Georgios Karagkounis

Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases.

Molecular biomarkers offer the potential for refining prognostic determinants in patients undergoing cancer surgery. Among patients with colorectal cancer, KRAS and BRAF are important biomarkers, but their role in patients undergoing surgical therapy for liver metastases is unknown. In this study, the incidence and prognostic significance of KRAS and BRAF mutations were determined in patients undergoing surgical therapy of colorectal liver metastases (CRLM).

Association Between Specific Mutations in KRAS Codon 12 and Colorectal Liver Metastasis

IMPORTANCE Currently, one of the most commonly available biomarkers in the treatment of patients with colorectal liver metastases (CRLM) is the Kirsten rat sarcoma viral oncogene homolog (KRAS); however, the prognostic implications of specific mutations of the KRAS gene are still not well defined. OBJECTIVE To investigate the prognostic impact of specific KRAS mutations on patients undergoing liver resection for CRLM. DESIGN, SETTING, AND PARTICIPANTS This retrospective single-center study was conducted from January 1, 2003, to December 31, 2013. Data about specific KRAS mutations for 331 patients who underwent hepatic resection for CRLM at Johns Hopkins Hospital between 2003 and 2013 were analyzed. Clinicopathological characteristics, perioperative details, and outcomes were stratified by specific KRAS mutation at codons 12 and 13. INTERVENTION Resection of CRLM. MAIN OUTCOMES AND MEASURES Overall survival (OS) and recurrence-free survival. RESULTS A mutated KRAS (mtKRAS) was identified in 91 patients (27.5%). At a median follow-up of 27.4 months, recurrence was observed in 48 patients (52.7%) with mtKRAS and 130 patients (54.2%) with wild-type KRAS (wtKRAS) (P = .82). Median and 5-year survival among patients with mtKRAS was 32.4 months and 32.7%, respectively, vs 58.5 months and 46.9%, respectively, for patients with wtKRAS (P = .02). Patients with KRAS codon 12 mutations had worse OS (hazard ratio [HR], 1.54; 95% CI, 1.05-2.27; P = .03) vs those with wtKRAS, whereas a KRAS codon 13 mutation was not associated with prognosis (HR, 1.47; 95% CI, 0.83-2.62; P = .19). Among the 6 most common mutations in codons 12 and 13, only G12V (HR, 1.78; 95% CI, 1.00-3.17; P = .05) and G12S (HR, 3.33; 95% CI, 1.22-9.10; P = .02) were associated with worse OS compared with patients with wtKRAS (both P < .05). Among patients who recurred, G12V (HR, 2.96; 95% CI, 1.32-6.61; P = .01), G12C (HR, 6.74; 95% CI, 2.05-22.2; P = .002), and G12S mutations (HR, 4.91; 95% CI, 1.52-15.8; P = .01) were associated with worse OS (both P < .05). CONCLUSIONS AND RELEVANCE G12V and G12S mutations of codon 12 were independent prognostic factors of worse OS. Among patients who recurred after resection of CRLM, G12V, G12C, and G12S mutations were associated with worse OS. Information on specific KRAS mutations may help individualize therapeutic and surveillance strategies for patients with resected CRLM.

Effect of KRAS Mutation on Long-Term Outcomes of Patients Undergoing Hepatic Resection for Colorectal Liver Metastases

AbstractPurpose To investigate the prognostic value of KRAS in a large cohort of patients undergoing liver resection for colorectal liver metastases (CRLM).MethodsBetween 2003 and 2013, 334 patients underwent hepatic resection for CRLM at Johns Hopkins Hospital and met the inclusion criteria. Clinicopathologic characteristics, perioperative details, and outcomes were stratified by KRAS status—mutant KRAS (mtKRAS) versus wild-type KRAS (wtKRAS)—and analyzed.ResultsmtKRAS was identified in 115 (34.4 %) patients. At a median follow-up of 28.2 months, recurrence was observed in 59 (51.3 %) patients with mtKRAS and 117 (53.4 %) patients with wtKRAS (P = 0.79); there was no difference in the pattern of recurrence (liver: mtKRAS 39.0 % vs. wtKRAS 52.1 %; lung: mtKRAS 55.6 % vs. wtKRAS 64.3 %; both P > 0.05). Although 5-year log-rank overall survival (OS) was comparable among mtKRAS (41.6 %) vs. wtKRAS (48.5 %), on multivariable Cox survival analysis and after adjusting for known predictors of OS mtKRAS was associated with worse OS (hazard ratio 1.65; 95 % confidence interval 1.07–2.54; P = 0.02). Among patients who experienced a recurrence, 5-year OS was worse among those patients who had mtKRAS (mtKRAS 28.1 % vs. wtKRAS 44.5 %; P = 0.004). After controlling for tumor factors and receipt of chemotherapy, mtKRAS status remained independently associated with a worse outcome among patients who experienced recurrence (hazard ratio 2.07; 95 % confidence interval 1.31–3.27; P = 0.002).ConclusionsmtKRAS was noted in one-third of patients with CRLM. Although KRAS status did not affect the pattern of recurrence and recurrence-free survival, mtKRAS was an independent predictor of worse OS. The effect was more pronounced among patients who experienced a recurrence after resection of CRLM.

Alternative Lengthening of Telomeres Predicts Site of Origin in Neuroendocrine Tumor Liver Metastases

BACKGROUND The determination of the primary tumor origin in patients with neuroendocrine tumor liver metastases (NELM) can pose a considerable management challenge. Recent studies have shown that the alternative lengthening of telomeres (ALT) is prevalent in some human tumors, including pancreatic neuroendocrine tumors (PanNET), and can be useful in predicting tumor biology. In this study, we aimed to evaluate the use of ALT as a biomarker in patients with NELM, in particular to predict the site of origin of metastases. METHODS Tissue microarrays (TMAs) were constructed using tumor tissue from NELM patients undergoing liver resection between 1998 and 2010. These included 43 PanNET and 47 gastrointestinal carcinoid tumors. The TMAs were tested for ALT using telomere-specific fluorescent in situ hybridization. The association between ALT positivity and clinicopathologic features and long-term outcomes was investigated. RESULTS Alternative lengthening of telomeres was positive (ALT+) in 26 (29%) of the 90 tumors included in the TMAs. Pancreatic neuroendocrine tumors were ALT+ in 56% of patients, compared with only 4% ALT+ among gastrointestinal carcinoid tumors (p < 0.001). The specificity of ALT for detecting pancreatic origin was 96% and the positive predictive value was 92%, and sensitivity was 56% and the negative predictive value was 70%. Additionally, ALT was associated with the pattern of metastatic disease: ALT+ NELM were more likely to have oligometastases (p = 0.001) and less likely to be bilateral in distribution (p = 0.05) than were ALT tumors. In addition, ALT+ was associated with improved prognosis in the PanNET patient population. CONCLUSIONS Alternative lengthening of telomeres was found to be a useful biomarker in patients with NELM. This marker can be helpful in guiding therapy by identifying the site of origin in patients in whom the primary site is unknown.

NPTX2 is associated with neoadjuvant therapy response in rectal cancer

BACKGROUND Neoadjuvant chemoradiation (CRT) is recommended for locally advanced rectal cancer. Tumor response varies from pathologic complete response (pCR) to no tumor regression. The mechanisms behind CRT resistance remain undefined. In our previously generated complementary DNA microarrays of pretreatment biopsies from rectal cancer patients, neuronal pentraxin 2 (NPTX2) expression discriminated patients with pCR from those with residual tumor. As tumor response is prognostic for survival, we sought to evaluate the clinical relevance of NPTX2 in rectal cancer. MATERIALS AND METHODS Real-time quantitative polymerase chain reaction was used to evaluate NPTX2 messenger RNA expression in individual rectal cancers before CRT. Tumors with NPTX2 expression <50% of normal rectum were defined as NPTX2-low and those with >50% were defined as NPTX2-high. NPTX2 levels were compared to response to therapy and oncologic outcomes using Mann-Whitney, Kruskal-Wallis, chi-square, and Mantel-Cox (log-rank) tests, as appropriate. RESULTS Rectal cancers from 40 patients were included. The mean patient age was 56.8 years, and 30% were female. pCR was achieved in eight of 40 patients (20%). In these patients, messenger RNA NPTX2 levels were significantly decreased compared to those with residual cancer (fold change 30.4, P = 0.017). Patients with NPTX2-low tumors (n = 13) achieved improved response to treatment (P = 0.012 versus NPXT2-high tumors), with 38.5% and 46.1% of patients achieving complete or moderate response, respectively. Of patients with NPTX2-high tumors (n = 27), 11.1% and 18.5% achieved complete or moderate response, respectively. No recurrence or death was recorded in patients with NPTX2-low tumors, reflecting more favorable disease-free survival (P = 0.045). CONCLUSIONS Decreased NPTX2 expression in rectal adenocarcinomas is associated with improved response to CRT and improved prognosis. Further studies to validate these results and elucidate the biological role of NPTX2 in rectal cancer are needed.

The Impact of Laparoscopic Approaches on Short-term Outcomes in Patients Undergoing Liver Surgery for Metastatic Tumors.

Purpose: To compare the perioperative outcomes associated with open and laparoscopic (LAP) surgical approaches for liver metastases. Methods: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify all adult patients who underwent surgical therapy for metastatic liver tumors between 2006 and 2012 (N=7684). Patients who underwent >1 procedure were excluded. Logistic regression after matching on propensity scores was used to assess the association between surgical approaches and perioperative outcomes. Results: A total of 4555 patients underwent open resection, 387 LAP resection, 297 open radiofrequency ablation (RFA), and 265 LAP RFA. In propensity-matched samples (over 95% of patients successfully matched), there was no significant difference between LAP resection and LAP RFA in perioperative complications and length of stay and both compared favorably with their open counterparts. Discussion: Minimally invasive approaches for secondary hepatic malignancies were associated with improved postoperative morbidity and length of stay and should be preferred in appropriate patients.

Molecular Biology: Are We Getting Any Closer to Providing Clinically Useful Information?

&NA; Advances in molecular biology and biomarker research have significantly impacted our understanding and treatment of multiple solid malignancies. In rectal cancer, where neoadjuvant chemoradiation is widely used for locally advanced disease, most efforts have focused on the identification of predictors of response in an attempt to appropriately select patients for multimodality therapy. A variety of biomarkers have been studied, including genetic mutations, chromosomal copy number alterations, and single as well as multigene expression patterns. Also, as transanal resection of rectal tumors requires accurate preoperative detection of lymph node metastasis, the identification of biomarkers of regional nodal involvement has been another important field of active research. While preliminary results have been promising, lack of external validation means has a limited translation to clinical use. This review summarizes recent developments in rectal cancer biomarker research, highlighting the challenges associated with their adoption, and evaluating their potential for clinical use.

PARP inhibition sensitizes colorectal cancer-initiating cells to chemotherapy: PARP Inhibition and Chemosensitivity

Colorectal cancer (CRC) remains a leading killer in the U.S. with resistance to treatment as the largest hurdle to cure. Colorectal cancer‐initiating cells (CICs) are a self‐renewing tumor population that contribute to tumor relapse. Here, we report that patient‐derived CICs display relative chemoresistance compared with differentiated progeny. In contrast, conventional cell lines failed model therapeutic resistance. CICs preferentially repaired chemotherapy‐induced DNA breaks, prompting us to interrogate DNA damage pathways against which pharmacologic inhibitors have been developed. We found that CICs critically depended on the key single‐strand break repair mediator, poly(ADP‐ribose) polymerase (PARP), to survive treatment with standard‐of‐care chemotherapy. Small molecule PARP inhibitors (PARPi) sensitized CICs to chemotherapy and reduced chemotherapy‐treated CIC viability, self‐renewal, and DNA damage repair. Although PARPi monotherapy failed to kill CICs, combined PARPi therapy with chemotherapy attenuated tumor growth in vivo. Clinical significance of PARPi for CRC patients was supported by elevated PARP levels in colorectal tumors compared with normal colon, with further increases in metastases. Collectively, our results suggest that PARP inhibition serves as a point of fragility for CICs by augmenting therapeutic efficacy of chemotherapy. Stem Cells 2019;37:42–53

Tall-Cell Variant Papillary Thyroid Carcinoma Arising from Struma Ovarll

OBJECTIVE To present a case of tall-cell variant (TCV) papillary thyroid carcinoma (PTC) arising from Struma ovarii (SO) and to discuss special considerations in the management of this patient. METHODS The clinical presentation and relevant pathologic features of a patient with PTC-TCV developing from SO are described, and a concise review of literature regarding this topic is also presented. RESULTS A 36-year-old woman with a history of stable right ovarian dermoid cyst presented with amenorrhea and was found to have a significantly enlarged right ovary with multiple cysts. Following laparoscopic cystectomy, pathology revealed mature cystic teratoma (SO) with associated PTC-TCV. Based on this finding, she underwent right salpingo-oophorectomy, right pelvic lymph node dissection, and partial omentectomy. Pathology was negative for extra-ovarian disease, and her tumor was staged as pT1pN0M0. Total thyroidectomy was performed in preparation for radioactive iodine (RAI) therapy. A diagnostic iodine-131 (I-131) scan showed residual uptake in the neck with faint uptake in the lower left quadrant of the abdomen and was followed by therapy with 90 mCi of I-131. The patient had an unremarkable course with no clinical or biochemical evidence of disease recurrence to date. CONCLUSIONS This is to our knowledge the first reported case of TCV-PTC arising from SO. The presence of this aggressive variant of PTC factored into our decision to proceed with thyroidectomy and I-131 ablation, despite the lack of conclusive evidence in the literature. Recent discoveries on the natural history of thyroid-derived TCV-PTC were critical in choosing the appropriate management for this patients disease.

The Evolving Use of Prognostic Factors After Resection of Colorectal Liver Metastases

The expanding use of surgical therapy for patients with colorectal liver metastases (CRLM) and developments in chemotherapeutic regimens have led to a significant improvement in survival. However, outcomes can vary substantially and criteria for determining the prognosis of individual patients are lacking. Traditionally, clinicopathologic factors, for example primary tumor stage, number and size of liver metastases, preoperative carcinoembryonic antigen levels, presence of extrahepatic disease, and others, have been used to determine which patients are more likely to experience recurrence and poor survival. However, these factors, both separately and as part of scoring systems, have been inconsistent and conflicting in determining prognosis. Recently, molecular and biological indicators have emerged as potential prognosticators for CRLM patients undergoing hepatic resection. Tumor response to chemotherapy, both on imaging and on pathology, mutation status of such oncogenes as KRAS and BRAF, and expression patterns of proliferative markers including MACC1 and Ki-67, have all furnished promising results in prediction of patient outcomes. Moreover, circulating tumor cells and tumor DNA may not only be a useful prognostic instrument but also an excellent means of screening for early detection of recurrence.