Detection of Hepatocellular Carcinoma in a High-Risk Population by a Mass Spectrometry-Based Test.

Hepatocellular carcinoma (HCC) is one of the fastest growing causes of cancer-related death. Guidelines recommend obtaining a screening ultrasound with or without alpha-fetoprotein (AFP) every 6 months in at-risk adults. AFP as a screening biomarker is plagued by low sensitivity/specificity, prompting interest in discovering alternatives. Mass spectrometry-based techniques are promising in their ability to identify potential biomarkers. This study aimed to use machine learning utilizing spectral data and AFP to create a model for early detection. Serum samples were collected from three separate cohorts, and data were compiled to make Development, Internal Validation, and Independent Validation sets. AFP levels were measured, and Deep MALDI® analysis was used to generate mass spectra. Spectral data were input into the VeriStrat® classification algorithm. Machine learning techniques then classified each sample as "Cancer" or "No Cancer". Sensitivity and specificity of the test were >80% to detect HCC. High specificity of the test was independent of cause and severity of underlying disease. When compared to AFP, there was improved cancer detection for all tumor sizes, especially small lesions. Overall, a machine learning algorithm incorporating mass spectral data and AFP values from serum samples offers a novel approach to diagnose HCC. Given the small sample size of the Independent Validation set, a further independent, prospective study is warranted.

Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer.

DNA methylation is the most frequent epigenetic alteration. Using methylation-specific polymerase chain reaction (MSP), the methylation status of the adenomatous polyposis coli (APC) and Ras association domain family 1 isoform A (RASSF1A) genes was examined in cell-free circulating DNA from 155 plasma samples obtained from patients with early and advanced colorectal cancer (CRC). APC and RASSF1A hypermethylation was frequently observed in both early and advanced disease, and was significantly associated with a poorer disease outcome. The methylation status of the APC and RASSF1A promoters was investigated in cell-free DNA of patients with CRC. Using MSP, the promoter methylation status of APC and RASSF1A was examined in 155 blood samples obtained from patients with CRC, 88 of whom had operable CRC (oCRC) and 67 had metastatic CRC (mCRC). The frequency of APC methylation in patients with oCRC was 33%. Methylated APC promoter was significantly associated with older age (P=0.012), higher stage (P=0.014) and methylated RASSF1A status (P=0.050). The frequency of APC methylation in patients with mCRC was 53.7%. In these patients, APC methylation was significantly associated with methylated RASSF1A status (P=0.016). The frequency of RASSF1A methylation in patients with oCRC was 25%. Methylated RASSF1A in oCRC was significantly associated with higher stage (P=0.021). The frequency of RASSF1A methylation in mCRC was 44.8%. Methylated RASSF1A in mCRC was associated with moderate differentiation (P=0.012), high levels of carcinoembryonic antigen (P=0.023) and methylated APC status (P=0.016). Patients with an unmethylated APC gene had better survival in both early (81±5 vs. 27±4 months, P<0.001) and advanced disease (37±7 vs. 15±3 months, P<0.001), compared with patients with methylated APC. Patients with an unmethylated RASSF1A gene had better survival in both early (71±6 vs. 46±8 months, P<0.001) and advanced disease (28±4 vs. 16±3 months, P<0.001) than patients with methylated RASSF1A. The observed significant correlations between APC and RASSF1A promoter methylation status and survival may be indicative of a prognostic role for these genes in CRC, which requires additional testing in larger studies.

Hyposmia: an underestimated and frequent adverse effect of chemotherapy.

OBJECTIVES: Optimal function of both the olfactory sensory neurons and the olfactory mucosa is a prerequisite for normal olfactory perception. Both the olfactory neurons and mucosa might be subjects to the neurotoxic and mucotoxic effects of chemotherapy. Despite the recognized importance of olfaction in nutrition and quality of life, the potential olfactory toxicity of chemotherapy regimens has not been adequately assessed. The aim of this study is to investigate whether mucotoxic and/or neurotoxic drugs compromise olfactory performance. PATIENTS AND METHODS: Forty-four consecutive patients completed the "Sniffin' Sticks" test, an objective quantitative/qualitative method to assess olfactory function, at diagnosis and immediately before the infusion of the last session of three to four chemotherapy cycles, according to the therapeutic protocol. The patients underwent therapy containing oxaliplatin and antimetabolites (5-FU or capecitabine; O+A group), taxanes and platinum analogues (cisplatin and carboplatin; T+P group), or taxanes and anthracyclines (doxorubicin or liposomal doxorubicin; T+A group). RESULTS: A significant decrease was noted for olfactory threshold (OT), olfactory discrimination (OD), olfactory identification (OI), and the composite threshold-discrimination-identification (TDI) score. A significant deterioration of all olfactory indices was found for each chemotherapy group. Pairwise comparisons revealed significant differences between the O+A and the T+P group regarding OT and TDI. TDI scores were significantly lower after chemotherapy in all age groups. Patients older than 50 years were found to be more susceptible to olfactory toxicity than younger patients. CONCLUSIONS: Patients who undergo chemotherapy experience significant compromise in their olfactory function. A grading system for olfactory toxicity is proposed.

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 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.

Reversible posterior leukoencephalopathy syndrome induced by pazopanib.

BACKGROUND: The 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 REPORT: We 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. CONCLUSION: In 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.

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.

Complete response after sorafenib therapy for hepatocellular carcinoma in an HIV-HBV co infected patient: Possible synergy with HAART ? A case report.

A significant proportion of HIV patients, ranging between 5-67%, are co-infected with hepatitis B virus (HBV). Several studies suggest an increasing incidence of hepatocellular carcinoma (HCC) in HIV infected individuals. We report the case of a 69 years old male co infected with HBV and HIV who developed HCC. The patient was unfit for curative approach and he underwent three sessions of transcatheter arterial chemoembolisation (TACE). After the last session the disease assessment showed progression and sorafenib therapy was initiated. Highly active antiretroviral therapy (HAART) was continued during sorafenib treatment. The patient achieved a radiological complete response (CR) after 6 months of therapy and remained with no sign of HCC progression at subsequent assessment. Meanwhile, patient's HIV and HBV infections remained stable. Regarding toxicity the patient developed grade 3 hand foot skin reaction (HFSR) that required 50% dose reduction of sorafenib, grade 3 hypertension and grade 2 diarrhea. In conclusion this is the first case of successful treatment of HCC in a HIV-HBV co-infected patient and only the second report of the co administration of sorafenib with HAART.

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

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 patient's 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/m(2). OX was administered on day 1 as a 2-hour (iv) infusion at escalating doses ranging from 70-80 mg/m(2). CAP was administered orally on days 1 to 7 at escalating doses ranging from 2,000-2,750 mg/m(2) 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/m(2) , DOC 50 mg/m(2) and OX 75 mg/m(2). 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.