Case Report: Chemoimmunotherapy in microsatellite-instability-high advanced goblet cell carcinoma of the colon.

Background: Mismatch repair (MMR) deficiency is a fundamental factor affecting the management treatment outcomes of colorectal cancer (CRC). MMR status can be diagnosed by both immunohistochemistry (IHC) polymerase chain reaction (PCR). Since tumors with MMR deficiency are prone to respond to immunotherapy immune checkpoint inhibitors are used to treat such tumors. Case presentation: A 69-year-old male patient presented to an outside clinic with weight loss and abdominal pain. Radiological investigations detected a mesenteric mass of 10 cm, peritoneal implants, and mediastinal lymphadenopathy. The eventual biopsy result from the mesenteric mass was mucinous adenocarcinoma with a goblet cell pattern. Since the IHC result was unclear for deficiency in mismatch repair (dMMR) metastatic CRC (mCRC), the diagnosis was confirmed with PCR. The patient received 8 cycles of FOLFIRINOX + bevacizumab followed by FOLFOX combined with pembrolizumab. No adverse effect was reported related to immunotherapy which resulted in radiologic and metabolic regression. The patient underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). The final pathology results revealed a pathological complete response and R0 resection. In the 6th month follow-up, no recurrence or metastasis was reported. Conclusion: Chemotherapy and immunotherapy combination is a promising treatment modality which can also be used for mCRC. This is the index case who received chemotherapy in combination with immunotherapy for mucinous adenocarcinoma of the colon with a goblet cell pattern and had pCR.

Discrepancy among microsatellite instability detection methodologies in non-colorectal cancer: Report of 3 cases.

BACKGROUND: Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy. The tumor-agnostic nature of MSI makes it a denominator for immunotherapy in several solid tumors. It can be assessed using next-generation sequencing (NGS), fluorescent multiplex PCR, and immunohistochemistry (IHC). CASE SUMMARY: Here, we report 3 cases with discordant MSI results detected using different methods. A cholangiocellular carcinoma case revealed proficient mismatch repair (MMR) by IHC but high MSI (MSI-H) by liquid NGS. A cervical cancer case revealed deficient MMR by IHC, microsatellite stable by PCR, and MSI-H by NGS. Lastly, an endometrial cancer case revealed proficient MMR by IHC but MSI-H by NGS. CONCLUSION: IHC for MMR status is the first choice due to several advantages. However, in cases of indeterminate IHC results, molecular testing by MSI-PCR is preferred. Recently, NGS-based MSI assays are being widely used to detect MSI-H tumors. All three methods have high accuracy; however, the inconsistencies between them may lead to misdiagnosis.

Intramural Component of Venous, Lymphatic, and Perineural Invasion in Colon Cancer: A Threat or an Illusion?

Background: Extramural venous invasion is an independent predictor of poor outcome in colorectal cancer, whereas the significance of the intramural component of venous and lymphatic and perineural invasion is unclear. Aims: To evaluate the prognostic impact of intramural components for venous, lymphatic, and perineural invasions and the relation of these invasion patterns with clinicopathological features in patients with colon cancer. Study Design: A retrospective cross-sectional study. Methods: The analysis included 626 patients with colon cancer in stages II and III. All patients were divided into four categories (no invasion, intramural invasion only, extramural invasion only, or both intramural and extramural invasions) for vascular invasion, lymphatic invasion and perineural invasion. The primary outcomes were 5-year disease-free and overall survival. Results: Right-sided (for vascular invasion, 24.7% vs. 33.9%, p = 0.007; for perineural invasion, 34.5% vs. 41.5%, p = 0.034) and dMMR tumors (for vascular invasion, 13.5% vs. 33.5, p < 0.001; for perineural invasion, 25% vs. 41.4%, p = 0.004) exhibited less venous and perineural invasion. Compared with no invasion, presence of intramural invasion only, did not exert any effect on disease-free or overall survival for vascular invasion, lymphatic invasion, and perineural invasion. Multivariate analyses revealed that the presence of both intramural and extramural invasion was independently associated with poor disease-free and overall survival for venous (hazard ratios: 2.39, p = 0.001; hazard ratios: 2.46, p = 0.001), lymphatic (hazard ratios: 2.456, p < 0.001; hazard ratios: 2.13, p = 0.02) and perineural invasion (hazard ratios: 2.99, p < 0.001; hazard ratios: 2.68, p < 0.001), respectively. Conclusion: Our data strongly advocates the importance of reporting intramural and extramural components of invasion since the presence of intramural invasion alone may not be considered as a high-risk factor for systemic recurrence.

Optimizing the Personalized Care for the Management of Rectal Cancer: A Consensus Statement.

Colorectal cancer is the third most common cancer in Turkey. The current guidelines do not provide sufficient information to cover all aspects of the management of rectal cancer. Although treatment has been standardized in terms of the basic principles of neoadjuvant, surgical, and adjuvant therapy, uncertainties in the management of rectal cancer may lead to significant differences in clinical practice. In order to clarify these uncertainties, a consensus program was constructed with the participation of the physicians from the Acibadem Mehmet Ali Aydinlar and Koç Universities. This program included the physicians from the departments of general surgery, gastroenterology, pathology, radiology, nuclear medicine, medical oncology, radiation oncology, and medical genetics. The gray zones in the management of rectal cancer were determined by reviewing the evidence-based data and current guidelines before the meeting. Topics to be discussed consisted of diagnosis, staging, surgical treatment for the primary disease, use of neoadjuvant and adjuvant treatment, management of recurrent disease, screening, follow-up, and genetic counseling. All those topics were discussed under supervision of a presenter and a chair with active participation of related physicians. The consensus text was structured by centralizing the decisions based on the existing data.

Sunitinib induced colitis manifesting as invasive diarrhea in a patient with renal cell carcinoma.

INTRODUCTION: Sunitinib is a tyrosine kinase inhibitor that binds to vascular endothelial factor receptor currently used for the treatment of renal cell carcinoma, as well as for several other conditions such as gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. We present a patient with invasive diarrhea who was treated with sunitinib for metastatic renal cell carcinoma. CASE REPORT: Drug induced colitis was confirmed with colonoscopy from histopathological specimens. Clinical recovery of diarrhea was achieved with oral budesonide. Remarkably, the pathologic findings were observed in both the macroscopically normal mucosa and the mucosa with aphthous ulcers in the colon. MANAGEMENT & OUTCOME: The patient was treated for sunitinib associated diarrhea, after exclusion of the other reasons. Metronidazole and piperacillin/tazobactam treatment were prescribed. DISCUSSION: Diarrhea is a frequent symptom in patients treated with tyrosine kinase inhibitors, however the described pathologic findings have rarely been reported. Our aim is to emphasize the importance of close follow-up in patients treated with tyrosine kinase inhibitors, and to raise awareness on the management of sunitinib induced colitis.

Impact of Prolonged Neoadjuvant Treatment-surgery Interval on Histopathologic and Operative Outcomes in Patients Undergoing Total Mesorectal Excision for Locally Advanced Rectal Cancer.

BACKGROUND: This study primarily aimed to assess the impact of prolonged neoadjuvant treatment-surgery interval (PNSI) on histopathologic and postoperative outcomes. Impacts of the mode of neoadjuvant treatment (NT) and surgery on the outcomes were also evaluated in the same patient population. PATIENTS AND METHODS: Between February 2011 and December 2017, patients who underwent NT and total mesorectal excision for locally advanced rectal cancer were included. PNSI was defined as >4 and >8 weeks after short-course and long-course NT modalities, respectively. RESULTS: A total of 44 (27%) patients received short-course NT (standard interval: n=28; PNSI: n=16) and 122 (73%) patients received long-course NT (standard interval: n=39; PNSI: n=83). Postoperative morbidity was similar between the standard interval and PNSI in patients undergoing short-course [n=3 (11%) vs. n=3 (19%), P=0.455] and long-course [n=6 (15%) vs. n=16 (19%), P=0.602] NT. PNSI was associated with increased complete pathologic response in patients receiving short-course NT [0 vs. n=5 (31%), P=0.002]. Compared with short-course NT, long-course NT was superior in terms of tumor response based on the Mandard [Mandard 1 to 2: n=6 (21%) vs. 6 (38%), P=0.012] and the College of American Pathologists (CAP) [CAP 0 to 1: n=13 (46%) vs. n=8 (50%), P=0.009] scores. Postoperative morbidity was similar after open, laparoscopic, and robotic total mesorectal excision [n=1 (14.2%) vs. n=21 (21%) vs. n=6 (12.5%), P=0.455] irrespective of the interval time to surgery and the type of NT. CONCLUSIONS: PNSI can be considered in patients undergoing short-course NT due to its potential oncological benefits. The mode of surgery performed at tertiary centers has no impact on postoperative morbidity after both NT modalities.

Helicobacter pylori-miRNA interaction in gastric cancer tissues: First prospective study from Turkey.

Helicobacter pylori (H. pylori) is involved in the etiology of gastric cancer (GC). miRNAs are short RNAs that regulate gene expression by marking mRNAs for degradation. miRNAs are involved in tumorigenesis, metastasis, and cell proliferation. We aimed to investigate the miRNA expression profiles of tissues from H. pylori (+) and (-) GC patients. Forty GC patients, 20 H. pylori (+) and 20 H. pylori (-), and a healthy control group were included. The miRNA expression levels were investigated by microarrays and quantitative RT-PCR. We detected 9 upregulated and 4 downregulated miRNAs by microarray. We selected 5 upregulated and 5 downregulated miRNAs for the quantitative RT-PCR assay. The relative fold changes of miRNAs in the cancerous tissue and non-tumor mucosa specimens of H. pylori (+) GC patients for hsa-miR-194 were 4.24- and 3.83-fold higher, respectively, whereas the hsa-miR-145 expression levels were downregulated 0.33-fold and 0.43-fold, respectively, in the same group. The presence of H. pylori significantly upregulated hsa-miR-194 and downregulated hsa-miR-145 expression levels in H. pylori (+) GC cases, compared to H. pylori (-) GC cases. Regional differences in the virulence of H. pylori strains may also be involved in the up- or downregulation of miRNA expression levels.

Association of clinicopathological features with E-cadherin (CDH1) gene-160 C>A promoter polymorphism in Turkish colorectal cancer patients.

BACKGROUND AND AIM OF STUDY: The role of E-cadherin (CDH1) gene-160 C>A (rs16260) promoter polymorphism in colorectal cancer (CRC) still remains inconclusive. The aim of this study is to investigate the associations between the CDH1-160 C>A polymorphism with the susceptibility and clinicopathological development of CRC in the Turkish patients. To our knowledge, this is the first report examining the role of CDH1 polymorphism in Turkish CRC patients. MATERIALS AND METHODS: A total of 92 colorectal carcinoma cases (including 62 colon and 30 rectal cancer patients) and the corresponding adjacent normal tissues as controls were studied. The polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis. Clinicopathological features including patient's age, gender, tumor stage, and tumor location (colon/rectum) were compared statistically with the polymorphism status. RESULTS: There was no significant difference in both genotype and allele frequencies of the CDH1 polymorphism between colorectal tumor cases and normal samples (P = 0.472 and 0.508, respectively). Furthermore, no significant associations were observed between the CDH1 polymorphism status and age, gender, tumor stage, and tumor location of the colorectal tumor cases (all P > 0.05). CONCLUSIONS: These results indicate that CDH1-160 C>A polymorphism does not contribute to the genetic susceptibility of CRC and the polymorphism may not be a direct effect on the progression of the disease in Turkish CRC patients.

Dealing with the gray zones in the management of gastric cancer: The consensus statement of the Istanbul Group.

The geographical location and differences in tumor biology significantly change the management of gastric cancer. The prevalence of gastric cancer ranks fifth and sixth among men and women, respectively, in Turkey. The international guidelines from the Eastern and Western countries fail to manage a considerable amount of inconclusive issues in the management of gastric cancer. The uncertainties lead to significant heterogeneities in clinical practice, lack of homogeneous data collection, and subsequently, diverse outcomes. The physicians who are professionally involved in the management of gastric cancer at two institutions in Istanbul, Turkey, organized a consensus meeting to address current problems and plan feasible, logical, measurable, and collective solutions in their clinical practice for this challenging disease. The evidence-based data and current guidelines were reviewed. The gray zones in the management of gastric cancer were determined in the first session of this consensus meeting. The second session was constructed to discuss, vote, and ratify the ultimate decisions. The identification of the T stage, the esophagogastric area, imaging algorithm for proper staging and follow-up, timing and patient selection for neoadjuvant treatment, and management of advanced and metastatic disease have been accepted as the major issues in the management of gastric cancer. The recommendations are presented with the percentage of supporting votes in the results section with related data.

Gastroenteropancreatic neuroendocrine tumors: recommendations of Turkish multidisciplinary neuroendocrine tumor study group on diagnosis, treatment and follow-up.

Gastroenteropancreatic neuroendocrine tumors (GEPNETs) are a relatively rare, heterogeneous group of diseases in which important advances have been observed in the diagnosis and treatment as well as in our understanding of the biology and genetics of the disease in recent years. Given the insufficient scientific data available on evidence-based management of GEPNETs and the differences in circumstances in individual countries, a multidisciplinary study group was established to provide guidelines for the management of GEPNETS. This study group consisted of a medical oncologist, endocrinologist, surgeon, pathologist, gastroenterologist, and a nuclear medicine specialist, who aimed to prepare a practical guide in the light of existing scientific data and international guidelines, to be used in common clinical practice.

Machine learning aided diagnosis of hepatic malignancies through in vivo dielectric measurements with microwaves.

In the past decade, extensive research on dielectric properties of biological tissues led to characterization of dielectric property discrepancy between the malignant and healthy tissues. Such discrepancy enabled the development of microwave therapeutic and diagnostic technologies. Traditionally, dielectric property measurements of biological tissues is performed with the well-known contact probe (open-ended coaxial probe) technique. However, the technique suffers from limited accuracy and low loss resolution for permittivity and conductivity measurements, respectively. Therefore, despite the inherent dielectric property discrepancy, a rigorous measurement routine with open-ended coaxial probes is required for accurate differentiation of malignant and healthy tissues. In this paper, we propose to eliminate the need for multiple measurements with open-ended coaxial probe for malignant and healthy tissue differentiation by applying support vector machine (SVM) classification algorithm to the dielectric measurement data. To do so, first, in vivo malignant and healthy rat liver tissue dielectric property measurements are collected with open-ended coaxial probe technique between 500 MHz to 6 GHz. Cole-Cole functions are fitted to the measured dielectric properties and measurement data is verified with the literature. Malign tissue classification is realized by applying SVM to the open-ended coaxial probe measurements where as high as 99.2% accuracy (F1 Score) is obtained.

Clinical and pathological characteristics and their effect on survival in elderly patients with gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumors (GISTs) are common tumors of the gastrointestinal tract. Their most frequent location is the stomach. Although the clinical and pathological characteristics of the disease are well-known, the clinical and pathological characteristics and the response to treatment are not clear in elderly patients. The purpose of this study was to evaluate the characteristics of GISTs in elderly patients with an aim at improving the therapeutic methodology and survival. METHODS: In this study, clinicopathological characteristics, evaluation of treatments administered and survival analyses were performed in patients aged 65 years or above, whose data were registered via a web-based patient records system following admission to three centers. RESULTS: A total of 85 patients aged 65 years or above were included in the study. According to the risk classification, 24 (28.2%) were in the low risk group, 20 (23.5%) in the moderate risk group, and 41 (48.3%) in high risk group, while no patient was in the very low risk group. At baseline, 70% of the patients had localized disease and 30% metastatic disease. The tumor was located in the stomach in the majority of the patients (45.6%). The tumor size most commonly seen was 5-10 cm (N=31; 36.4%). Of the 85 patients 23 (27%) were treated with imatinib 400 mg/d. Eight patients (9.4%) with metastatic disease switched from imatinib to sunitinib. At a median follow-up of 76 months (range 1-323), median overall survival (OS) was 72 months, without significant difference between elderly and younger patients. CONCLUSION: Clinicopathological characteristics and their prognostic impact on the disease course of elderly GIST patients should be elucidated in depth. Since age didn't show prognostic importance, other parameters should be used as prognostic/predictive factors in the tyrosine kinase inhibitors era in order to obtain improved therapeutic results.

Microsatellite instability and B-type Raf proto-oncogene mutation in colorectal cancer: Clinicopathological characteristics and effects on survival.

Prognostic significance of microsatellite instability (MSI) status and B-type Raf proto-oncogene (BRAF) mutation in colorectal cancer is controversial. The aim of this study was to examine the clinical and pathological characteristics associated with microsatellite stability and the effect of MSI and BRAF mutation on the survival of patients with colorectal cancer. The study included 145 colorectal cancer cases. All the patients were examined for DNA mismatch repair (MMR) proteins with an immunohistochemical method. Molecular assessment of MSI was available in a subset of 41 patients. In addition, BRAF mutation analysis was performed in 30 cases. Immunohistochemically, MMR deficiency was present in 28 (19.3%) patients. Female gender (p = 0.001), lesion size ≥5 cm (p = 0.013), Crohn-like response (p = 0.035), and right-sided localization (p < 0.001) were significantly more frequent among MMR-deficient patients. The overall survival was 44.1 ± 5.1 months (95% confidence interval [CI], 33.7-54.4). Multivariate analyses identified only high tumor grade as an independent predictor of poor overall survival: odd ratio, 6.7 (95% CI 2.1-21.7), p = 0.002. In the subset of patients with available BRAF assessment (n = 30), a negative BRAF status was associated with better survival when compared to a positive BRAF status (36.7 ± 2.1 vs. 34.1 ± 7.2 months, p = 0.048). The sensitivity and specificity of the immunohistochemical method in predicting positive MSI status, with the molecular method as a reference, were 85.7% (95% CI: 56.2%-97.5%) and 88.9% (95% CI: 69.7%-97.1%), respectively. BRAF appears to be a significant predictor of a worse outcome in patients with colorectal cancer. Further studies with a large spectrum of clinical and biological variables are warranted.

Fistula tract curettage and the use of biological dermal plugs improve high transsphincteric fistula healing in an animal model.

PURPOSE: The treatment of high transsphincteric fistula is a complex procedure, which may be associated with the risk of recurrence and fecal incontinence. In this study, we used an animal model to compare different types of sphincter-preserving treatments for transsphincteric fistula. METHODS: Sixteen female New Zealand rabbits, weighing 2.8-4.8 kg underwent a surgical creation of high transsphincteric fistula. After 6 weeks, magnetic resonance imaging (MRI) was performed in order to confirm fistula formation and measure the fistula diameter. The rabbits were divided into three groups. Group 1 received no plug treatment (control). Autologous dermal graft and acellular dermal matrix were used as a plug in groups 2 and 3, respectively. Five weeks after treatment, fistula tract healing was determined by measuring the largest fistula diameter with MRI. All rabbits were euthanized and the anorectum excised en bloc for histopathological examination. RESULTS: According to the MRI findings, all groups showed significant healing after the treatment (p < 0.05). The healing rate of fistula diameters after treatment was 40, 66, and 29% in the control, dermal graft, and acellular dermal matrix groups, respectively. In terms of negative healing parameters such as neutrophil, eosinophil, lymphocyte, and plasmocyte accumulation, dermal graft and acellular dermal matrix groups showed significantly lower results than those in the control group (p < 0.05). CONCLUSION: According to MRI and histopathological results, fistula tract curettage and fistula orifice closure improved transsphincteric anal fistula healing. Additionally, in this study, plug treatment favoring autologous dermal graft resulted in better healing.

Increased Caseload Volume is Associated With Better Oncologic Outcomes After Laparoscopic Resections for Colorectal Cancer.

PURPOSE: To evaluate the impact of caseload volume on the outcomes of open and laparoscopic surgery for colorectal cancer. METHODS: Between April 1999 and January 2011, patients who underwent open or laparoscopic resection for colorectal adenocarcinoma with curative intent were identified. There were 2 groups of surgeons, whose primary practice is gastrointestinal surgery (n=5, group A) and general surgery (n=14, group B). Histopathologic and oncologic outcomes, as well as survival data were evaluated. RESULTS: A total of 815 patients fulfilled the study criteria and 356 (group A: 120, group B: 236) patients who had >2 years' follow-up data were included. Colorectal procedures constituted 33% and 19% of all the operations in A and B groups, respectively (P<0.0001). Among the colorectal cases, rates of laparoscopic surgery were 37% and 20% in the group A and B, respectively (P<0.0001). Practice pattern was independently associated with better overall survival and was favoring the group A (P=0.02). CONCLUSIONS: Increased caseload volume improves oncologic outcomes in patients undergoing colorectal resection for nonmetastatic cancer.

Is perineural invasion (PN) a determinant of disease free survival in early stage colorectal cancer?

BACKGROUND/AIMS: The prognostic importance of perineural invasion (PN) in colorectal cancer (CRC) is unclear. The aim of this study to find out whether the PN was an independent stratification factor of postoperative relapse in curatively resected high-risk stage II & III CRC patients who were treated with adjuvant therapy. METHODOLOGY: Data of patients with high risk stage II & all stage III CRCs treated with adjuvant chemotherapy were retrospectively analyzed. Pathological features of final surgical specimen were noted. Disease-free survival was determined by Kaplan-Meier estimator, with differences determined by multivariate analysis using the Cox multiple hazards model. Results were compared using the log-rank test. RESULTS: PN was found to be positive in 26% in the files of 593 eligible patients. In 21% of the reports PN status was not reported. Presence of PN in the resected primary tumors did not have independent effect on DFS. Further analyses for importance of PN on DFS of colon or rectal cancers did not show any effect. CONCLUSIONS: This study had failed to demonstrate any prognostic effect of PN for DFS in surgically resected stage II and III CRC patients who received adjuvant treatments.

Epidermal growth factor receptor in CRC patients in the era of the RAS.

The aim of this study was to investigate EGFR expression patterns and the effect of EGFR expression on stage, prognosis and response to conventional chemotherapy agents other than monoclonal antibodies in CRC patients. This study included 59 metastatic CRC patients. The expression of EGFR was quantified by immunochemistry in biopsy specimens that were obtained before treatment was initiated. The cases were considered to be positive for EGFR if >1% of the tumor cells had complete circumferential membranous staining. The median age of the patients was 54.6 years, and 59% of the patients were male. Twenty-six patients presented with stage IV disease, and the remaining patients developed distant metastasis during follow-up. Fifty-one patients were treated with regimens containing irinotecan. The numbers of patients with EGFR expression in the primary tumors, the metastatic lymph nodes and the normal colonic tissue were 34 (65.4%), 10 (76.9%) and 34 (65.4%) respectively. The initial disease stage and lymph node stage were correlated with EGFR expression (p<0.05). Additionally, EGFR positivity was correlated with a statistically significant reduction in the response rate to chemotherapy, the overall survival (21 vs. 28 months) and the progression-free survival (15 vs. 22 months) in metastatic patiens treated with chemotherapy other than targeted therapies. In conclusion, EGFR expression in correlated with stage in all CRC patients and response to chemotherapy and survival in metastatic CRC patients.

What is the optimal treatment in clinical stage T3N0M0 rectal cancer?

PURPOSE: Some previous studies suggested that certain rectal cancer patients with stage T3N0 and favorable features may be adequately treated with surgery and adjuvant chemotherapy. However, the optimal management of clinical (c) T3N0 rectal adenocarcinoma based on preoperative imaging is unclear. In this study, we aimed to determine the frequency of lymph node metastases in patients clinically staged as T3N0 rectal adenocarcinoma following preoperative chemoradiotherapy (CTR). METHODS: The medical records of 105 patients with clinico- imaging stage T3N0M0 rectal cancer who received preoperative CRT between 2004-2011 were retrospectively analyzed. Chemotherapy used concurrently with preoperative radiotherapy (RT) was protracted 5-fluorouracil (5FU) infusion. RESULTS: Twenty-seven percent of the patients clinically staged as T3N0 before preoperative CRT had pathological (p) lymph node involvement on surgical material. The rate of pathological lymph node involvement was 0% in pT1, 20% in pT2 , 35% in pT3 and 34% in pT4 patients. A significant association was demonstrated between pT stages and pN status (p=0.03). CONCLUSION: Our study demonstrated that the accuracy of preoperative imaging for staging rectal cancer is limited because at least 27% of the patients may have undetected lymph node involvement after preoperative CRT in surgical material.

Analysis of PTEN, BRAF and PI3K status for determination of benefit from cetuximab therapy in metastatic colorectal cancer patients refractory to chemotherapy with wild-type KRAS.

We investigated predictive values of BRAF, PI3K and PTEN in cetuximab responses in KRAS wild-type (+) chemotherapy refractory, metastatic colorectal cancer (CRC) patients. Primary tumour tissues of 41 KRAS wild-type mCRC patients receiving cetuximab-based chemotherapy were investigated for PI3K, PTEN, KRAS and BRAF mutations. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan-Meier method and the Cox proportional hazards model was used. PTEN and PI3K expressions were 63 and 42 %, respectively. BRAF mutation was observed as 9.8 % among patients. Tumours with BRAF mutation had statistically lower response rates (RR) for cetuximab-based treatment than tumours with BRAF wild type (0 vs. 58 %, p = 0.02). PTEN expressing tumours had statistically higher RR for cetuximab-based treatment than tumours with PTEN loss (42 vs. 12 %, p = 0.04). PI3K expression had worse significant effect on cetuximab RR than PI3K non-expressed tumours (15 vs. 44 %, p = 0.023). Median PFS was significantly longer in patients with PTEN expression (14 months) than in patients with PTEN loss (5 months) (HR, 0.4; p = 0.028). Median PFS was significantly longer in patients with PI3K non-expression (15.2 months) than in patients with PI3K expression (4.1 months) (HR, 0.31; p = 0.001). Significant difference in PFS and OS between patients with BRAF mutated and BRAF wild-type tumours was not detected. However, patients with PTEN expression had significantly longer OS (15.1 months) than patients with PTEN loss tumour (9.9 months) (HR, 0.34; p = 0.008). Patients without PI3K expression had significantly longer OS (18.2 months) than patients with PI3K expression (10.1 months) (HR, 0.27; p = 0.001). Multivariate analyses revealed that PTEN expression (HR, 0.48; p = 0.02) and absence of PI3K expression (HR, 0.2; p = 0.001) were independent prognostic factors for increased PFS. Similarly, PTEN overexpression (HR, 0.62; p = 0.03) and absence of PI3K expression (HR, 0.27; p = 0.005) were independent prognostic factors for increased OS. In PTEN loss, PI3K expression may be used as biomarkers to further select KRAS wild-type patients undergoing anti-epidermal growth factor receptor treatment.

Preoperative versus postoperative chemoradiotherapy in stage T3, N0 rectal cancer.

BACKGROUND: The study populations of previous preoperative chemoradiotherapy (pre-CRT) studies have consisted of mixed clinical stages, such as cT3-cT4 and/or cN positive. For this reason, it has not been possible to demonstrate whether pre-CRT is of benefit for individual subgroups. METHODS: The medical records of 137 rectal cancer patients with clinical stage T3, N0 disease who received either pre-CRT or postoperative chemoradiotherapy (post-CRT) between 2002 and 2011 were retrospectively analyzed. The regimen of pre-CRT consisted of slow fluorouracil (5FU) infusion and that of post-CRT consisted of bolus 5FU and leucovorin concurrent with radiation. RESULTS: Following pre-CRT, significant downstaging was achieved. However, administration of pre-CRT did not influence the type of surgical resection in tumours ≤5 cm distant from the anal verge (p = 0.14). Pathological complete response was achieved in 16 % of the patients in the pre-CRT group. The local recurrence rate (LRR) at 5 years was 5.7 % in the pre-CRT and 11.1 % in the post-CRT groups (p = 0.04). The distant recurrence rate (DRR) at 5 years was 76 % and 77 % in the pre-CRT and post-CRT groups, respectively (p = 0.1). Overall survival was similar in two groups (74.8 % vs. 75.3 %, p = 0.3). CONCLUSIONS: The treatment of stage T3, N0 rectal cancer patients with pre-CRT followed by surgery decreased LRR, but did not improve DRR or OS as compared with surgery followed by post-CRT in our patient cohort.