Mehmet Ali Nahit Şendur

Predictors of Blood Pressure Reduction With Nocturnal Continuous Positive Airway Pressure Therapy in Patients With Obstructive Sleep Apnea and Prehypertension

Previous studies showed that treatment of obstructive sleep apnea syndrome (OSAS) with continuous positive airway pressure (CPAP) significantly reduced the blood pressure (BP) in hypertensive patients. We investigated the predictors of BP change in normotensive patients with OSAS who underwent CPAP. A total of 24 patients with OSAS (19 male; age: 48.7 ± 10.4 years) were enrolled. The 24-hour mean BP (24 hMBP), subjective sleepiness, fasting venous blood samples, and anthropometric measurements were assessed at baseline, 6th week and 12th week of CPAP treatment. The 24 hMBP fell at 12 weeks from 89.2 ± 8.4 to 82.9 ± 7.3 mm Hg (P < .0001) irrespective of the severity of disease. Also, both daytime and nighttime BP showed significant reduction after CPAP. Male gender, Epworth sleepiness scale, body mass index, smoking, alcohol use, and baseline 24 hMPB were the independent predictors of a fall in 24 hMBP. The CPAP therapy may provide benefit even in the absence of overt hypertension by reducing both daytime and nighttime BP.

Statin use may improve clinicopathological characteristics and recurrence risk of invasive breast cancer

To the editor, Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors, are widely used in both primary and secondary prevention of cardiovascular diseases [1]. Statins, by interrupting the pathway of mevalonate, inhibit several critical pathways for cancer growth and progression. In vitro studies showed that statins have antiproliferative, antiapoptotic, antiangiogenetic and immunomodulatory effect which prevent cancer growth [2]. A meta-analysis of randomized controlled trials failed to show reduced risk of breast cancer with statin use, but a meta-analysis of case controlled studies has showed reduced risk of breast cancer and any other cancer risk [3]. As a result of the published studies and meta-analyses, there were contradictory results with statin use on breast cancer risk. But the effect on clinical and pathological properties of breast cancer with statin use was not known exactly. In this study, we aimed to investigate retrospectively the effect of statin usage on clinicopathological characteristics and recurrence risk of patients with

Brugada syndrome with aborted sudden cardiac death related to liquorice-induced hypokalemia.

Objective: It was the aim of this study to report an aborted cardiac arrest due to ventricular fibrillation and electrocardiographic changes consistent with Brugada syndrome due to liquorice-induced hypokalemia. Clinical Presentation and Intervention: Ventricular fibrillation was witnessed in a 50-year-old woman who was admitted to our emergency department with a history of liquorice ingestion, a herbal product. After stopping liquorice ingestion, the Brugada-like electrocardiographic pattern changed progressively with potassium replacement. A diagnosis of Brugada syndrome was made after the ajmaline challenge test. The patient was discharged with an implantable cardioverter defibrillator and had an uneventfull follow-up. Conclusion: This report illustrates the importance of the investigation for herbal medications in the detailed history of a patient in the cases of electrolyte disturbances and the potential role of hypokalemia in the induction of malignant arrhythmia in Brugada syndrome.

Comparison of the long term cardiac effects associated with 9 and 52 weeks of trastuzumab in HER2-positive early breast cancer

Abstract Purpose: Trastuzumab induced cardiotoxicity (TIC) was defined as the most serious side effect. Long term cardiac effects of trastuzumab are still not known, thus we aimed to compare the long term cardiac effects of adjuvant trastuzumab therapies of HER2-positive breast cancer according to the treatment duration. Methods: Patients who completed adjuvant trastuzumab treatment at least 6 months before for the adjuvant setting in HER2-positive breast cancer were included in the study. A total of 164 patients were included in this study: 108 and 56 patients were treated with 9 weeks and 52 weeks of trastuzumab, respectively. The main limitation of our study is that due to the cross-sectional evaluation of cardiac biomarkers we cannot predict the status of baseline cardiac biomarkers of this population. Results: The median follow-up of the study was 32 (10–95) months. The accompanying chronic diseases were similar in both groups. Baseline left ventricular ejection fraction (LVEF) was 65.5 ± 3.4% vs 67.1 ± 4.5% in the 9 weeks and 52 weeks trastuzumab treatment groups, respectively (p = 0.13). Symptomatic heart failure was not observed during trastuzumab treatment in either group. Trastuzumab induced cardiotoxicity (TIC) was observed in 2 (1.9%) and 17 (30.3%) patients in the 9 and 52 weeks trastuzumab treatment groups, respectively (p < 0.001). After a median 24 months of follow-up from the last dose of trastuzumab, mean LVEF values were similar between the two treatment arms (p = 0.29). In the subgroup analyses, mean LVEF values were significantly lower in patients who developed TIC compared to those who did not develop TIC (61.9 ± 3.6% vs 64.4 ± 2.6%, p = 0.04). Average mean LVEF loss from baseline was significantly higher in patients who developed TIC compared to those who did not develop TIC (10.0 ± 6.0% vs 1.5 ± 6.2%, p < 0.001). Cardiac biomarkers were similar in both treatment groups. In the subgroup analyses serum High-sensitivity C-reactive protein (hs-CRP) and prohormone brain natriuretic peptide (pro-BNP) levels were significantly higher in patients who developed TIC compared to those who did not develop TIC. Conclusions: TIC was observed to be significantly higher in the 52 weeks trastuzumab group. At the end of 32 months of follow-up mean LVEF values and cardiac biomarkers were similar between the two treatment groups. In the subgroup analyses, significant LVEF loss and higher cardiac biomarkers which show cardiac damage in patients who developed TIC can be permanent in some of the patients and long term cardiac damage may be underestimated.

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.

Dermatomyositis complicated with a soft tissue sarcoma

To the Editor, The association between malignancy and dermatomyositis (DM) was known for nearly a century, but its significance remained unclear. The incidence of the malignancy increased five- to sevenfold compared to general population [1]. The peak incidence of malignancy diagnosis occurs within the 2 years of the diagnosis of dermatomyositis. The most common cancers associated with dermatomyositis include ovarian, lung, pancreatic, breast, and stomach cancer [2]. We present here a case of dermatomyositis and soft tissue sarcoma at the same time at diagnosis. In our review of the literature, coincidence of dermatomyositis and soft tissue sarcoma was not reported before.

Small cell carcinoma of the urinary bladder with hypercalcemia.

To the editor, Small cell carcinomas are usually seen in the lung and represents approximately 16% of lung cancers [1]. Small cell carcinoma of the urinary bladder is a rare tumor accounting for less than 1% of all bladder tumors and represents 0.1–0.4% of all small cell carcinomas [2]. Small cell carcinomas in the bladder usually have an aggressive clinical course, often presenting with metastases at the time of diagnosis. Although most clinicians believe that optimal treatment for small cell carcinoma of the bladder is a combination of surgical resection and adjuvant chemotherapy, the surgical resection is not curative, with adjuvant chemotherapy extending patient survival. This letter presents a case of small cell carcinoma of the bladder with hypercalcemia, which is rarely seen. A 52-year-old woman presented with acute painless hematuria and backache. Physical examination revealed a very ill patient with common pain and distended urinary bladder. The patient had been a smoker for 33 years. Laboratory evaluation showed a mild anemia with microscopic hematuria. Abdominal tomography revealed a 50 9 36 mm hypoechoic mass in the left lateral side of urinary bladder. The patient was operated and radical cystectomy with pelvic lymphadenectomy was performed. The pathology revealed poor differentiation small cell carcinoma with lymph node metastases. Whole body–bone scintigraphy was normal, and no distant metastasis was observed. The patient was treated with cisplatin–etoposidbased chemotherapy. After three cycles of chemotherapy, patient readmitted with skeletal pain and hypercalcemia. Laboratory results showed calcium level as high as 14.4 mg/dl (normal range 8.6–10.2 mg/dl) with normal parathyroid hormone level and renal functions. Further works up including bone scan showed that bilateral femoral head uptake compatible with metastases. By zoledronic acid treatment, the patient’s serum calcium level was controlled. The local radiotherapy was given to the bilateral head of femur. And in the second step, cyclophosphamid–adriamisin–vincristin (CAVi) chemotherapy was given. Then, the patient was still treated with CAVi protocol and zoledronic acid monthly for 4 months. Hypercalcemia associated with certain types of malignancy is a well-known finding. Hypercalcemia has been reported to occur in up to 20–30 percent of patients with cancer at some time during the course of their disease [3]. The detection of hypercalcemia in a patient with cancer signifies a very poor prognosis; approximately 50 percent of such patients die within 30 days [4]. Small cell carcinoma rarely presented with hypercalcemia. Hypercalcemia associated with cancer results by prostaglandin, osteoclast stimulating factor, parathormone-like substance, or pseudohyperparathyroidism [5]. Genitourinary small cell carcinoma has a poor prognosis, and radical surgeries with cisplatin-based chemotherapy are the only factors improved survival [6]. The first case of small cell carcinoma of urinary bladder reported in 1981, the only small cell carcinoma of urinary bladder with hypercalcemia reported in 1985 by Reyes et.al [7]. Small cell carcinoma associated with hypercalcemia is a rare finding. In our case, there was no relation between serum parathyroid hormone level and hypercalcemia. Hypercalcemia in our patient is probably related to bone invasion M. A. N. Şendur (&) S. Aksoy Z. Arık Ş. Yaman N. Y. Özdemir D. Uncu N. Zengin Department of Medical Oncology, Ankara Numune Education and Research Hospital, 06100 Sihhiye, Ankara, Turkey e-mail: masendur@yahoo.com.tr

Do Statins Really Improve Colorectal Cancer–Specific Mortality?

TO THE EDITOR: Cardwell et al 1 recently reported the impact of using statins on survival in patients with colorectal cancer in a population-based cohort study. The authors demonstrated that the use of statins after diagnosis was associated with a decreased risk in colorectal cancer–specific and all-cause mortality. We have some comments about the beneficial effect of statin use after colorectal cancer diagnosis. Before we comment that statins improve survival after colorectal cancer diagnosis, we should mention some confounding factors that affect survival. In the revised tumor node categorization of the American Joint Committee on Cancer staging (sixth edition) for colorectal cancer according to the National Survival Outcomes Data, the number of positive nodes and T stage affect survival significantly. 2 According to this revision, in patients with node-negative colorectal cancer, the 5-year overall survival (OS) rate was 87.5% for those with T3 tumors, whereas it was 79.6% and 58.4% for those with T4a and T4b tumors, respectively. In patients with stage III disease, the number of positive nodes can also affect survival for each T category. The 5-year OS rate was between 68.7% and 87.3% in patients with T1 to T2 node-positive disease, whereas it was between 19.7% and 68.7% in those with T3 to T4 node-positive disease. 2 However, there are no available data on T or N stage in the Cardwell et al 1 study. In addition, the authors stated that patients with colorectal cancer newly diagnosed between 1998 and 2009 were included in the cohort. In the study, 1 statin users were more likely to have been diagnosed recently, compared with statin nonusers. In 2004, oxaliplatin was approved by the US Food and Drug Administration for patients with stage III colon cancer, because of the significant OS and disease-free survival advantages shown in the international MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in Adjuvant Treatment of Colon Cancer) trial. 3-5 Because there were more recently diagnosed patients in the statin-user group of the Cardwell et al study, oxaliplatin-based adjuvant treatments may have been administered at a higher rate among statin users compared with nonusers. Adjusted analyses were conducted according to year of diagnosis, chemotherapy receipt within 6 months, and cancer stage, which may have had a bias effect because of the missing data on T stage, N stage, and chemotherapeutic regimen subgroup. Furthermore, the presence of extranodal tumor deposits is significantly associated with worse OS in patients with node-negative stage III colorectal cancer. 6,7 Presence of perineural invasion (PNI) has also been associated with worse prognosis in several studies. Liebig et al 8 reported that the 5-year OS rate was 72% and 25% in patients with PNI-negative and PNI-positive colorectal cancer, respectively, and on multivariable analysis, PNI was found to be an independent prognostic factor for both colorectal cancer–specific OS and disease-free survival. Thus, the missing data about the distribution of positivity of PNI and extranodal tumor deposits may also have had a bias effect on survival outcome regarding statins. On these grounds, it would be interesting to know the distribution of prognostic markers such as T stage, N stage, chemotherapeutic regimen subgroup, PNI positivity, and presence of extranodal tumor deposits before commenting that statin use after diagnosis of colorectal cancer improves survival.

Metastatic parenchymal renal squamous cell carcinoma with hypercalcemia

Renal tumors originated from renal parenchyme or renal pelvis with different histological subtypes. The most common observed malign renal tumors are clear cell renal cell carcinoma (CCRCC), multilocular cystic renal cell carcinoma (MCRCC), papillary renal cell carcinoma (PRCC), chromophobe RCC and carcinoma of the collecting ducts of Bellini, respectively [1]. Primary squamous cell carcinoma (SCC) of the renal parenchyme or renal pelvis is very unusual and rare entity which accounts less than 1 % of renal malign tumors [2]. To our knowledge, there are only two renal parenchymal SCC cases reported until today [3]. This letter presents a case of metastatic renal parenchymal squamous cell carcinoma associated with hypercalcemia, which is not reported until now. A 53-year-old male patient was admitted to our clinic with severe left-sided flank pain and intermittent hematuria. The patient was non-smoker and had a history of intermittent flank pain due to nephrolithiasis. Laboratory evaluation revealed mild anemia and hypercalcemia with microscopic hematuria. Serum calcium level was 13.2 mg/ dl (normal range 8.6–10.2 mg/dl) and serum albumin was 2.9 g/dl (normal range 3.5–4.5 mg/dl) with suppressed parathyroid hormone levels and normal renal functions. Corrected calcium level was calculated as 14.1 mg/dl. By intense hydration and zoledronic acid treatment, serum calcium level was corrected to normal levels. Thoracic and abdominal computed tomography (CT) was performed, and multiple metastatic nodular lesions in both lung and multilocular metastatic hypodense masses with the largest 61 9 55 mm in the right posterior lobe of liver were revealed. Additionally, prominent parenchymal mass in the right kidney and perirenal multiple lymphadenopathies with the biggest size of 18 9 33 mm were found. The patient underwent cytoreductive nephrectomy and right hemicolectomy due to direct tumoral invasion. On the gross examination, the tumor measuring 6.2 9 4.2 9 3.1 cm diameter with multiple calculus was seemed as ulcerative and necrotic confined to the upper pole of right kidney. No tumoral invasion to the renal pelvis was found. Pathological examination of the surgical material revealed moderately differentiated SCC in the renal parenchyma directly invasive to the serosal surface of the right colon without mucosal involvement. Then, due to the extensive disease, patient was treated with six cycles of gemcitabine and carboplatin regimen every 3 weeks plus zoledronic acid. After six cycles of chemotherapy, the patient was progressively deteriorated and died. Squamous cell carcinomas are associated with chronic inflammatory conditions such as renal calculi, recurrent urinary tract infections and schistosomiasis. So, a patient with SCC should be evaluated for such predisposing risk factors that associated with squamous metaplasia and subsequently SCC [4]. In our case, renal calculi were established in both radiologic studies and gross examination of the surgical material. Due to the renal pelvis SCCs tend to be invasive and sessile, the diagnosis of the renal parenchymal SCC should be confirmed with the evaluation Y. Acikgoz Department of Internal Medicine, Ankara Numune Education and Research Hospital, Ankara, Turkey

Plasma VEGF levels may not accurately reflect the truth all the time

To the editor, We read with great interest the study by She-Juan An et al., which showed that posttreatment plasma VEGF levels associated with the overall survival of patients with advanced non-small-cell lung cancer treated with bevacizumab plus chemotherapy. In this study, before and 6 weeks after treatment, vascular endothelial growth factor (VEGF) levels measured. Also, this study showed that low posttreatment VEGF levels associated with better overall survival (OS) [1]. We have some insights for this decrease in serum VEGF levels. VEGF circulating in the blood of patients with cancer may be derived from various sources, as depicted in Fig. 1. Circulating levels of VEGF are dependent on the amount released from tumor cells (Fig. 1A) and/or platelets activated at the tumor-vessel endothelium. Activated platelets release VEGF (Fig. 1B), and platelet consumption causes increased levels of thrombopoietin, which in turn stimulates megakaryopoiesis and platelet production in the bone marrow. Newly produced platelets are larger in size than those produced during steady-state thrombopoiesis, and therefore contain an elevated amount of VEGF (Fig. 1C). Finally, host immune cells as macrophages that infiltrate tumor tissues can be an additional source of VEGF (Fig. 1 D) [2]. Serum VEGF levels have also been found to correlate with platelet count in a mixed population of metastatic cancers and renal cancer, and some investigators have also stated that VEGF should be corrected for platelet counts. To correct for variation in platelet counts between patients, it has been proposed that the concentration of VEGF per platelet (pg/10) can be calculated by dividing the serum VEGF concentration (pg/ml) by the platelet count (910/ml) [3]. In the study, She-Juan An et al., mean VEGF levels decreased from 81.5 pg/ml to 50.5 pg/ml after 6 weeks of treatment (P = 0.08), with a mean reduction of 31 pg/ml in overall. The relationship of the plasma VEGF levels with OS and progression-free survival (PFS), the patients were divided in the two groups based on their median VEGF value. The OS differed significantly between the low and high posttreatment VEGF levels (25.6 months vs. 13.4 months, P = 0.0284). No other relationship was found with plasma VEGF levels. It is known that most cytotoxic chemotherapeutics decrease the platelet count. In this study, thrombocytopenia was developed in 27.3% patients treated with bevacizumab plus chemotherapy. The association between VEGF levels and thrombocytopenia was not reported. Also, it is possible that platelet counts decreased with chemotherapy, but remained within normal limits. Because platelet counts before and after therapy has not been reported, the possible contribution of platelets on the decreasing VEGF levels remains obscure. We believe that the decrease in serum VEGF levels may at least in part be due to decreased platelet counts secondary to chemotherapy, and plasma VEGF levels may not accurately reflect the truth all the time before correcting the VEGF levels for platelet counts. M. A. N. Şendur S. Aksoy (&) Ş. Yaman Z. Arik N. Y. Ozdemir N. Zengin Department of Medical Oncology, Ankara Numune Education and Research Hospital, 06100 Sihhiye, Ankara, Turkey e-mail: saksoy07@yahoo.com