Muhammed Bulent Akinci

Targeting the PD-1 pathway: a new hope for gastrointestinal cancers

Abstract Background: VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most gastrointestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. In this review article, we aim to discuss the efficacy and safety of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in published or reported recent studies. Scope: A literature search was made from PubMed and ASCO Annual Meeting abstracts by using the following search keywords: “nivolumab”, “pembrolizumab”, “avelumab”, “GI cancers” “anti-PD1 therapy” and “anti-PD-L1 therapy”. The last search was on 2 November 2016. The most important limitation of our review is that most of the data on anti-PD-1/PD-L1 therapies in GI cancers relies on phase 1 and 2 trials. Findings: Currently, there are two anti-PD-1 (nivolumab and pembrolizumab) and one anti-PDL1 (atezolizumab) agents approved by FDA. After the treatment efficacy of immune checkpoint blockade was shown in melanoma, renal cell cancer and non-squamous lung cancer, trials which evaluate immune checkpoint blockade in GI cancers are ongoing. Early results of trials have been promising and encouraging for patients with advanced stage gastroesophageal cancer. According to early results of published trials, response to anti-PD1/PD-L1 agents appears to be associated with tumor PD-L1 levels. According to two recently published phase 2 trials, the clinical benefits of immune checkpoint blockade with both nivolumab and pembrolizumab were limited in patients with microsatellite instability (MSI) positive advanced colorectal cancer. However, several phase 2/3 trials are still ongoing. Conclusion: Both pembrolizumab and nivolumab show promising efficacy with acceptable safety data in published trials in GI cancers, especially in refractory MSI positive metastatic colorectal cancer.

Risk Factors for Stage IV Breast Cancer at the Time of Presentation in Turkey

BACKGROUND Breast cancer (BC) is the one of the most common cancers in women. It is also a leading cause of death. Unfortunately, some patients initially present with distant metastases and are diagnosed with stage IV disease that is nearly always, by then, incurable. This retrospective analysis investigated the risk factors for stage IV BC that may underlie such late presentation. MATERIALS AND METHODS In all, 916 patients with BC who visited the medical oncology polyclinic of eight different centres in Turkeybetween December 2011 and January 2013 were analysed. RESULTS A total of 115 patients (12.6%) presented with stage IV disease. In univariate analysis; to comparing these with patients at other stages, no statistical difference was found for median diagnosis age or age at menarche (p=0.611 and p=0.820), whereas age at menopause and age at first live birth were significant (p=0.018 and p=0.003). No difference was detected in terms of accompanying diseases, use of oral contraceptives and hormone replacement therapy, smoking, alcohol consumption and the rate of family history of BC between the patients (p=0.655, p=0.389, p=0.762, p=0.813, p=0.229, p=0.737). However, screening methods were employed less often, the rate of illiteracy was higher, and the rate of other cancers was higher in patients with stage IV BC (p=0.022, p=0.022, p=0.018). No statistical difference was observed between the patients in terms of tumour histopathology, and status of oestrogen receptor, progesterone receptor, or human epidermal growth factor-2 receptor (p=0.389, p=0.326, p=0.949, p=0.326). Grade 3 tumours were more frequent in patients with stage IV disease (p<0.001). On multivariate analysis, risk factors for stage IV breast cancer at the time of presentation were found to be age at first live birth and educational level (p=0.003 and p=0.047). CONCLUSIONS Efforts should be made to perform mammography scans, in particular, at regular intervals through national training programs for all women, particularly those with family histories of breast and other types of cancer, and to establish early diagnosis of BC long before it proceeds to stage IV. Additionally, womens education had better be upgraded. In order to make women aware of BC, national education-programmes must be organised.

Medication Errors in Chemotherapy Preparation and Administration: a Survey Conducted among Oncology Nurses in Turkey

BACKGROUND Medication errors in oncology may cause severe clinical problems due to low therapeutic indices and high toxicity of chemotherapeutic agents. We aimed to investigate unintentional medication errors and underlying factors during chemotherapy preparation and administration based on a systematic survey conducted to reflect oncology nurses experience. MATERIALS AND METHODS This study was conducted in 18 adult chemotherapy units with volunteer participation of 206 nurses. A survey developed by primary investigators and medication errors (MAEs) defined preventable errors during prescription of medication, ordering, preparation or administration. The survey consisted of 4 parts: demographic features of nurses; workload of chemotherapy units; errors and their estimated monthly number during chemotherapy preparation and administration; and evaluation of the possible factors responsible from ME. The survey was conducted by face to face interview and data analyses were performed with descriptive statistics. Chi-square or Fisher exact tests were used for a comparative analysis of categorical data. RESULTS Some 83.4% of the 210 nurses reported one or more than one error during chemotherapy preparation and administration. Prescribing or ordering wrong doses by physicians (65.7%) and noncompliance with administration sequences during chemotherapy administration (50.5%) were the most common errors. The most common estimated average monthly error was not following the administration sequence of the chemotherapeutic agents (4.1 times/month, range 1-20). The most important underlying reasons for medication errors were heavy workload (49.7%) and insufficient number of staff (36.5%). CONCLUSIONS Our findings suggest that the probability of medication error is very high during chemotherapy preparation and administration, the most common involving prescribing and ordering errors. Further studies must address the strategies to minimize medication error in chemotherapy receiving patients, determine sufficient protective measures and establishing multistep control mechanisms.

A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer

Abstract Background: Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinase (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates. Scope: A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; “palbociclib”, “abemaciclib”, “ribociclib”, “cyclin-dependent kinase inhibitors” and “CDK 4/6” in metastatic breast cancer (MBC). The last search was on 10 June 2017. Findings: CDKs and cyclins are two molecules that have a key role in cell cycle progression. Today, there are three highly selective CDK4/6 inhibitors in clinical development – palbociclib, ribociclib and abemaciclib. Palbociclib and ribociclib were recently approved by the US FDA in combination with letrozole for the treatment of MBC in a first-line setting, as well as palbociclib in combination with fulvestrant for hormone-receptor (HR)-positive MBC that had progressed while on previous endocrine therapy according to the PALOMA-1, MONALEESA-2 and PALOMA-3 trials, respectively. In the recently published randomized phase III MONARCH 2 trial, abemaciclib plus letrozole had longer progression-free survival and higher objective response rates with less serious adverse events in advanced HR-positive breast cancer previously treated with hormonal treatment. Conclusion: CDK4/6 inhibition is a new and promising target for patients with hormone-receptor-positive MBC. Both palbociclib and ribociclib showed significant additive benefit for patients receiving first-line treatment for HR-positive, epidermal growth factor receptor-2-negative advanced breast cancer. Palbociclib and abemaciclib also had significant activity in combination with fulvestrant for patients with MBC that progressed on previous endocrine therapy.

Is exon mutation analysis needed for adjuvant treatment of gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are the most common soft tissue sarcoma of the gastrointestinal tract, resulting from an activating mutation of stem cell factor receptor (KIT), and an activating mutation of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase. Most GISTs (90%-95%) are KIT-positive. About 5% of GISTs are truly negative for KIT expression. GISTs have been documented to resistant conventional chemotherapeutics. Due to the KIT activation that occurs in the majority of the cases, KIT inhibition is the primary treatment approach in the adjuvant treatment of metastatic GISTs. Imatinib mesylate is an oral agent that is a selective protein tyrosine kinase inhibitor of the KIT protein tyrosine kinase, and it has demonstrated clinical benefit and objective tumor responses in most GIST patients in phase II and III trials. The presence and the type of KIT or PDGFRA mutation are predictive of response to imatinib therapy in patients with advanced and metastatic disease. Molecular analysis in phase I-II trials revealed significant differences in objective response, progression-free survival, and overall survival between GISTs with different kinase mutations. The aim of this letter is to touch on the need for exon mutation analysis for adjuvant treatment with imatinib in GIST patients.

Neutrophil to lymphocyte ratio--not an independent prognostic factor in patients with the myelodysplastic syndrome.

PURPOSE Neutrophil-to-lymphocyte ratio (NLR) was evaluated as a potential prognostic factor in patients with myelodysplastic syndrome (MDS). MATERIALS AND METHODS Between December 2009 and April 2014, 14 female (35%) and 26 male (65%) MDS patients who were followed up in our hematology clinic were included in the study for NLR during diagnosis. Division was into two groups according to the NLR, and the correlation with mortality was evaluated. The prognostic significance of NLR regarding treatment outcome was also evaluated with adjustment for known confounding risk factors. RESULTS The mortality rate of the patient group was 55%, and median survival was 18 months. There was no significant correlation between mortality and NLR at a median value of 1.8 (p=0.75). Thrombocytopenia was observed to increase mortality (p=0.027), and there was a significant correlation between mortality and pancytopenia (p=0.017). CONCLUSIONS This first study of NLR and mortality did not show any significant correlation . In centres with limited access to genetic evaluation for the presence of pancytopenia and/or thrombocytopenia at the time of diagnosis, a platelet level less than 50?109/l may be poor prognostic markers in MDS patients.

Hospitalization Risk According to Geriatric Assessment and Laboratory Parameters in Elderly Hematologic Cancer Patients

BACKGROUND Utilizing geriatric screening tools for the identification of vulnerable older patients with cancer is important. The aim of this study is to evaluate the hospitalization risk of elderly hematologic cancer patients based on geriatric assessment and laboratory parameters. MATERIALS AND METHODS In this cross sectional study 61 patients with hematologic malignancies, age 65 years and older, were assessed at a hematology outpatient clinic. Standard geriatric screening tests; activities of daily living (ADL), instrumental activities of daily living (IADL), Mini Nutritional Assessment (MNA), Mini Mental State Examination (MMSE), timed up and go test (TUG), geriatrics depression scale (GDS) were administered. Demographic and medical data were obtained from patient medical records. The number of hospitalizations in the following six months was then recorded to allow analysis of associations with geriatric assessment tools and laboratory parameters. RESULTS The median age of the patients, 37 being males, was 66 years. Positive TUG test and declined ADL was found as significant risk factors for hospitalization (p=0.028 and p=0.015 respectively). Correlations of hospitalization with thrombocytopenia, vitamin B12 and folic acid deficiency were statistically significant (p=0.004, p=0.011 and p=0.05 respectively). CONCLUSIONS In this study, geriatric conditions which are usually unrecognized in a regular oncology office visit were identified. Our study indicates TUG and ADL might be use as predictive tests for hospitalization in elderly oncology populations. Also thrombocytopenia, and vitamin B12 and folic acid deficiencies are among the risk factors for hospitalization. The importance of vitamin B12 and folic acid vitamin replacement should not be underestimated in this population.

Serum 25-hydroxy vitamin D status is not related to osteopenia/osteoporosis risk in colorectal cancer survivors.

BACKGROUND The incidence of colorectal cancer increases with vitamin D deficiency as shown in recently published studies. In addition, prospective investigations have indicated that low vitamin D levels may be associated with increased mortality of colorectal cancer, especially in stage III and IV cases. However, the exact incidence of vitamin D deficiency and the relation between vitamin D deficiency and osteopenia/osteporosis is still not known. The aim of this study is to identify severity of vitamin D deficiency and absolute risk factors of osteopenia/osteoporosis in colorectal cancer survivors. MATERIALS AND METHODS A total of 113 colorectal cancer survivors treated with surgery and/or chemotherapy ± radiotherapy were recruited from medical oncology outpatient clinics during routine follow-up visits in 2012-2013. Bone mineral densitometry (BMD) was performed, and serum 25-OH vitamin D levels were also checked on the same day of the questionnaire. The patients was divided into 2 groups, group A with normal BMD and group B with osteopenia/osteoporosis. RESULTS The median age of the study population was 58 (40-76). Thirty (30.0%) were female, whereas 79 (70.0%) were male. The median follow-up was 48 months (14-120 months). Vitamin D deficiency was found in 109 (96.5%); mild deficiency (20-30 ng/ml) in 19 (16.8%), moderate deficiency (10-20 ng/ml) in 54 (47.8%) and severe deficiency (<10 ng/ml) in 36 (31.9%). Osteopenia was evident in 58 (51.4%) patients whereas osteoporosis was noted in 17 (15.0%) . Normal BMD was observed in 38 (33.6%). No apparent effects of type of surgery, presence of stoma, chemotherapy, radiotherapy and TNM stage were found regarding the risk of osteopenia and osteoporosis. Also, the severity of the vitamin D deficiency had no effect in the risk of osteopenia and osteporosis (p=0.93). In female patients, osteopenia/osteoporosis were observed in 79.5% patients as compared to 60.7% of male patients (p=0.04). CONCLUSIONS In our study, vitamin D deficiency and osteopenia/osteoporosis was observed in 96.5% and 66.4% of colorectal cancer survivors, respectively. There is no defined absolute risk factor of osteopenia and osteoporosis in colorectal cancer survivors. To our knowledge, in the literature, our study is the first to evaluate all the risk factors of osteopenia and osteoporosis in colorectal cancer survivors.

Selective internal radiation therapy in untreated patients with unresectable liver dominant metastatic colorectal cancer.

10.2217/fon-2016-0276

Role of obesity on the efficacy of exemestane plus ovarian suppression in hormone receptor-positive premenopausal breast cancer

10.2217/FON.15.6