Leonidas Chelis

Transtympanic Injections of N-acetylcysteine for the Prevention of Cisplatin-induced Ototoxicity A Feasible Method With Promising Efficacy

Objectives:Ototoxicity is a common and irreversible adverse effect of cisplatin treatment with great impact on the patients’ quality of life. N-acetylcysteine is a low-molecular-weight agent which has shown substantial otoprotective activity. The role of transtympanic infusions of N-acetylcysteine was examined in a cohort of patients treated with cisplatin-based regimens. Patients and Methods:Twenty cisplatin-treated patients were subjected, under local anesthesia, to transtympanic N-acetylcysteine (10%) infusions in 1 ear, during the hydration procedure preceding intravenous effusion of cisplatin. The contralateral ear was used as control. The number of transtympanic infusions was respective to the number of administered cycles. Hearing acuity was evaluated before each cycle with pure tone audiometry by an audiologist blinded to the treated ear. Results:A total of 84 transtympanic infusions were performed. In treated ears, no significant changes in auditory thresholds were recorded. In the control ears cisplatin induced a significant decrease of auditory thresholds at the 8000 Hz frequency band (P=0.008). At the same frequency (8000 Hz), the changes in auditory thresholds were significantly larger for the control ears than the treated ones (P=0.005). An acute pain starting shortly after the injection and lasting for a few minutes seemed to be the only significant adverse effect. Conclusions:Transtympanic injections of N-acetylcysteine seem to be a feasible and effective otoprotective strategy for the prevention of cisplatin-induced ototoxicity. Additional studies are required to further clarify the efficiency of this treatment and determine the optimal dosage and protocol.

Prognostic role of APC and RASSF1A promoter methylation status in cell free circulating DNA of operable gastric cancer patients

Gastric carcinogenesis is a multistep process including not only genetic mutations but also epigenetic alterations. The best known and more frequent epigenetic alteration is DNA methylation affecting tumor suppressor genes that may be involved in various carcinogenetic pathways. The aim of the present study was to investigate the methylation status of APC promoter 1A and RASSF1A promoter in cell free DNA of operable gastric cancer patients. Using methylation specific PCR, we examined the methylation status of APC promoter 1A and RASSF1A promoter in 73 blood samples obtained from patients with gastric cancer. APC and RASSF1A promoters were found to be methylated in 61 (83.6%) and 50 (68.5%) of the 73 gastric cancer samples examined, but in none of the healthy control samples (p < 0.001). A significant association between methylated RASSF1A promoter status and lymph node positivity was observed (p = 0.005). Additionally, a significant correlation between a methylated APC promoter and elevated CEA (p = 0.033) as well as CA-19.9 (p = 0.032) levels, was noticed. The Kaplan-Meier estimates of survival, significantly favored patients with a non-methylated APC promoter status (p = 0.008). No other significant correlations between APC and RASSF1A methylation status and different tumor variables examined was observed. Serum RASSF1A and APC promoter hypermethylation is a frequent epigenetic event in patients with early operable gastric cancer. The observed correlations between APC promoter methylation status and survival as well as between a hypermethylated RASSF1A promoter and nodal positivity may be indicative of a prognostic role for those genes in early operable gastric cancer. Additional studies, in a larger cohort of patients are required to further explore whether these findings could serve as potential molecular biomarkers of survival and/or response to specific treatments.

Reversible Posterior Leukoencephalopathy Syndrome Induced by Pazopanib

BackgroundThe reversible posterior leukoencephalopathy syndrome is a clinical/radiological syndrome characterized by headache, seizures, impaired vision, acute hypertension, and typical magnetic resonance imaging findings. There are several reports in the literature that depict its occurrence in cancer patients. The list of common anticancer and supportive care drugs that predispose to reversible posterior leukoencephalopathy syndrome is expanding and includes not only a large number of chemotherapeutic agents but also an increased number of new targeted drugs, particularly angiogenesis inhibitors such as bevacizumab,sorefenib and sunitinib. Pazopanib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit which after a positive phase III randomized clinical trial in patients with advanced renal cell cancer received FDA approval for the treatment of advanced renal cell carcinoma. Until now no cases of reversible posterior leukoencephalopathy syndrome induced by pazopanib have been reported.Case reportWe present the case of a 40 years old female patient with heavily pre-treated metastatic renal cell carcinoma who received pazopanib as salvage treatment. After 21 days of pazopanib therapy the patient referred to the emergency department with epileptic seizure, impaired vision at both eyes and headache. MRI of the brain revealed subcortical oedema at the occipital and parietal lobes bilaterally. She was treated with anticonvulsants, i.v. administration of mannitol and antihypertensives and she recovered completely from her symptoms and was discharged on the tenth hospital day. A brain MRI performed 3 weeks after showed that the subcortical oedema had been subsided.ConclusionIn conclusion this is the first case of pazopanib induced reversible posterior leukoencephalopathy syndrome. Although usually reversible, this syndrome is a serious and potentially life threatening adverse effect, if untreated, that should be considered by physicians treating metastatic renal cell carcinoma patients with pazopanib.

Hepatoid Adenocarcinoma of the Gallbladder Case Report and Literature Review

Hepatoid adenocarcinoma (HAC) is a rare tumor consisting of three distinct patters, solid, tubular and trabecular, with morphological and functional features resembling hepatocellular carcinoma (HCC). The tumor is found most frequently in the stomach [1, 2], where it was originally described by Ishikura et al. [3] as a specific subtype of primary gastric carcinoma, with occasional reports describing locations in other organs such as the lung [4, 5], kidney [6], female reproductive tract [7–11], pancreas [12–14], and gallbladder [15, 16]. In this report, we present a case of HAC of the gallbladder. Case Report

Biweekly Vinorelbine and Gemcitabine as Second-Line Treatment and Beyond in Non-Small Cell Lung Cancer

Background: To evaluate the activity and tolerance of gemcitabine (GEM) in combination with vinorelbine (VRL) in pretreated patients with advanced non-small cell lung cancer (NSCLC). Patients and Methods: Fifteen patients with advanced NSCLC who had disease progression after a cisplatin- or taxane-based front-line regimen were enrolled into a 2-stage design trial and were treated with VRL 30 mg/m2 i.v. for 10 min followed by GEM 1,200 mg/m2 i.v. for 30 min on days 1 and 15 of each 28-day cycle. Chemotherapy was given for 6 cycles unless disease progression or unacceptable toxicity was seen. The patients’ median age was 64 years and the performance status (WHO) was 0 (n = 7), 1 (n = 5), and 2 (n = 3). The treatment was second line for 10 (67%) and third line or more for 5 (33%) patients. Results: No complete or partial responses were observed. Stable disease was seen in 4 (27%) patients and progressive disease in 11 (73%). The median time to tumor progression was 3 months (range 1–12) and the median survival was 4 months (range 2–31). Severe myelotoxicity was infrequent. Grade 2 neutropenia was observed in 2 (13%) patients, grade 2 thrombocytopenia in 1 (7%), and grade 2 anemia in 3 (20%). Nonhematologic toxicities were very mild and easily manageable. Conclusion: The GEM plus VRL combination at the present doses and schedule is a safe but ineffective regimen; therefore, it is not recommended as second-line treatment in patients with advanced NSCLC.

Prognostic significance of different immunohistochemical S100A2 protein expression patterns in patients with operable nonsmall cell lung carcinoma

S100 proteins are involved in carcinogenesis, metastasis, and survival. S100A2 is a member of the S100 family, and its expression and precise role in patients with non-small cell lung carcinoma (NSCLC) has been debated. Therefore, we examined the immunohistochemical expression patterns of S100A2 in NSCLC in relation to clinicopathological parameters, important molecular biomarkers, and patient outcome. Microarray data for 74 paraffin-embedded specimens from patients with NSCLC were immunostained for S100A2 and p53 proteins. Immunohistochemical staining patterns of S100A2 in the NSCLC tissue samples examined were either nuclear (nS100A2), cytoplasmic (cS100A2), or both. A significant association between nS100A2 positivity and better disease-free interval was observed (hazards ratio 0.47; 95% confidence interval 0.23–0.99; P = 0.047). Similarly, cS100A2 negativity was marginally associated with shorter overall survival (P = 0.07). Patients without lymphatic infiltration and an earlier disease stage had significantly better overall survival and disease-free interval. The S100A2 expression pattern in operable NSCLC varies widely, and this differential expression (nuclear, cytoplasmic or both) seems to correlate with prognosis. Intensity of expression was highest in the early and advanced stages, and equally distributed in the middle stages. This observation may be indicative of a dual role for this protein both during earlier and advanced disease stages, and may also explain the differential immunoexpression of S100A2. Analysis of the disease-free interval showed that nS100A2-negative and p53-positive expression was associated with a statistically significant (P = 0.003) shorter disease-free interval in comparison with nS100A2-positive and p53-negative expression (12 versus 30 months, respectively). Further studies are required to establish whether S100A2 protein may have a substantial role as a prognostic or predictive indicator in this unfavorable group of patients.

Synchronous Breast and Rectal Cancers in a Man

Breast cancer in men is relatively rare and its coexistence with other primary non-breast cancers exceptional. Here, we report the case of a 50-year-old man who presented with symptoms of rectal adenocarcinoma and in whom a synchronous, asymptomatic cancer of the left breast was found incidentally at physical examination.

A dose escalation study of docetaxel plus capecitabine in combination with oxaliplatin in patients with advanced solid tumors.

Abstract Objectives. Capecitabine (CAP), Oxaliplatin (OX) and Docetaxel (DOC) have shown considerable activity in a wide range of solid tumors. A phase I study was conducted in order to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of their combination in patients with advanced solid tumors. Patients and methods. Twenty-one patients were enrolled. The patients median age was 68 years, 15 were male, and 12 were chemo-naïve. DOC was administered on day 1 as an 1-hour (iv) infusion at a standard dose of 50 mg/m2. OX was administered on day 1 as a 2-hour (iv) infusion at escalating doses ranging from 70–80 mg/m2. CAP was administered orally on days 1 to 7 at escalating doses ranging from 2 000–2 750 mg/m2 given as two daily divided doses. Treatment was repeated every two weeks. Results. Six different dose-levels were examined. At dose-level VI, two of three enrolled patients presented DLTs (one patient diarrhea and asthenia grade 3 and another grade 3 diarrhea), and thus, the recommended MTD for future phase II studies is CAP 2 750 mg/m2 , DOC 50 mg/m2 and OX 75 mg/m2. A total of 121 treatment cycles were administered. Grade 3 neutropenia was observed in six (5%) treatment cycles and grade 3 thrombocytopenia in one (1%). There was no febrile episode. Grade 3 asthenia was observed in three (14%) patients, grade 3 diarrhea in four (19%), grade 3 neuropathy in one (5%), and grade 1/2 hand-foot syndrome in three (14%). Other toxicities were uncommon. There was no treatment related death. Four (29%) PRs and seven (50%) SD were observed among 14 evaluable patients. Responses were seen in patients with renal (n = 1), gastric (n = 2) and pancreatic (n = 1) cancer. Conclusions. These results demonstrate that CAP, DOC and OX can be safely combined at clinically relevant doses and this regimen merits further evaluation.

Abstract 1567: A mass spectrometry based serum test for the detection of hepatocellular carcinoma (HCC) in high risk patients

Improved screening protocols (SP) for patients at high risk of developing HCC could lead to improved patient outcome and possibly cure if detected early. The current SPs, ultrasound with the possible addition of alphafetoprotein (AFP) measurement, suffer from insufficient sensitivity and specificity, and less than 30% of patients are diagnosed early enough to be suitable candidates for resection or transplantation. An easy to use biomarker for the early detection of HCC is clearly needed. We used mass spectrometry analysis of serum samples combined with specialized deep learning techniques to train and validate such a test. The development cohort consisted of patients undergoing transplant or resection for HCC (N = 52; median MELD = 14), and patients with advanced cirrhosis undergoing liver transplant (N = 53; median MELD = 25). Underlying cause of liver disease was 51% hepatitis C infection. The validation cohort consisted of patients with advanced HCC (N = 103; 70/26/7 Child-Pugh A/B/C) and liver disease but no HCC (N = 77; 68/7/2 Child-Pugh A/B/C), with 68% of patients having hepatitis B infection (HBV). The classifier was trained especially to avoid confounding by liver function. The resulting test showed a sensitivity/specificity of 73%/95% in cross validation in the development set overall. In the subset of T1 patients (or lesion size The developed test shows promise in the early detection of HCC as a screening tool in high risk patients independent of the cause of underlying liver disease. While further validation will be necessary to conclusively prove its clinical validity, we believe such a test could substantially improve early detection of HCC. Citation Format: Devalingam Mahalingam, William K. Washburn, Glenn Halff, Leonidas Chelis, Stylianos Kakolyris, Stylianos Vradelis, Julia Grigorieva, Carlos Oliveira, Heinrich Roder, Joanna Roder. A mass spectrometry based serum test for the detection of hepatocellular carcinoma (HCC) in high risk patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1567. doi:10.1158/1538-7445.AM2015-1567

The importance of sequence in rescheduling bevacizumab and chemotherapy administration in the first-line treatment of metastatic colorectal carcinoma (mCRC).

617 Background: One of the proposed mechanisms of action for bevacizumab is by reducing the interstitial fluid pressure (IFP) allowing an increased penetration and uptake of chemotherapy agents in tumors. Clinical and laboratory data suggest that the decrease of IFP occurs after a few days of bevacizumab administration and intratumoral delivery of chemotherapy increase when bevacizumab precedes chemotherapy. We hypothesized that altering the schedule of BEV/FOLFOX regimen would improve the efficacy of the regimen and increase objective response rate. Methods: Patients (pts) with mCRC or locally advanced colorectal cancer, with ECOG PS 0-2 were eligible. The treatment schedule was Bevacizumab 5mg/Kg on day 1, standard FOLFOX-4 regimen on days 8-9 at cycles repeated every 14 days. Prior 5-FU/oxaliplatin adjuvant treatment was allowed. The pts were treated for 6 months or until reaching a plateau of response. Standard RECIST v1.1 response evaluation criteria were used. Primary endpoint of the study was the p...