Recommendations for cyclin­dependent kinase 4/6 inhibitor treatments in the context of co­morbidity and drug interactions (Review).

Breast cancer is most frequently diagnosed among women aged 65-74 years and the prevalence of comorbidities in elderly patients with breast cancer is 32.2%. In addition, polypharmacy is quite common in these patients. Understanding the interaction between breast cancer treatment modalities and comorbidities is important, particularly in elderly patients, as comorbidities affect the choice of appropriate treatment and are independent risk factors for survival. A total of three oral cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), palbociclib, ribociclib and abemaciclib, notably prolonged progression-free survival when combined with endocrine therapy (ET), compared with ET alone in patients with advanced breast cancer (ABC). The present review article therefore addressed the safety, tolerability and toxicity of CDK4/6i treatment in ABC management, compiled real-world data on how multiple clinical and pharmacological features may affect the choice of these drugs and provided practical recommendations for clinical approaches. Before starting treatment with CDK4/6i drugs, all ongoing medical conditions should be inventorized and re-graded, and examination should be performed for any additional disease that the patient may not be aware of. It is also important to obtain a detailed history of concomitant drugs, including prescription and over-the-counter drugs, vitamins, supplements and herbal products. In addition, patients should be advised to consult their oncologist before starting any new medication.

Prognostic values of various hematological variables as markers of systemic inflammation in metastatic lung cancer.

BACKGROUND: Chronic state of inflammation is an important factor in advanced cancer which is used by tumor cells for maintaining survival and growth. Hematological parameters such as neutrophil/lymphocyte ratio (NLR), thrombocyte/lymphocyte ratio (TLR), and lymphocyte/monocyte ratio (LMR) are reliable indicators of systemic inflammation. We aimed to elucidate the effect of hematological parameters and clinical features of patients on the prognosis of advanced-stage non-small cell lung cancer (NSCLC). METHODS: We included 102 Stage IV NSCLC patients who presented to the oncology clinic between 2010 and 2016. Pretreatment clinical parameters and NLR, TLR, and LMR were retrieved from the medical records. The cutoff values, calculated with receiver operating curve analysis, for NLR, LMR, and TLR were 2.5, 3, and 183, respectively. All patients were divided into two groups according to cutoff values and analyzed accordingly. RESULTS: Median overall survival and progression-free survival were 10 and 6 months, respectively. In univariate analysis, high NLR, high TLR, and low LMR were found to be significantly associated with survival. Among clinical parameters having eastern cooperative oncology group performance score 0-1, older age (≥70 years) single metastatic disease was prognostic. In multivariate Cox regression analysis, only the number of metastatic lesions and LMR were found to be independent predictors for survival. CONCLUSION: Among hematological parameters, only LMR was found to be an independent predictor of survival in patients with advanced-stage NSCLC.

Antihormonal treatment associated musculoskeletal pain in women with breast cancer in the adjuvant setting.

PURPOSE: Antihormonal treatment is an effective therapy in the adjuvant setting. However, musculoskeletal pain is a common adverse effect encountered in patients receiving this treatment. We aimed to evaluate the risk factors for the development of antihormonal treatment-associated musculoskeletal pain (AHAMP) and its impact on the health-related quality of life (HRQOL). PATIENTS AND METHODS: A cross-sectional survey of 78 consecutive breast cancer patients receiving adjuvant antihormonal treatment for early-stage breast cancer in an academic medical oncology clinic was conducted. AHAMP was assessed by Health Assessment Questionnaire (HAQ) and 10 cm visual analog scale (VAS). HRQOL was assessed by self-administered short form 36 and Functional Assessment of Cancer Therapy-Breast subscale surveys. RESULTS: AHAMP was found to be present in 37 (47.7%) patients. In multivariate regression analysis, having a normal body mass index (<30 kg/m(2)), cigarette smoking, and low serum vitamin D level (20 ng/mL) were found to be independent risk factors. In HRQOL assessment, physical and mental scores were found to be significantly lower in patients with joint arthralgia. CONCLUSION: AHAMP has an adverse effect on the quality of life of breast cancer patients receiving adjuvant antihormonal treatment, and assessment of predictive factors is important for identification of patient groups at risk of developing this condition.

Recurrent squamous cell carcinoma of the skin treated successfully with single agent cetuximab therapy.

Recurrent squamous cell carcinoma of the skin is a rare but difficult to treat condition. Frequently, the disease presents itself in elderly patients with poor performance status and bearing many comorbidities, thus the decision to administer systemic chemotherapy becomes difficult to make. In addition, current chemotherapeutic protocols response rates are far from satisfactory. Recently cetuximab, a chimeric antibody against epidermal growth factor receptor, is increasingly being reported as an alternative treatment. We therefore report this case of a recurrent squamous cell carcinoma of the skin in an elderly woman with poor performance status and who had an excellent clinical response to single agent cetuximab therapy with complete resolution of the disease and minimal toxicity during the course of the treatment to provide evidence for future prospective clinical trials.

Review of the current role of targeted therapies as maintenance therapies in first and second line treatment of epithelial ovarian cancer; In the light of completed trials.

Late and recurrent stage ovarian cancer has a high mortality and low response rate to therapy beyond first line treatment. Although first line platinum/taxane based regimens have a satisfactory response rate eventually in most cases disease recurrence is common and second-line treatments are not curative. Delaying progression or recurrence is the main goal of current ongoing clinical studies by means of establishing an effective maintenance regimen with acceptable toxicity profile. Clearly, the persistence of dormant and drug-resistant cells after front-line treatments results in the inability to cure the disease. Over the past several years, the idea of prolongation of therapy for ovarian cancer has garnered clinical attention and academic debate. As a result of a greater understanding of the molecular pathways involved in carcinogenesis and tumor growth, a large number of potential therapeutic targets have been identified and drugs to block receptors, ligands or pathways are being developed. Currently, numerous clinical trials with targeted agents have just been completed or are ongoing involving patients achieving a complete or durable response after first-line and beyond the first line chemotherapy in order to evaluate the efficacy of different therapeutic approaches in terms of progression-free survival and overall survival.

Retrospective evaluation of totally implantable venous access port devices: early and late complications.

PURPOSE: The role totally implantable vascular devices (TIVAD) have an important role in providing care to cancer patients who require continuous or frequent venous access route either for their primary or supportive care treatments. This retrospective study aimed to analyze the efficacy of TIVAD and device-related complications. METHODS: A total of 324 consecutive patients (185 male,139 female, median age 56 years, mean 48 ± 10.91; min:16, max:87) who were implanted with TIVAD between January 2012 - May 2014 were included. We retrospectively assessed all TIVAD complications and focused on early and late complications. RESULTS: A total of 324 devices were implanted successfully without major complications. The overall complication rate was 33.95% )N=110). Of them, 87 (26.85%) were early and 23 (7.09%) were late complications. In total, 39 (11.23%) catheters were removed, in 8 (2.30%) patients due to complication and in 31 (9.56%) due to the end of treatment. CONCLUSION: Most of the complications of TIVAD were early without requiring removal. Port catheters for chemotherapy are safe and well tolerated with acceptable complication rates.

Clinical outcome of Turkish metastatic breast cancer patients with currently available treatment modalities--single center experience.

BACKGROUND: Breast cancer is the most common malignancy and the second leading cause of cancer-related death among women in the developed countries. Despite advances in screening, improved local therapies and adjuvant systemic treatments, median survival of metastatic breast cancer patients (MBC) is in the range of 2-3 years at most. We aimed to investigate whether the prognostic factors and therapeutic responses of our Turkish patients are similar to those in the literature. MATERIALS AND METHODS: We reviewed the medical records of MBC patients who had been treated in our institution between 1999-2009 and analyzed their clinicopathological features and survival outcomes retrospectively. RESULTS: A hundred and sixty patients were included. Median age was 47 (23-82), median follow up was 24 (2-186) months. At the time of diagnosis 59% of patients were under the age of 50 and 46% were postmenopausal. The majority (37%) had multiple sites of metastases. Forty percent received endocrine therapy and 40% chemotherapy as first line metastatic treatment. Thirty (20%) patients were treated with molecular targeting agents like trastuzumab, lapatinib and sunitinib, frequently combined with a chemotherapy agent. Five-year overall survival (OS) was 32% and median OS was 38 months for the whole group. Five year progression free survival (PFS) was 10% and median PFS was 10 months. Menopausal status, hormone receptor expression and disease free status had a significant impact on overall survival in the multivariate analysis (p 0.018, p 0.018 and p:0.003, respectively). CONCLUSIONS: All our patients were treated with the modern oncologic therapies recommended by the international guidelines. From our data, MBC patients live up to 3-4 years, indicating that further improvement beyond that requires development of new treatment modalities. The survival outcomes of our patients were consistent with the data reported in the literature.

Primary renal carcinoid: treatment and prognosis.

Primary carcinoid tumors of the kidney are very rare, malignant tumors consisting of neuroendocrine cells. The pathogenesis of renal carcinoid is unclear because neuroendocrine cells are not normally found in adult renal parenchyma. Electron microscopy, immunohistochemistry, octreotide scan, positron emission tomography along with conventional radiographic imaging techniques are used in diagnosis and follow-up. Presenting symptoms usually include flank pain and haematuria. Early stage disease is treated with surgery only. However, randomized trials are lacking because of the very low number of reported cases. Thus, the role of debulking surgery, chemotherapy, radiotherapy, octreotide and targeted therapy in the management of advanced disease remains an open question. In this article the clinicopathologic features and prognosis of this very rare disease along with treatment outcomes of the reported cases are reviewed. In addition, we report a new case of a metastatic primary renal atypical carcinoid tumor treated with octreotide therapy.

Serum thymidine kinase 1 levels correlates with FDG uptake and prognosis in patients with non small cell lung cancer.

CONTEXT: TK1 found to be elevated biomarker in many solid cancers. OBJECTIVES: The study aimed to assess the prognostic significance of a serum TK1 in patients with metastatic NSCLC. METHODS: The study included 48 consecutive patients, newly diagnosed with metastatic NSCLC, and 10 healthy volunteers. Serum TK1 activity determined by ELISA method. RESULTS: Patients with a bTK1 level >156 Du L(-1) had significantly shorter survival. TK1 level showed a strong correlation with primary tumor SUV(max). DISCUSSION AND CONCLUSION: The magnitude of maximum fluorodeoxyglucose uptake in primary tumors and the serum TK1 level in patients with metastatic NSCLC were found to be independent prognostic predictors of overall survival.

Clinical outcome of breast cancer patients with N3a (≥10 positive lymph nodes) disease: has it changed over years?

It has been shown that breast cancer patients with N3a (10 positive lymph nodes) had a poor prognosis. We planned to investigate the clinical outcome BC patients who presented with N3a disease and had no evidence of systemic metastasis at the time of diagnosis. We made a retrospective chart review of breast cancer patients who had ≥10 positive lymph nodes and received adjuvant systemic therapy in Marmara University Hospital between 1998 and 2008. We recorded clinical, pathologic and treatment characteristics of the patients and analyzed the survival outcome. We identified 73 patients with N3a disease who were treated in Marmara University Hospital between 1998 and 2008. The median age was 52. Most (75%) of the patients had invasive ductal histology, 75% had T2/T3 tumors, 36% had grade 3 tumors. The median number of metastatic lymph nodes was 15. Estrogen and progesterone receptors were both positive in 61% and both negative in 16+ tumors. Her-2/neu status was assessed in 68% of the tumors; 18% of patients had 3+ and 50% had negative scores. Six patients had triple negative tumors. All patients except one received adjuvant chemotherapy and radiotherapy. Seventy-four percent of patients received anthracycline/taxane-based chemotherapy. Fifty-nine patients received adjuvant endocrine therapy, 42% them received aromatase inhibitors. Five of the 13 Her-2 positive patients received adjuvant trastuzumab. With a median follow-up of 47 months, 5-year disease and overall survival rates were 66 and 81%, respectively. Twenty-four patients had relapsed and 14 patients died. Her-2 status and the number of lymph nodes (<20 vs. ≥20) had significant impact on disease-free survival in the univariate analysis (P=0.03 and 0.05, respectively) and Her-2 retained its significant impact on disease-free survival in the multivariate analysis (P=0.05). The prognosis of BC patients with N3a disease has changed favorably in the past decade with the current standards of care.

Recurrent pericarditis as the initial manifestation of Familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever is an autosomal recessive disease largely restricted to certain ethnic groups and presenting with recurrent febrile serositis attacks. Peritonitis, pleuritis, and synovitis are common manifestations; however, the pericardium is rarely affected. CASE REPORT: In this case report, we describe a 25-year-old Turkish woman who presented with recurrent pericarditis of no obvious cause, which eventually responded to colchicine therapy. Using gene mutation analysis to detect the MEFV gene, the patient's condition was finally diagnosed as Familial Mediterranean fever. CONCLUSIONS: Familial Mediterranean fever should be considered in patients with idiopathic recurrent pericarditis unresponsive to nonsteroidal anti-inflammatory medications and corticosteroids. Mutation analyses should be done.

After myocardial infarction carvedilol improves insulin resistance compared to metoprolol.

PRINCIPLES: Both carvedilol and metoprolol have cardioprotective effects and decrease infarct size in myocardium. We compared effects of carvedilol and metoprolol on insulin resistance and serum lipid levels after myocardial infarction. METHODS: Fifty-nine patients aged between 30 and 70 and BMI = 25-30 kg/m2, who were diagnosed with myocardial infarction with ST segment elevation, were considered to be eligible for the study. Patients were randomly allocated to two different therapy protocols. Metoprolol 100 mg bid or carvedilol 25 mg bid was added to their standardized therapy regimen. Baseline to week 4 and 12, fasting blood glucose, serum lipid profile, BMI, C-peptide, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. RESULTS: After 12 weeks of metoprolol therapy HOMA-IR, insulin and C-peptide levels were significantly higher (p < 0.05 for all) and total cholesterol and triglyceride levels decreased significantly (p < 0.05 for all) compared to baseline. After 12 weeks of carvedilol therapy HOMA-IR, insulin and C-peptide (p < 0.05 for all), total cholesterol and triglyceride (p = 0.001 for all) decreased significantly compared to baseline. Carvedilol provided more decrease in total cholesterol and LDL levels than metoprolol (p = 0.043 and p = 0.021, respectively). CONCLUSIONS: In patients after myocardial infarction, carvedilol added to background therapy improved insulin resistance and lipid profile.

The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients.

We assessed the additive effect of dual peroxisome proliferators activated receptors (PPAR) alpha/gamma induction, achieved by the addition of fenofibrate to rosiglitazone, on metabolic control and diabetic dyslipidemia. Fourty type 2 diabetic patients with poor metabolic control who were taking oral antidiabetic agents and/or insulin were included in the study. Patients received 4 mg of rosiglitazone per day for 12 weeks. Later, 200mg of fenofibrate per day was added to the therapy regimen for another 12 weeks. HbA1c, uric acid, serum lipid profile and body mass index (BMI) were assessed at the start and at the 12th and the 24th weeks of the study. BMI values at the 12th and the 24th weeks of the study increased significantly (p<0.01) while for HbA1c levels there was a reduction at the 12th and the 24th weeks of 11% (p<0.001) and 13% (p<0.002), respectively. The change in HbA1c levels after the addition of fenofibrate to the rosiglitazone therapy was not statistically significant. The change in LDL levels with rosiglitazone at the 12th week was not statistically significant while the addition of fenofibrate to rosiglitazone decreased mean LDL levels from 126.8+/-29.6 mg/dL to 106.7+/-26.7 mg/dL (p<0.001). The mean percent reduction in triglyceride levels at the 12th and the 24th weeks were 19% and 33%, respectively (p<0.001). HDL levels increased from 44.59 mg/dL to 50.14 mg/dL (p<0.001) at week 12. A further increase of 16% (p<0.001) was observed after the addition of fenofibrate to rosiglitazone. In type 2 diabetic patients dual PPAR alpha/gamma stimulation by means of concomitant administration of rosiglitazone and fenofibrate improves the atherogenic dyslipidemic profile of these patients with good tolerability.

Comparison of lunch and bedtime NPH insulin plus mealtime insulin Lispro therapy with premeal regular insulin plus bedtime NPH insulin therapy in type 2 diabetes.

AIM: Nonfasting plasma glucose is claimed to be a better marker of diabetic control than fasting plasma glucose in type 2 diabetes. In this study we compared the efficacy and safety profile of two different intensive insulin treatment strategies in patients with uncontrolled type 2 diabetes despite using a twice-daily insulin regimen. METHODS: We studied 60 insulin-treated patients who had uncontrolled type 2 diabetes. The study was a 6-month, open-label, randomised, parallel clinical trial conducted in two diabetes centres. The main end-points for analysis were weekly self-monitored blood glucose readings, HbA1c levels, total daily insulin dose, weight gain and the number of hypoglycaemic episodes. RESULTS: The breakfast 2-h, lunch 2-h and dinner 2-h postprandial glucose values and pre-dinner glucose values were significantly lower in the Lispro group than the regular insulin group. The HbA1c value at the end of the study was significantly lower in the Lispro group (7.3 +/- 0.7%) compared with the regular insulin group (7.7 +/- 0.7%; P<0.05). Mean insulin doses were similar in the treatment groups initially and at the end. There was a statistically significant increase in insulin dose in both groups from baseline to the end of the study (P<0.05). Overall hypoglycaemia rates were comparably low and similar in both groups during the study. CONCLUSIONS: We have shown that mealtime insulin Lispro plus additional lunch and bedtime NPH insulin is superior to premeal regular insulin plus bedtime NPH insulin for overall glycaemic regulation with similar weight gain and comparable rates of hypoglycaemia.

Combination of pentoxifylline with angiotensin converting enzyme inhibitors produces an additional reduction in microalbuminuria in hypertensive type 2 diabetic patients.

OBJECTIVE: To investigate the anti proteinuric effect of pentoxifylline in diabetic patients, we prospectively studied in 25 hypertensive type 2 diabetic patients with persistent microalbuminuria and normal renal function the impact of combining pentoxifylline with an angiotensin converting enzyme inhibitor, lisinopril, on urinary albumin excretion and compared the results with those obtained in a control group of 25 type 2 diabetic patients treated with lisinopril only. MATERIAL AND METHODS: Fifty hypertensive type 2 diabetic patients with persistent microalbuminuria (31 males and 19 females, aged between 47-73 years) were randomly assigned to two groups. Group A received lisinopril 10 mg/day, while group B was given lisinopril 10 mg/day and pentoxifylline 600 mg/day for nine months. There were no significant differences between serum creatinine, HbA1c, blood pressure and urinary albumin excretion in both groups (p > 0.05). RESULTS: Serum creatinine, creatinine clearance, blood pressure, HbA1c levels did not change significantly during the study. Urinary albumin excretion decreased from 228 +/- 28 to 148 +/- 15 mg/day in group A (p < 0.05). In group B urinary albumin excretion decreased from 219 +/- 26 to 128 +/- 12 mg/day (p < 0.05). Pentoxifylline and lisinopril combination caused a significant additional reduction in urinary albumin excretion when compared to lisinopril regimen (p < 0.05). CONCLUSIONS: Our findings suggest that the combination of pentoxifylline with an angiotensin converting enzyme inhibitor in hypertensive type 2 diabetic patients with persistent microalbuminuria causes a significant reduction in urinary albumin excretion and this effect seems independent from blood pressure and glycemic control.

Rhabdomyolysis and severe haemolytic anaemia, hepatic dysfunction and intestinal osteopathy due to hypophosphataemia in a patient after Billroth II gastrectomy.

Hypophosphataemic syndromes lead to appreciable morbidity and mortality. A deficiency or lack of phosphate leads to tissue hypoxia and disruption of cellular function, which may cause severe clinical complications. We present various manifestations of hypophosphataemia; in all cases, diagnosis was delayed due to lack of follow-up. We present the case of a patient with rhabdomyolysis, severe haemolytic anaemia, hepatic dysfunction and intestinal osteopathy due to hypophosphataemia complicated by gastric Billroth II anastomosis surgery. We also review the literature concerning hypophosphataemic conditions. In conclusion, the determination of serum calcium and phosphate levels should be included in the routine follow-up of Billroth II anastomosed patients.