elevated mGPS (p=0.002) were independent predictors of worse overall survival. Surgical complications (p=0.015), non-curative resection (p=0.005), worse histological type (p=0.002), and elevated mGPS (p=0.022) were also independent predictors of worse recurrence-free survival. Curative resection was important for long-term survival for GBCA. A high preoperative mGPS and occurrence of surgical complications were independent prognostic indicators of poor survival in GBCA.

Occult lymph node metastasis and risk of regional recurrence in papillary thyroid cancer after bilateral prophylactic central neck dissection: A multi-institutional study

The impact of occult lymph node metastasis on regional recurrence after prophylactic central neck dissection for preoperative, nodal-negative papillary thyroid cancer is controversial. We investigated risk factors for regional lymph node recurrence in papillary thyroid cancer patients who underwent total thyroidectomy and bilateral prophylactic central neck dissection. Analysis was according to clinicopathologic characteristics and occult lymph node metastasis patterns. This multicenter study enrolled 211 consecutive patients who underwent total thyroidectomy with bilateral prophylactic central neck dissection for papillary thyroid cancer without evidence of central lymph node metastasis on preoperative imaging. Clinicopathologic features and central lymph node metastasis patterns were analyzed for predicting regional recurrence. Multivariate Cox regression analysis was used to identify independent factors for recurrence. Median follow-up time was 43months (24-95months). Ten patients (4.7%) showed regional lymph node recurrence. The estimated 5-year, regional recurrence-free survival was 95.2%. Tumor size ≥1cm, central lymph node metastasis, lymph node ratio, and prelaryngeal lymph node metastasis were associated with regional recurrence in univariate analysis (P<.05). In multivariate analysis, a lymph node ratio ≥ 0.26 was a significant risk factor for regional lymph node recurrence (odds ratio=11.63, P=.003). Lymph node ratio ≥ 0.26 was an independent predictor of worse recurrence-free survival on Cox regression analysis (hazard ratio=11.49, P=.002). Although no significant association was observed between the presence of occult lymph node metastasis and regional recurrence, lymph node ratio ≥ 0.26 was an independent predictor of regional lymph node recurrence in papillary thyroid cancer patients who underwent total thyroidectomy and bilateral prophylactic central neck dissection.

Abstract 681: Prognostic role of Perp in breast cancer

Abstract Perp, a tetraspan plasma membrane protein, is activated by p53 during apoptosis and is also regulated by p63 where it functions as an essential component of the desmosome and contributes to epithelial integrity. A single nucleotide polymorphism (SNP) in Perp was identified by its effect on apoptotic efficiency in irradiated lymphoblastoid cell lines. Therefore, this SNP may have functional significance in clinical outcomes of cancer. In this study, this SNP in PERP was evaluated as a prognostic marker and in its relationship to other known prognostic factors. Genotyping was performed on DNA isolated from peripheral blood of 1020 patients with breast cancer and genotypes were linked with annotated clinical information. Analysis of recurrence free survival was performed on a subset limited to 790 Caucasians. Among Caucasian cases, homozygous SNP genotypes were nearly equally distributed (AA: 25% and GG: 26%). Using a COX proportional hazards survival analysis, the AA genotype was found to be an independent predictor of worse recurrence-free survival (RFS, hazard ratio [HR]: 1.95, 95% CI: 1.38-2.76, p=0.0001). RFS was similar between AG and GG carriers and was more favorable as compared to AA carriers. For patients receiving breast-conserving surgery followed by radiation, patients diagnosed at or above 51 years of age or patients with stage III disease, the deleterious effect of AA genotype on RFS was more significant. In addition, the AA genotype associated with decreased RFS in subgroups of Caucasian cases regardless of stratification by hormone receptor status, HER2 status, and whether they received chemotherapy or hormonal therapy. Adjusting for effects due to stage and chemotherapy, this association remained significant in estrogen receptor positive and progesterone receptor negative cases. We also analyzed the NCI-60 cell line panel for an association between this polymorphism and response to 132 standard chemotherapeutic drugs. A significant association was observed with respect to genotype and response to anti-mitotic agents. Collectively, cell lines with the AA genotype were more sensitive to anti-mitotic agents than the GG genotype. Clinical data suggest that the AA genotype of Perp has a functional phenotype leading to increased risk of recurrence. Further studies are needed to determine the mechanism behind this association, but ultimately this SNP may be useful as a prognostic marker in breast cancer and could be used as a tool to optimize treatment strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 681. doi:1538-7445.AM2012-681