DPYD c.1905 + 1G>A Promotes Fluoropyrimidine-Induced Anemia, a Prognostic Factor in Disease-Free Survival, in Colorectal Cancer.

Background and Aim: In 10-30% of colorectal cancer (CRC) patients, toxic reactions occur after fluoropyrimidine-based chemotherapy. A dihydropyridine dehydrogenase (DPYD) gene variant, c.1905 + 1G>A, leads to intolerance to fluoropyrimidines. Due to the low frequency of this variant in many populations, the prevalence of fluoropyrimidine-induced hematologic side effects in CRC patients with the c.1905 + 1G>A variant is unclear. In this study, we investigated the prevalence of the DPYD c.1905 + 1 variants in a Turkish CRC cohort and the potential effects of these variants on fluoropyrimidine-induced hematologic side effects. Materials and Methods: The DPYD c.1905 + 1 variant was genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis and confirmed by Sanger sequencing in peripheral blood samples of 100 CRC patients who received fluoropyrimidine-based chemotherapy and 60 healthy volunteers. The association of c.1905 + 1 variants with susceptibility to hematologic side effects was evaluated. Results: The DPYD c.1905 + 1G>A variant was more common in the CRC group than in the healthy control group (p = 0.001). The presence of the c.1905 + 1G>A variant was associated with thrombocytopenia (p = 0.039) and anemia (p = 0.035). CRC patients with fluoropyrimidine-induced anemia had shorter disease-free survival than CRC patients without fluoropyrimidine-induced anemia (p = 0.0009). Conclusions: Before administering fluoropyrimidine-based chemotherapy, genetic screening for the DPYD c.1905 + 1G>A variant should be performed with the aim of preventing anemia and anemia-induced complications in CRC patients.

Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations.

The treatment of metastatic colorectal cancer (mCRC) harboring BRAF V600 mutations is challenging. These tumors are often refractory to standard treatment. Therefore, the patients may exhibit rapid clinical deterioration, depriving them of the chance to receive salvage therapy. In newly diagnosed patients with good performance status, the administration of an intensive chemotherapy regimen like FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) along with the antiangiogenic agent bevacizumab can modify this aggressive behavior of the disease and improve patient clinical outcomes. The recently published results of the BEACON (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) study demonstrated that a combination therapy consisting of BRAF, epidermal growth factor receptor, and mitogen-activated protein kinase kinase inhibitors could be a useful second-or third-line alternative. This review summarizes the current treatment strategies for BRAF-mutant mCRC.

Existing anti-angiogenic therapeutic strategies for patients with metastatic colorectal cancer progressing following first-line bevacizumab-based therapy.

Continuous inhibition of angiogenesis beyond progression is an emerging treatment concept in the management of metastatic colorectal cancer patients with prior bevacizumab exposure. Treatment options include the continuation or reintroduction of bevacizumab during the second-line chemotherapy or switching to a different antiangiogenic monoclonal antibody such as aflibercept or ramucirumab. In the selection of treatment, patient-based factors such as performance status, age, tumor burden, and tolerance and sensitivity to the first-line bevacizumab-based therapy, as well as treatment-related factors such as toxicity, efficacy, and cost, should be taken into consideration.

Dual HER2 inhibition strategies in the management of treatment-refractory metastatic colorectal cancer: History and status.

Human epidermal growth factor receptor 2 (HER2) signaling pathway activation has been identified as a contributor to de novo or acquired resistance to epidermal growth factor receptor (EGFR) inhibitors in a small subset of patients with metastatic colorectal cancer (mCRC). Dual anti-HER2-targeted treatment exhibits strong antitumor activity in preclinical models of HER2-positive mCRC, supporting its testing in clinical trials. The HERACLES trial at four Italian academic cancer centers has confirmed the effectiveness of dual blockage of HER2 with trastuzumab plus lapatinib in patients with heavily pretreated HER2-positive mCRC, refractory to the anti-EGFR antibodies cetuximab or panitumumab. Here, we reviewed the preclinical studies exploring the role of HER2 signaling in the development of anti-EGFR therapy resistance and discussed the status of clinical trials assessing the activity of HER2 inhibitors in this setting.

Shattering the castle walls: Anti-stromal therapy for pancreatic cancer.

Despite the availability of potent chemotherapy regimens, such as 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel plus gemcitabine, treatment outcomes in metastatic pancreatic cancer (PC) remain unsatisfactory. The presence of an abundant fibrous stroma in PC is considered a crucial factor for its unfavorable condition. Apparently, stroma acts as a physical barrier to restrict intratumoral cytotoxic drug penetration and creates a hypoxic environment that reduces the efficacy of radiotherapy. In addition, stroma plays a vital supportive role in the development and progression of PC, which has prompted researchers to assess the potential benefits of agents targeting several cellular (e.g., stellate cells) and acellular (e.g., hyaluronan) elements of the stroma. This study aims to briefly review the primary structural properties of PC stroma and its interaction with cancer cells and summarize the current status of anti-stromal therapies in the management of metastatic PC.

Platinum-induced neurotoxicity: A review of possible mechanisms.

Patients treated with platinum-based chemotherapy frequently experience neurotoxic symptoms, which may lead to premature discontinuation of therapy. Despite discontinuation of platinum drugs, these symptoms can persist over a long period of time. Cisplatin and oxaliplatin, among all platinum drugs, have significant neurotoxic potential. A distal dose-dependent symmetrical sensory neuropathy is the most common presentation of platinum neurotoxicity. DNA damage-induced apoptosis of dorsal root ganglion (DRG) neurons seems to be the principal cause of neurological symptoms. However, DRG injury alone cannot explain some unique symptoms such as cold-aggravated burning pain affecting distal extremities that is observed with oxaliplatin administration. In this article, we briefly reviewed potential mechanisms for the development of platinum drugs-associated neurological manifestations.

Immunohistochemical expression of CDX2, CK7, HER2 and HER4 in periampullary adenocarcinoma : implications for clinicopathology and patient outcomes.

Background: Periampullary carcinomas originate from the pancreatic head, the ampulla, the distal bile duct, or the duodenum. The expression of CK7 and CDX2 has been used in the classification of periampullary carcinomas. There is prognostic value of human epidermal growth factor receptor (HER) 2 and HER 4, which have been linked to poor prognosis in several types of tumors, such as breast and gastric carcinomas. We aimed to evaluate the expression and prognostic value of CDX2, CK7, HER 2, and HER4 in periampullary adenocarcinoma. Patients and Methods: We retrospectively selected 98 patients who had undergone pancreatoduodenectomy for periampullary adenocarcinoma at our pathology department. The tumor location, pathological subtype, involvement of vessels and lymph nodes, perineural invasion, clinical follow-up, and tumorstage were noted. Immunohistochemistry was performed for CK7, CDX2, HER2, and HER4. Results: CDX2 staining was predictive of perineural invasion. Additionally, there was a significant association between the overexpression of HER2 and HER4 and the presence of perineural invasion. HER4 was significantly positive in patients with the pancreatobiliary subtype compared with patients with the intestinal subtype. Patients with the pancreatobiliary subtype, lymph node involvement, and advanced pT and UICC stages had significantly lower median survival. Conclusion: Our findings suggest that only pancreatobiliary subtype, lymph node involvement and advanced pT and UICC stages were independent predictors of short survival, but the ampulla tumor location predicted a significantly better survival time. The immunohistochemical expression of CDX2, CK7, HER4, and HER2, vessel involvement, and perineural invasion were not associated with the survival of patients with periampullary adenocarcinoma.

Glutathione S-transferase T1, M1 and P1 Genetic Polymorphisms and Susceptibility to Colorectal Cancer in Turkey.

Colorectal cancer (CRC) is reported to be the third most common cancer worldwide and the fourth most common cause of cancer related deaths. CRC is considered to be a multifactorial disease whose risk varies due to the complex interaction between individual genetic basis and exposure to multiple endogenous factors. Glutathione S-transferases are pro-carcinogenic in CRC and are required for the conjugation between chemotherapeutics and broad spectrum xenobiotics. One hundred and eleven patients with CRC and 128 control subjects without any cancer history were enrolled in this study. Multiplex PCR was applied to determine polymorphisms for the GSTT1 and M1 genes, and PCR-RFLP was applied for the GSTP1 (Ile105Val) gene polymorphism. Values <0.05 were defined as statistically significant. We detected a significant high correlation between predisposition for CRC and presence of the Ile/Ile genotype of the GSTP1 (IIe105Val) gene polymorphism, but we did not find a significant relationship between predisposition for CRC and GSTT1 and M1 deletion polymorphisms. In addition, we did not determine a relationship between GSTT1, M1 and P1 gene polymorphisms and any clinicopathological features of CRC. GSTT1 null/GSTM1 positive and GSTT1 null/GSTM1 positive/GSTP1 Ile/ Ile genotypes were significantly higher in the patient group. Our results revealed that there is no relationship among CRC, its clinicopathologic features, and GSTT1 M1 gene polymorphisms. However, there was a significant correlation between CRC and the GSTP1 Ile/Ile genotype. Further studies with larger patient groups are required to delineate the relationships between GST gene polymorphisms and the clinicopathologic features of CRC in Turkey.

Immunohistochemical expression of human epidermal growth factor receptor (HER)-4 and prognosis in patients with metastatic breast cancer.

PURPOSE: The clinical value of HER4 - a cell surface receptor that belongs to the human epidermal growth factor receptor family - for predicting survival outcomes in patients with breast cancer remains controversial. Herein, we sought to investigate the prognostic significance of HER4 immunohistochemical expression with respect to progression-free survival (PFS) and overall survival (OS) in Turkish patients with metastatic breast cancer (MBC). METHODS: MBC patients (N=45; mean age=50.5±12.7 years) were consecutively enrolled between 2000 and 2006 in the Department of Oncology at the Uludag University Medical Center, Bursa, Turkey. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections. The predictive value of HER4 expression was investigated by multivariate analysis after allowance for potential confounders. RESULTS: The mean PFS in the study participants was 11.35 months (range:1-50), whereas the median OS was 22.18 months (range:1-76). The mean PFS in patients with a HER4 immunohistochemical score of 0, 1+, 2+, and 3+ was 11.0 ± 4.8, 11.3 ± 7.7, 11.7 ± 8.1, and 10.4 ± 7.4 months, respectively (p=0.99) . The mean OS in patients with a HER4 score of 0, 1+, 2+, and 3+ was 13.3 ± 6.8, 25.6 ± 10.8, 22.9 ± 10.7, and 13.5 ± 9.9, months, respectively (p=0.44). The results of multivariate Cox regression analysis indicated that the presence of visceral metastases was the only independent prognostic factor for both OS (HR=3.01, 95% CI=1.56-3.99, p <0.01) and PFS (HR=2.91, 95% CI=1.51-3.78, p <0.01). CONCLUSION: HER4 immunohistochemical expression is not an independent predictor of OS and PFS in Turkish MBC patients.

Distribution of KRAS and BRAF Mutations in Metastatic Colorectal Cancers in Turkish Patients.

The results of this study demonstrate the potential prognostic and predictive values of KRAS and BRAF gene mutations in patients with colorectal cancer (CRC). It has been proven that KRAS and BRAF mutations are predictive biomarkers for resistance to anti-EGFR monoclonal antibody treatment in patients with metastatic CRC (mCRC). We demonstrated the distribution of KRAS (codons 12, 13 and 61) and BRAF (codon 600) gene mutations in 50 mCRCs using direct sequencing and compared the results with clinicopathological data. KRAS and BRAF mutations were identified in 15 (30%) and 1 (2%) patients, respectively. We identified KRAS mutations in codon 12, 13 and 61 in 73.3% (11/15), 20% (3/15) and 6.67% (1/15) of the positive patients, respectively. The KRAS mutation frequency was significantly higher in tumors located in the ascending colon (p=0.043). Thus, we found that approximately 1/3 of the patients with mCRC had KRAS mutations and the only clinicopathological factor related to this mutation was tumor location. Future studies with larger patient groups should yield more accurate data regarding the molecular mechanism of CRC and the association between KRAS and BRAF mutations and clinicopathological features.

Current treatment options for patients with initially unresectable isolated colorectal liver metastases.

The development of liver metastases is a common clinical entity in the clinical course of colorectal cancer. For patients with isolated liver involvement, surgical resection is the only treatment that can provide a chance of prolonged survival and cure. However, most of these patients are not initially eligible for the surgery. Selected patients with initially considered to have unresectable disease may become resectable after systemic (chemotherapy ± biological therapy) and loco-regional treatment modalities including hepatic arterial infusion. Patients who have colorectal liver metastases ideally should be referred to a multidisciplinary cancer care team in order to identify the most optimal management approach.

Targeted therapy for advanced gastric cancer: A review of current status and future prospects.

In the West in particular, the vast majority of gastric cancer (GC) patients present with advanced-stage disease. Although combination chemotherapy is still the most important component of treatment for these patients, it confers a modest survival advantage. Recently, increased knowledge of the key molecular signaling pathways involved in gastric carcinogenesis has led to the discovery of specific molecular-targeted therapeutic agents. Some of these agents such as trastuzumab and ramucirumab have changed the treatment paradigm for this disease. In this paper, we will summarize the current clinical status of targeted drug therapy in the management of GC.

Clinical significance of adiponectin expression in colon cancer patients.

PURPOSE: Surgery is the definitive treatment for early colon cancers. Adjuvant therapies are used with the aim of eradicating micrometastases and improving cure rates. Recent studies have proposed that adiponectin might be responsible for obesity-related malignancies. We investigated the prognostic value of this cytokine. MATERIALS AND METHODS: Patients who underwent surgical removal of stage II or III (TNM staging) primary tumors and were followed for at least three years were included in the study given adequate specimen for immunohistochemical evaluation. Based on these criteria, 53 patients were included. RESULTS: Mean age was 58.3 ± 10.1 years (35-78 years). The mean follow-up time was 41 months (10-96 months). Immunohistochemical evaluation identified 21 patients (39.6%) with cytoplasmic adiponectin present in their specimens. The rates of recurrence were 42.9% (9/21) and 34.4% (11/32) in patients with and without adiponectin expression, respectively. In cases with adiponectin expression, mean disease - free survival was 60.3 ± 9.03 months, and in cases without adiponectin expression, mean disease - free survival was 68.7 ± 6.67 months (P = 0.414). Mean overall survival of patients with adiponectin expression was 65 months compared to 67 months for patients without (P = 0.786). CONCLUSION: Adiponectin, which is secreted by adipose tissue, may have a role in the development and progression of cancer via its pro-apoptotic and/or anti-proliferative effects. Adiponectin expression in tumor tissues is likely to have a negative effect on disease - free survival in patients with stage II/III colon cancer; however, no statistically significant effect was demonstrated.

Solitary bone metastases of unknown origin.

Patients with a newly detected solitary bone metastasis and no history of cancer need extensive diagnostic testing. One hundred and twenty biopsy samples of patients with metastatic bone disease were referred to the authors' pathology department between June 2005 and December 2012. Thirty-three (27.5%) of these patients with a solitary metastasis of unknown origin, and without visceral metastases, were studied retrospectively. Most metastases were found in the spine (14/33 or 42.4%), or in the pelvis (7/33 or 21.2%). The lung was the most common primary site, but this is not universal in the literature. A useful flowchart for the clinician, confronted with a bone metastasis from an unknown primary site, is the following, according to the literature: history and physical examination, biochemistry with tumor markers and immunoelectrophoresis, chest radiograph, CT-scan of chest and abdomen, and bone scan.

Lack of prognostic significance of adiponectin immunohistochemical expression in patients with triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancers (TNBCs) - which lack the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) - have no established markers that can be used for prognostic stratification. As adiponectin has been previously implicated in a more aggressive phenotype of primary breast cancer, we explored the relation between adiponectin immunohistochemical expression and prognosis in TNBCs. MATERIAL AND METHODS: Immunohistochemical staining for adiponectin was performed in 38 TNBC patients. Disease-free survival (DFS) and overall survival (OS) served as the main outcome measures. RESULTS: Of the 38 TNBC patients, 18 (47%) had negative and 20 (53%) positive adiponectin immunohistochemical expression. We did not find any significant association between adiponectin immunohistochemical expression and the baseline characteristics. In addition, there were no associations between adiponectin immunohistochemical expression and prognosis. CONCLUSIONS: Although our results suggest that adiponectin immunohistochemical expression is not of prognostic significance in TNBCs, further studies are warranted to determine the role of this adipokine in breast cancer biology.

Role of central arginine vasopressin receptors in the analgesic effect of CDP-choline on acute and neuropathic pain.

Recent studies have demonstrated that arginine vasopressin (AVP) plays a crucial role in pain modulation. In addition, our previous studies have proven that centrally administered cytidine-5'-diphosphate-choline (CDP-choline; citicoline) elicits an analgesic effect in different pain models in rats. Given that CDP-choline enhances central and peripheral vasopressin levels, the present study was designed to investigate the role of central AVP receptors in the analgesic effect of CDP-choline in acute and chronic constriction injury-induced neuropathic pain models. For this purpose, rats were pretreated intracerebroventricularly with the AVP V1 or AVP V2 receptor antagonist 15 min before intracerebroventricular injection of CDP-choline or saline, and pain threshold was determined using the Randall-Selitto test. AVP V1 and AVP V2 receptor antagonist blocked the CDP-choline-induced analgesic effect either in acute or neuropathic models of pain in rats. These results suggest, for the first time, that central AVP receptors are involved in the CDP-choline-elicited analgesic effect.

Prognostic significance of human epidermal receptor (HER)- 3 immunohistochemical expression in patients with metastatic breast cancer.

BACKGROUND: Previous reports have shown that human epidermal receptor (HER)-3 overexpression may be associated with poor prognosis in patients with breast cancer, but results have been conflicting. In this study, we sought to investigate the prognostic significance of HER-3 immunohistochemical expression in patients with metastatic breast cancer. METHODS: We retrospectively analyzed HER-3 immunohistochemical expression profiles in 45 paraffin-embedded specimens from patients who had been treated between 1996 and 2006 in the Department of Oncology of the Uludag University School of Medicine, Bursa, Turkey. Membranous or cytoplasmic dominant expression patterns of HER-3 were analyzed using the Rajkumar score and a cytoplasmic 4-point scoring system, respectively. Progression-free survival (PFS) and overall survival (OS) served as the main outcome measures. RESULTS: The median PFS in the study participants was 9 months (interquartile range: 4.5-13 months), whereas the median OS was 20 months (interquartile range: 7.5-28 months). Categorization of the patient population according to HER-3 positive immunohistochemical expression did not reveal any statistically significant difference in terms of both PFS (p=0.70) and OS (p=0.81). The results of multivariable Cox regression analysis indicated that tumor size was the only independent predictor of PFS, whereas estrogen and progesterone receptor status was independently associated with OS. CONCLUSIONS: HER-3 immunohistochemical expression did not correlate with outcomes in Turkish patients with metastatic breast cancer. Although our results suggest that HER-3 expression in cancer specimens is not of prognostic significance, further prospective studies are warranted to confirm these results.

Comparison of three different treatment modalities in the management of cancer cachexia.

AIMS AND BACKGROUND: The optimal treatment of cancer cachexia remains unknown. In this study, we compared the efficacy of three different treatment modalities in the management of cancer cachexia. METHODS: Sixty-two assessable cachectic cancer patients were randomized to one of the following three arms: 1) megesterol acetate (MA) plus meloxicam (n = 23); 2) MA plus meloxicam plus oral eicosapentaenoic acid (EPA)-enriched nutritional supplement (n = 21); or 3) meloxicam plus oral EPA-enriched nutritional supplement (n = 18). Treatment duration was 3 months. RESULTS: The treatment arms were well balanced at baseline. The primary efficacy (body weight and lean body mass) and secondary efficacy (body mass index, quality of life, and serum levels of IL-6 and TNF-α) parameters improved after treatment in all three arms. There were no statistically significant differences between treatment groups in the mean percentage changes in all efficacy parameters from baseline to end of study. CONCLUSIONS: MA plus meloxicam or EPA supplement plus meloxicam may be effective treatment options in the management of cancer cachexia. The combined use of these agents does not provide further advantages.

Metastatic gastric cancer treatment: a little slow but worthy progress.

Metastatic gastric cancer is incurable and remains one of the leading causes of cancer-related deaths around the world. Despite the significant progress in its systemic treatment, metastatic gastric cancer is still a major therapeutic challenge for oncologists. Newer chemotherapy regimens and the addition of molecularly targeted agents to chemotherapy seem to provide better clinical outcomes for patients with metastatic gastric cancer. The objective of this article is to review the current treatment approach for this formidable disease.