The number of hepatocellular carcinoma foci as predictor of poor response to tumor-directed therapies in patients awaiting liver transplantation: a prospective cohort study.

BACKGROUND AND AIMS: Tumor-directed therapies (TDTs) are a constitutive part of hepatocellular carcinoma (HCC) treatment in patients awaiting liver transplantation (LT). While most patients benefit from TDTs as a bridge to LT, some patients drop out from the waiting list due to tumor progression. The study aimed to determine the risk factors for poor treatment outcome following TDTs among patients with HCC awaiting LT. METHODS: A total of 123 patients with HCC were evaluated with 92 patients meeting Milan Criteria enrolled in the prospective cohort study. Tumor response was evaluated using the modified Response Evaluation Criteria for Solid Tumors for HCC 1 month after the procedure. The risk factors for progressive disease (PD) and dropout were evaluated. RESULTS: After TDT, 55 patients (59.8%) achieved complete or partial response (44.6% and 15.2% respectively), 17 patients (18.5%) had stable disease, and 20 patients (21.7%) were assessed as PD. Multivariate analysis revealed a significant and independent association between the number of HCC foci and PD ( P  = 0.03, OR = 2.68). There was no statistically significant association between treatment response and demographics, MELDNa score, pre-and post-treatment alpha-fetoprotein (AFP), cumulative tumor burden the largest tumor size, or TDT modality. PD was the major cause of dropout in our cohort. Pre-treatment AFP levels ≥200 ng/ml had a strong association with dropout after TDTs ( P  = 0.0005). CONCLUSION: This study demonstrated the presence of multifocal HCC is the sole prognostic factor for PD following TDTs in HCC patients awaiting LT. We recommend prioritizing patients with multifocal HCC within Milan criteria by exception points for LT to improve the dropout rate.

Investigation of DPYD, MTHFR and TYMS polymorphisms on 5-fluorouracil related toxicities in colorectal cancer.

Aim: To investigate the association of DPYD, MTHFR and TYMS polymorphisms on 5-fluorouracil (5-FU) related toxicities and patient survival. Materials & methods: A total of 103 colorectal cancer patients prescribed 5-FU were included in the study. Genotyping was conducted for several DPYD, MTHFR and TYMS polymorphisms using a microarray analyzer. Results: DPYD 496A>G polymorphism was found to be significantly associated with 5-FU related grade 0-2, but not severe toxicities (p = 0.02). Furthermore, patients with DPYD 85TC and CC genotypes had longer progression and overall survival times compared to TT genotypes in our study group (log rank = 6.60; p = 0.01 and log rank = 4.40; p = 0.04, respectively). Conclusion: According to our results, DPYD 496AG and GG genotypes might be protective against severe adverse events compared to the AA genotype. Another DPYD polymorphism, 85T>C, may be useful in colorectal cancer prognosis. Further studies for both polymorphisms should be conducted in larger populations to achieve accurate results.

5-fluorouracil (5-FU) is a widely used drug for chemotherapy in colorectal cancer. In this study, we investigated the relationship between the severity of 5-FU induced adverse events and several variations in DPYD, MTHFR and TYMS genes, which encode the enzymes involved in 5-FU metabolism in a total of 103 colorectal patients. We also examined the relationship between the polymorphisms and progression-free and overall survival times of the patients in our study group. Among the variations, DPDY 496A>G polymorphism was found to be associated with 5-FU induced adverse events. Also, the DPYD 85T>C polymorphism was detected to be associated with longer progression-free and overall survival times.

Investigation of Vascular Endothelial Growth Factor Polymorphisms on Risk, Metastasis, Laterality, and Prognosis of Colorectal Cancer in Turkish Subjects.

Objectives: Tumor angiogenesis is known to support the spread and invasion of tumor cells, allow distant organ metastasis and to result in poorer prognoses and increased mortality. Since vascular endothelial growth factor-A (VEGF-A) is the major regulator of angiogenesis, in the present study the associations of the VEGF-A +405G>C and -460C>T polymorphisms with risk, primary tumor location, prognosis and metastasis of colorectal cancer (CRC) were investigated in Turkish subjects. Material and Methods: A total of 153 subjects consist of 74 controls and 79 CRC diagnosed patients were included in the study. VEGF-A +405G>C and -460C>T polymorphisms were analyzed using the Agena MassARRAY platform. Results: The VEGF +405GC+CC genotypes were found to be significantly associated with left colon cancer (unadjusted OR = 5.208 95% CI: 1.064-25.496, p = 0.04). The VEGF -460TT and CT+TT genotypes were associated with reduced liver metastasis risk (OR = 0.080 95% CI: 0.009-0.689 p = 0.02 and OR = 0.191 95% CI: 0.039-0.925, p = 0.04, respectively). Patients with the VEGF +405GG genotype showed longer progression-free survival in response to bevacizumab treatment (Log rank = 6.92, p = 0.03). Conclusion: According to our results, the VEGF +405G>C and -460C>T polymorphisms were found to be associated with CRC prognosis, sidedness and metastases. Our findings need to be replicated in further studies.

Association of PD-1 and PDL-1 gene polymorphisms with colorectal cancer risk and prognosis.

BACKGROUND: Programmed Cell Death-1 (PD-1) together with Programmed Death Ligand 1 (PDL-1) have crucial roles in anti-tumor immune response, cancer susceptibility and prognosis. Since PD-1 and PDL-1 have been considered as important genetic risk factors in cancer development and their functions can be affected by polymorphic sites, we investigated the effects of PD-1 rs2227981, rs2227982, rs36084323 and PDL-1 rs2282055, rs822336 gene polymorphisms on colorectal cancer (CRC) risk and prognosis in Turkish subjects. METHODS AND RESULTS: Our study group consisted of 5-FU or Capacitabine prescribed CRC diagnosed patients and healthy controls. Genotype analyses of PD1 and PDL-1 polymorphisms were performed with Agena MassARRAY platform. rs36084323 CT genotype frequency was found to be higher in controls compared to cases (p < 0.001). rs36084323 CT genotype was highly associated with reduced CRC risk compared to CC genotype (OR 0.068, 95% CI 0.022-0.211, p < 0.001). In adjusted analysis, rs2282055 GG genotype was found to be associated with reduced CRC risk (OR 0.271, 95% CI 0.078-0.940, p = 0.040). rs2282055 TT genotype was found to be related to longer progression-free (Bonferroni corrected Log rank p = 0.013) and overall survival (Bonferroni corrected Log rank p = 0.009) to that of GG genotypes. Patients with rs822336 GC+CC genotypes showed longer overall survival times compared to GG (Log rank p = 0.044). CONCLUSIONS: According to our results, PD-1 rs822336 G > C polymorphism might be useful in predicting CRC prognosis. PDL-1 rs2282055 T > G polymorphism might be useful in predicting both CRC risk and prognosis. Further studies should be conducted in larger and different populations to clear the roles of PD-1 and PDL-1 polymorphisms in CRC risk and prognosis.

A Case Report with Severe Thrombocytopenia Induced by Axitinib.

Axitinib is an oral, second-generation tyrosine kinase inhibitor that is selective for vascular endothelial growth factor receptors (VEGFR). This agent is approved as monotherapy or in combination with immune checkpoint inhibitors for the treatment of metastatic renal cell carcinoma. Axitinib is associated with a safety profile very similar to other anti-VEGFR inhibitors but usually with fewer hematologic adverse events, due to the selectivity for VEGF. In this report, we presented a rare case of grade 4 axitinib-induced thrombocytopenia, not observed with other antiangiogenic therapies. We discuss the differential diagnostic work-up, the necessary multidisciplinary approach, and the successful management of the case.

Evaluation of the genomic alterations in the androgen receptor gene during treatment with high-dose testosterone for metastatic castrate-resistant prostate cancer.

INTRODUCTION: Castration resistant prostate cancer (CRPC) has been characterized by a reactivation of the androgen receptor (AR) signaling pathway via alterations in androgen metabolism and AR aberrations. High-dose testosterone (HDT) is emerging as an active treatment in metastatic CRPC, however, biomarkers of response are unknown. We hypothesized that responses to HDT might impact the genomic expression of AR alterations found in circulating-tumor DNA (ctDNA). METHODS: Retrospective analysis of mCRPC patients treated with HDT (testosterone cypionate q 2-4 weeks) with available clinical and somatic genomic data using a commercially available assay (Guardant360, Redwood City, CA). Clinical outcomes included PSA response (PSA50), time to PSA progression (TPP) and safety. RESULTS: A total of 33 mCRPC patients were treated with ≥2 testosterone cypionate injections. ctDNA testing revealed alterations in AR (39%), TP53 (48%), and DNA repair genes (12%). HDT was given for median of 4.0 months (95% CI, 2.6-5.3) with 24% of PSA50. Twenty patients were re-challenged with abiraterone (n = 2) or enzalutamide (n = 18) with 30% PSA50. Significant (grade ≥3) adverse events were observed in 5% of patients (grade 4 thrombocytopenia and asthenia). Patients with median baseline ctDNA% of ≥1.10 had numerically worse TPP outcomes and all patients with AR alterations exhibited decreased AR expression post-HDT (n = 9), yet no association between clinical outcomes and ctDNA findings was observed. CONCLUSIONS: HDT led to a decrease in AR copy number and mutations which was independent from responses to therapy. Further understanding of the genomic alterations as potential predictor of response to HDT is needed.

Prognostic Significance of Adjuvant Chemotherapy Induced Amenorrhea in Luminal A and B Subtypes.

OBJECTIVE: In this retrospective study, chemotherapy induced amenorrhea in patients with early stage breast cancer and its effects on survival were investigated. MATERIALS AND METHODS: Two hundred fifty-two patients received adjuvant chemotherapy without ovarian suppression treatment (OST) from 600 premenopausal patients were included in the study. Patients were divided into two groups; with amenorrhea and without, and compared with clinicopathologic features and survival. SPSS version 17 was used. RESULTS: Chemotherapy-induced amenorrhea (CIA) was observed in 145 (57.5%) of 252 patients who received no OST during follow-up. The 5-year OS rate of patients with CIA was significantly higher than patients without CIA (p= 0.042, 95.9% vs. 89.7% vs. 158.88 vs. 135.33 months, respectively). In the subgroup analysis, the OS in patients with hormone receptor (+) was significantly higher than in those receptor (-) in patients with CIA (p=0.011, 97.5% vs. 90.9% vs. 162.13 vs. 126.16 months, respectively). The OS was significantly longer in the luminal A molecular subtype than in those with luminal B molecular subtype, in patients with CIA, but the difference was not significant in patients without CIA (p=0.027 vs. p=0.074, respectively). CONCLUSION: As a conclusion; survival advantage of the chemotherapy induced amenorrhea more pronounced with hormone receptor positivity, lymph node involvement, and advanced disease over patients who do not develop amenorrhea. This advantage of amenorrhea development further prolongs survival compared with luminal B in the luminal A molecular subtype.

Synchronous and metachronous bilateral breast cancer: A long-term experience.

PURPOSE: The objective of this study was to assess the demographic, pathologic and survival characteristics of patients who were diagnosed as having bilateral breast cancer. METHODS: A review was conducted of the records pertaining to patients who presented to our clinic and were diagnosed as having breast cancer. Any second cancer diagnosed within 12 months of initial diagnosis was defined as synchronous bilateral breast cancer. Assessment included treatments administered to the patients and survival rates, as well as their demographic, reproductive and pathologic features. RESULTS: The total number of patients who were diagnosed as having bilateral breast cancer in the context of the present study was 99. Among the patients with synchronous breast cancer, the median age at the time of initial diagnosis was found as 57 years. The median age of the discovery of first tumor among the patients with metachronous tumor was 52 years and the median age of second tumor detection was 59 years. Family history in metachronous tumor was significantly greater (p=0.041). The median time of metachronous cancer incidence was 96 months. The length of disease-free period among the patients with synchronous tumor was 126.3 months, whereas it was 243.7 months in those with metachronous tumor (p=0.041). CONCLUSION: The incidence rate of synchronous breast tumors has been rising thanks to growing awareness and the leading-edge imaging methods. The fact that the second tumor developed after more than 5 years among the patients with metachronous cancer gave rise to the increased rate of survival.

What is the Importance of Body Composition in Obesity-related Depression?

OBJECTIVE: It is known that depression is common in obese individuals. Besides the effects of obesity, pathogenic effects of increase in visceral and abdominal fat mass on depression are also being investigated. Our study aimed to show the relationship between visceral fat percentage detected with practical methods and the presence and severity of depression. MATERIALS AND METHODS: Our study included 104 obese patients and 50 healthy controls. In all individuals, the severity of depression was assessed using the Beck Depression Inventory (BDI). Anthropometric measurements, visceral fat percentage, and body fat percentage were measured using the bioelectric impedance method. RESULTS: The mean age was 51.5±12.3 years, and 65 participants (62.5%) were women. BDI scores were statistically higher in the obese group than in the control group (23.1±10.9 and 12.1±9.4, p<0.001). In the obese group, 63.5% of patients were depressed, and in the control group, this was 24%. Women were more depressed in the obese group, but there was no significant difference between men and women in the control group. Body fat percentage was the highest correlating parameter with depression severity. Positive correlation was found between depression severity and body mass index, waist circumference, hip circumference, and visceral fat percentage. In the logistic regression analysis, obesity was found as an independent risk factor for depression (OR: 4.84, 2.1-10.7, p<0.001). CONCLUSION: According to the results of our study, obesity is a significant and independent risk factor for depression. Obesity type and body composition are important factors that determine the severity of depression.

The Prognostic Impact of Molecular Subtypes and Very Young Age on Breast Conserving Surgery in Early Stage Breast Cancer.

BACKGROUND: Premenopausal breast cancer with a triple-negative phenotype (TNBC) has been associated with inferior locoregional recurrence free survival (LRFS) and overall survival (OS) after breast conserving surgery (BCS). The aim of this study is to analyze the association between age, subtype, and surgical treatment on survival in young women (≤40 years) with early breast cancer in a population with a high rate of breast cancer in young women. METHODS: Three hundred thirty-two patients ≤40 years old with stage I-II invasive breast cancer who underwent surgery at a single institution between 1998 and 2012 were identified retrospectively. Uni- and multivariate analysis evaluated predictors of LRFS, OS, and disease free survival (DFS). RESULTS: Most patients (64.2%) underwent BCS. Mean age and follow-up time were 35 (25 ± 3.61) years, and 72 months (range, 24-252), respectively. In multivariate analysis, multicentricity/multifocality and young age (<35 years) independently predicted for poorer DFS and OS. Those aged 35-40 years had higher LRFS and DFS than those <35 in the mastectomy group (p=0.007 and p=0.039, respectively). Patients with TNBC had lower OS compared with patients with luminal A subtype (p=0.042), and those who underwent BCS had higher OS than patients after mastectomy (p=0.015). CONCLUSION: Young age (< 35 years) is an independent predictor of poorer OS and DFS as compared with ages 35-40, even in countries with a lower average age of breast cancer presentation. In addition, TNBC in the young predicts for poorer OS. BCS can be performed in young patients with TNBC, despite their poorer overall survival.

Prognostic relevance of sunitinib toxicities and comparison of continuous vs. intermittent sunitinib dosing schedule in metastatic renal cell cancer patients.

AIM OF THE STUDY: Sunitinib-related side effects may develop as a result of the pharmacokinetic pathway affects the of the drug. MATERIAL AND METHODS: Data on mRCC patients were obtained from the hospital archives. Outcomes of patients were evaluated in terms of related prognostic factors, sunitinib adverse events during the treatment, and two different sunitinib dosing schedules. RESULTS: Seventy patients diagnosed with mRCC and treated with sunitinib were analyzed for prognostic factors and survival rates. During the mean follow-up of 33.5 months, 38 (54%) patients were alive and 32 (46%) patients died. The median time of overall survival (OS) and progression-free survival (PFS) was 27 months (12-61) and 19 months (5-45), respectively. In univariate analysis, good prognostic risk group according to the Memorial Sloan-Kettering Cancer Center (MSKCC), hypothyroidism as sunitinib toxicity and patients on sunitinib treatment more than 1 year were favorable prognostic factors for OS. Leukopenia and fatigue as sunitinib toxicity were poor prognostic factors for OS. PFS and OS of the patients were not significantly different when we compared intermittent (4/2) vs. continuous treatment dosing schedules. CONCLUSIONS: As a result of this trial, having hypothyroidism as an adverse effect of sunitinib was a favorable prognostic factor for OS and PFS in mRCC patients. It was also found that 4/2 and continuous dosing schedules of sunitinib did not give rise to different outcomes in mRCC patients.

Chronomodulated oxaliplatin plus Capecitabine (XELOX) as a first line chemotherapy in metastatic colorectal cancer: A Phase II Brunch regimen study.

PURPOSE: The aim of this study was to evaluate safety and toxicity of chronomodulated capecitabine administered in the morning and at noon according to a specific time schedule (Brunch Regimen: Breakfast and Lunch) as a part of first-line XELOX chemotherapy in patients with metastatic colorectal cancer. METHODS: A total of 30 treatment-naïve colorectal cancer patients with metastatic disease were included. Oxaliplatin 130 mg/m(2) on day 1 plus chronomodulated oral capecitabine 2000 mg/m(2) per day were administered (50 % dose at 8:00 a.m. and 50 % dose at 12:00 noon on days 1-14, every 21 days). All adverse events, treatment responses and survival were evaluated. In addition, pharmacokinetic profile of capecitabine was examined in a subset of 5 patients. RESULTS: Median age was 57.1 years (range 32-77 years). Median follow-up was 19 months (range 3-36 months). Three patients (10 %) had complete response, 13 patients (43.3 %) had partial response and 4 patients (13.3 %) had stabile disease. Ten patients had progressive disease at their first evaluation (33.3 %). The median progression-free survival (PFS) was 10 months (range 2-36 months). There were no grade 4 toxicities. One patient (3.3 %) had grade 3 neutropenia. Hand-foot syndrome developed in three patients (10 %): 6.6 %, grade 1 and 3.3 %, grade 2. CONCLUSIONS: Chronomodulated XELOX seems to represent a promising therapeutic option in the first-line treatment of metastatic colorectal carcinoma due to good tumor control and favorable toxicity profile. Phase III randomized trials are required to assess the actual clinical efficacy and side effect profile of this regimen.

Dramatic Response to Catumaxomab Treatment for Malign Ascites Related to Renal Cell Carcinoma With Sarcomotoid Differentiation.

Refractory malignant ascites (MA) is a common complication in cancer patients. Renal cell carcinoma (RCC) is rarely present with peritoneal ascites, which is commonly associated with carcinomas of the gastrointestinal and female reproductive tracts; including especially ovarian high-grade serous carcinoma. Currently, chemotherapy and paracentesis represent the most widely used methods to relieve the symptoms. Recently, intraperitoneal therapy with catumaxomab-a trifunctional hybrid antibody-has been introduced for the treatment of MA. The benefit of this treatment has been demonstrated in patients with distinct abdominal malignancies. In this case report, we present the first case of successful catumaxomab treatment against MA in a patient with advanced RCC with sarcomatoid differentiation. After the second administration of catumaxomab, paracentesis became no longer necessary. Catumaxomab might represent a safe treatment option for MA in the course of metastatic RCC with sarcomatoid differentiation.

A Rare Case of Sunitinib-Induced Hyperammonemic Encephalopathy and Hypothyroidism in Metastatic Renal Cell Carcinoma.

Sunitinib has become a standard treatment agent for metastatic renal cell carcinoma (RCC) for several years. However, various adverse events have been reported. We present a rare adverse effect of hyperammonemic encephalopathy induced by sunitinib. A 66-year-old woman with metastatic RCC referred to the emergency department with confusion that developed 14 days after the initiation of 50 mg/d of sunitinib. Her serum ammonia and thyroid-stimulating hormone levels were markedly elevated (146 µg/dL and 27.27 µIU/mL, respectively). Sunitinib was discontinued, and an enema with lactulose and L-thyroxine were administered. Her mental status and neurologic symptoms were normalized 7 days after the treatment. Serum ammonia level decreased to 61 µg/dL and thyroid stimulating hormone level decreased 22.34 µIU/mL. The incidence of sunitinib-induced hyperammonemia is rarely reported. The relationship between sunitinib and the development of hyperammonemia is not well understood, and the mechanism is unclear. Sunitinib-induced hyperammonemia is very rare, and to the best of our knowledge, this is fourth case hyperammonemia and first case hyperammonemic encephalopathy with hypothyroidism as an adverse effect. Therefore, it is important for clinicians to be aware of hyperammonemia that can occur in several days after the initiation of sunitinib treatment in metastatic RCC.

Trichomegaly Induced by Cetuximab: Case Series and Review the Literature.

Trichomegaly is a rare side effect of epidermal growth factor receptor inhibitors. We present here 4 patients who treated with cetuximab (an epidermal growth factor receptor inhibitor) for metastatic colorectal cancer. All of the cases were treated with cetuximab 500 mg/m biweekly in combination protocol. The mean period from the start of the treatment until the development the trichomegaly was 4.75 (3-6) months. In all of the patients after the end of the cetuximab therapy, trichomegaly was regressed. Only 1 case resolved with topical treatment that conjunctivitis with trichomegaly. Trichomegaly is an important ocular toxicity of cetuximab that can cause visual discomfort and corneal damages. However, these side effects usually do not require discontinuation of treatment.

PET-MRI Findings of Two Patients with Breast Carcinoma before Treatment.

Integrated positron-emission tomography-magnetic resonance imaging (PET-MRI) is a new hybrid simultaneous imaging modality with higher soft tissue contrast and lower radiation doses compared with PET-CT. Two patients who were referred to our hospital with left breast masses that were pathologically diagnosed as invasive ductal carcinoma. The women were then scanned using the first PET-MRI system in Turkey, which was established in our department. In this case report, we aimed to determine the advantages of PET-MRI in staging, follow-up, neoadjuvant chemotherapy response, and to compare the usefulness of this modality with PET-CT and dynamic contrast-enhanced breast MRI.

The Relationship between Bone Mineral Density and Estrogen Receptor Positivity in Patients with Breast Cancer.

OBJECTIVE: The effect of estrogen on bone mineral density (BMD) and breast cancer has been known for a long time. The aim of this study was to compare of the BMD of patients with breast cancer and healthy individuals, and to investigate the degree of correlation of estrogen receptor (ER) with BMD. MATERIALS AND METHODS: Seventy-one patients with postmenopausal breast cancer and 79 healthy dividuals were included in the study. The patient demographics (age, menopause age, body mass index, number of children, BMD, Z scores, and estrogen status for breast cancer patients) were taken from hospital records. RESULTS: No significant difference was detected between the case and control groups in lumbar region Z scores (p=0.074). At the femur neck, the control group Z scores was higher than patient group (p=0.002). BMI was higher in the patients with breast cancer (p=0.001). There was no statistically significant correlation between ER positivity, BMD, and BMI in ER-positive patients (p=0.495, p=0.8, p=0.846, respectively). There was no difference between the Z scores when the patients were divided into two groups as ER positive and negative (p=0.156, p=0.335, respectively). CONCLUSION: This study revealed that there is no difference in lumbar region Z scores between patients with breast cancer and heathy controls; however, the Z scores were higher in the femur neck in the control group, and the BMI was lower in the patient group. Tumor ER positivity does not positively affect BMD.

Can megestrol acetate induce thrombosis in advanced oncology patients receiving chemotherapy?

BACKGROUND: Megestrol acetate (MA) is a steroid origin medicine often used for control of cachexia in oncologic palliative care. Thrombosis is a common problem in oncology patients. One question is whether MA can cause thrombosis. This retrospective, registry-based analysis was therefore conducted to assess thrombotic processes in oncology patients using MA concurrent with chemotherapy. MATERIALS AND METHODS: Data on oncology patients at the metastatic stage using MA were obtained from the archives of our center. Outcomes of patients were evaluated for thromboembolic events (VTEs) during treatment. RESULTS: Ninety-seven oncology patients with a median age of 62 (33-84) years were included. During the median follow-up of 17 months, 58 (59.8%) died leaving 39 (31.2%) still alive. Median overall survival (OS) was 19 months (6-180). Mean time of MA use was 8.69 months(±3.53), with a median dose of 160mg (range 160-480mg). Eleven VTEs were detected after MA use, 4 of these in pancreatic cancer cases. The patients with thrombosis non-significantly had worse OS, than those without thrombosis (p=0.106). CONCLUSIONS: This trial revealed that the 11.3% of all patients developed thrombosis,who had been treated with MA and chemotherapy concomittantly. There was no statistically significant difference regarding to occurrence of thrombotic process, among the patients receiving different chemotherapy regimens with MA concomittantly. Pancreatic cancer seemed to be related to thrombosis rather than MA use.