Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial.

BACKGROUND: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. MATERIALS AND METHODS: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). RESULTS: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. CONCLUSIONS: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. CLINICAL TRIAL NUMBER: NCT01086826, www.clinicaltrials.gov.

Are strong opioids equally effective and safe in the treatment of chronic cancer pain? A multicenter randomized phase IV 'real life' trial on the variability of response to opioids.

BACKGROUND: Guidelines tend to consider morphine and morphine-like opioids comparable and interchangeable in the treatment of chronic cancer pain, but individual responses can vary. This study compared the analgesic efficacy, changes of therapy and safety profile over time of four strong opioids given for cancer pain. PATIENT AND METHODS: In this four-arm multicenter, randomized, comparative, of superiority, phase IV trial, oncological patients with moderate to severe pain requiring WHO step III opioids were randomly assigned to receive oral morphine or oxycodone or transdermal fentanyl or buprenorphine for 28 days. At each visit, pain intensity, modifications of therapy and adverse drug reactions (ADRs) were recorded. The primary efficacy end point was the proportion of nonresponders, meaning patients with worse or unchanged average pain intensity (API) between the first and last visit, measured on a 0-10 numerical rating scale. (NCT01809106). RESULTS: Forty-four centers participated in the trial and recruited 520 patients. Worst pain intensity and API decreased over 4 weeks with no significant differences between drugs. Nonresponders ranged from 11.5% (morphine) to 14.4% (buprenorphine). Appreciable changes were made in the treatment schedules over time. Each group required increases in the daily dose, from 32.7% (morphine) to 121.2% (transdermal fentanyl). Patients requiring adjuvant analgesics ranged from 68.9% (morphine) to 81.6% (oxycodone), switches varied from 22.1% (morphine) to 12% (oxycodone), discontinuation of treatment from 27% ( morphine) to 14.5% (fentanyl). ADRs were similar except for effects on the nervous system, which significantly prevailed with morphine. CONCLUSION: The main findings were the similarity in pain control, response rates and main adverse reactions among opioids. Changes in therapy schedules were notable over time. A considerable proportion of patients were nonresponders or poor responders. CLINICAL TRIAL REGISTRATION: NCT01809106 (https://clinicaltrials.gov/ct2/show/NCT01809106?term=cerp&rank=2).

Laparoscopic total fallopian tube removal at the time of bilateral salpingo-oophorectomy in BRCA2 positive women.

About 10% of all serous ovarian cancer has BRCA1 and/or BRCA2 mutations. Recent data showed that following the SEE FIM protocol it is possible to evidence more fimbriae cancers. Due to those studies, fallopian tube cancer in recent years has become the predominant site of cancer in BRCA1 and/or 2 mutation carriers. The pathological study of the fallopian tube is not complete during salpingo-oophorectomy because a small part (intramural site) is situated inside the uterus. In this case report we demonstrate how it is possible to remove the tubes entirely for pathological analysis without hysterectomy by laparoscopic surgery.

A new nested primer pair improves the specificity of CK-19 mRNA detection by RT-PCR in occult breast cancer cells.

Reverse transcription polymerase chain reaction (RT-PCR) of cytokeratin-19 (CK-19) has been widely used to detect small numbers of circulating malignant epithelial cells in the bone marrow or the peripheral blood of patients with breast cancer. However, a high percentage of false positive results has been recorded and conflicting reports question the clinical relevance of this technical approach. We demonstrate that the use of a new nested primer pair for CK-19 RT-PCR avoids false positive results without affecting the sensitivity of the assay. Our experiments were carried out using MCF-7 cells alone or mixed with peripheral blood mononuclear cells (PBMNC) of healthy donors. The results were also validated in a large series of healthy donors and in a preliminary study on a limited number of patients with breast cancer, thus suggesting that our assay is feasible for application in the clinical evaluation of occult malignant epithelial cells.

[Alcohol sclerotherapy of biliary cysts. Our experience]. / Traitement par alcoolisation des kystes biliaires. Expérience personnelle sur 13 cases.

AIM OF THE STUDY: To evaluate if percutaneous ethanol injection treatment, introduced twelve years ago as palliative therapy for inoperable hepatocellular carcinoma, can be used with curative intent to treat biliary cysts with good results. MATERIALS AND METHODS: For the study were observed 13 symptomatic patients (M 4; F 9 - age 38-71, medium 54 years). All the patients were treated by percutaneous alcoholization under ultrasonographic control. RESULTS: Better technique and protocol standardisation give us the possibility to utilise percutaneous ethanol injection like a good treatment for symptomatic patients. CONCLUSIONS: Easy technique, low cost and very small number of complications gives to percutaneous ethanol injection the possibility to become the gold standard for the treatment of biliary cysts.

The impact of a psychological intervention on quality of life in non-metastatic breast cancer.

The aim of this study was to determine whether psychological intervention had a beneficial effect on the quality of life and behaviour of women diagnosed with breast cancer. 36 consecutive patients with non-metastatic breast cancer assigned to surgery and systemic chemotherapy were randomised to receive either psychological intervention (weekly cognitive individual psychotherapy and bimonthly family counselling) or standard follow-up. Personality (16-PF and IIQ), quality of life (FLIC), and depression (BDI) scores were the endpoints for this study, and the questionnaires were completed by the patients at diagnosis, and up to 9 months after diagnosis. Cognitive psychotherapy and family counselling improved both depression and quality of life indexes compared with the control group. Better emotional coping behaviours were also revealed by some changes in personality traits in the intervention group.

Myosin isoform expression in rat rhabdomyosarcoma induced by Moloney murine sarcoma virus.

Myosin isoform expression was analyzed in experimental rhabdomyosarcoma (RMS) using monoclonal antibodies (mAbs) and immunofluorescence techniques. Tumors induced by inoculating newborn rats with Moloney murine sarcoma virus (Mo-MSV) were examined 30-90 days after birth. Nine tumors and two lymph node metastases were studied by direct, indirect, and double immunofluorescence assays using a panel of five anti-myosin mAbs. The mAb BF-45 was specifically reactive with embryonic myosin heavy chain (MHC), mAb BF-34 was specific for a neonatal MHC epitope, mAb BF-B6 was directed against an epitope present in both embryonic and neonatal MHC, and mAbs BF-F3 and BF-32 detected epitopes present in adult MHC isoforms. Anti-desmin antibodies were also used for comparison. The results of this study show that: (1) the majority of neoplastic cells stained for desmin while only a minority of neoplastic cells were labeled by anti-myosin antibodies; (2) myosin positive tumor cells contained predominantly embryonic and neonatal MHC types but rare RMS cells reacted exclusively with anti-adult myosin antibodies; and (3) adult and embryonic MHC phenotypes were occasionally detected within the same tumor cell especially in RMS with the longest latencies. Together these results would suggest that the mechanism(s) regulating MHC gene expression in skeletal muscle cells can be altered by the transforming activity of Mo-MSV.

Differentiation, proliferation and apoptosis levels in human leiomyoma and leiomyosarcoma.

A comparative analysis of the differentiation pattern, the proliferative behaviour, and the level of apoptosis between human benign and malignant neoplasms of smooth-muscle (SM) tissue is lacking. The clinical, histopathological, immunochemical, and immunocytochemical features of leiomyomas (LM) and leiomyosarcomas (LMS) were investigated by a panel of monoclonal antibodies specific for some differentiation markers of SM tissue (SM myosin and alpha-actin, desmin, and SM22) and for markers of non-muscle tissue (vimentin and non-muscle myosin). Proliferating normal and neoplastic cells were identified by proliferating-cell nuclear antigen (PCNA)/Ki67 immunostainings and the apoptotic cells were revealed by means of the terminal-deoxynucleotidyltransferase-mediated dUTP nick-end labelling technique. Gel electrophoresis and Western blotting, performed with anti-(SM1/SM2 myosin isoform) antibody, indicated quantitative differences between LMS and LM, which mirrored higher positive to negative nuclear ratios for PCNA, Ki67 and apoptosis in malignant as opposed to benign neoplasms. With LM, however, a similar SM1 to SM2 ratio could be associated with different proliferation levels. Uterine, gastric and intestinal LMS displayed specific patterns of SM1/SM2 and/or non-muscle myosin expression that were not paralleled by different levels of proliferation/apoptosis. While the level of PCNA/Ki67 correlated with the level of apoptosis in normal SM tissues and LM, that of LMS did not. In vivo at the cellular level, LM and uterine LMS displayed a near-uniform SM tissue differentiation, whereas the other LMS displayed a lesser or a heterogeneous immunoreactivity. In vitro, cultured LMS cells showed a limited and peculiar expression of SM myosin. In conclusion, there is no reciprocal relationship between degree of differentiation and the level of proliferation, as exemplified by the finding that the less differentiated intestinal LMS displays the lowest proliferative behaviour and that the relatively more differentiated gastric LMS/metastasis is more proliferative.

CD 34 expression in chronic and neoplastic liver diseases.

BACKGROUND: Capillarisation of hepatic sinusoids is a well recognized phenomen occurring in long standing liver disease, in hepatic cirrhosis as well as in hepatocellular carcinoma. To study immunohistochemically the expression and distribution of CD34 in chronic liver disease and hepatocellular carcinoma in order to evaluate the possible diagnostic implication of this marker. METHODS: Sixty-five samples of liver tissue showing normal liver, different degrees of chronic inflammation, cirrhosis and histological features of hepatocellular adenoma and carcinoma (HCC) were included in the study. The specimens were fixed in formalin and embedded in paraffin and an immunohistochemical investigation was performed by the standard avidin-biotin-peroxidase complex method with CD34. RESULTS: The sinusoids of normal liver showed no immunoreactivity. The sinusoids of liver affected by different degrees of chronic active hepatitis showed no or focal immunostaining for CD34; an increased immunoreactivity was observed in the periportal sinusoids of the cirrhotic nodules whereas diffuse and strong staining was observed in the overall HCC as well as in the hepatocellular adenoma tested. CONCLUSIONS: In HCC, immunoreactivity for CD34 represents an effective method to evaluate angiogenesis and to distinguish well-differentiated HCC from non-neoplastic liver. Its role in clinical stage and prognostic evaluation needs further investigation.

Multimodal therapy of hepatocarcinoma: personal experience on 90 cases.

BACKGROUND/AIMS: In recent years, surgical and non-surgical options have been developed in the treatment of hepatocellular carcinoma in cirrhotic patients. We review our personal series from 1995-1999, in order to assess the choice of treatment. METHODOLOGY: Of 90 cases of hepatocellular carcinoma observed in the years 1995-1999, 15 underwent curative resective surgery; in 42 cases TAE, PEI or RITA were utilized (9 of them as multimodal therapy). In the remaining 33 patients any kind of therapy was scheduled. RESULTS: The mean survival of the 15 resected patients was 18 months, non-statistically better than RITA survival, compared by Log-Rank test. Perioperative mortality calculated in all procedures was 5.2% (2 pts surgery, 1 pt TAE). CONCLUSIONS: The high percentage of not treated hepatocellular carcinomas in our series is generally due to large tumor size diagnosed in advanced Child's stage. PEI, TAE and RITA have to be considered effective and safe for palliation for HCCs. However, surgical resection represents the curative therapy in selected cirrhotic patients affected by HCC.

[Effect of methisoprinol on postoperative immunodepression in subjects with malignant neoplasms]. / Effetto del metisoprinolo sulla immunodepressione post-operatoria in soggetti affetti da neoplasie maligne.

The authors investigated the state of immunity, before and after surgery, in a group of 6 methisoprinol-treated patients and in a 10-patient control group both affected by malignant neoplasia. All the patients exhibited various degrees of immuno-depression. Versus the control group the group treated with 1-g methisoprinol injections at the dosage of 4 g daily for 7 days after surgery showed a positive effect on post-surgical immuno-depression.

Incidence of prostate cancer in Sicily: results of a multicenter case-findings protocol.

OBJECTIVE: To establish the incidence of prostate cancer (PCa) in Sicily in patients who entered an early detection protocol. METHODS: From February 2002 to February 2004, 16,298 subjects aged 40-75 entered the protocol. Patients with suspicious DRE, PSA>10 ng/ml, PSA

Expression of non-muscle myosin isoforms in rabbit myometrium is estrogen-dependent.

The putatative effects of different estrogen levels on the expression of non-muscle myosin isoforms in rabbit myometrium have been investigated using three monoclonal anti-platelet myosin heavy chain (MyHC) antibodies (NM-F6, NM-G2, and NM-A9). Western blotting analysis of proteolytic digests of human platelet actomyosin indicates that these antibodies are specific for three distinct epitopes. Comparative immunofluorescence tests on cultered human fibroblasts with polyclonal sequence-specific anti-MyHCA antibody suggest that the patterns of NM-F6, NM-.G2 and NM-A9, although similar, do not overlap with that of type-A MyHC. Distribution of NM myosin isoforms has been studied in indirect immunofluorescence assays using cryosections of tissues from rabbits at various stages of development, pregnancy, or from ovariectomized, 17beta-estradiol-treated ovariectomized, and human chorionic gonadotropin-treated animals. Non-muscle myosin antigenicity is still present in the myometrium when the female becomes sexually competent. The immunoreactivity of non-muscle myosin for NM-F6 is steroid-independent, since it does not change with pregnancy or ovariectomy, but that of NM-G2 is estrogen-dependent; the latter disappears during pregnancy and in ovariectomized animals treated with estradiol, whereas it is expressed in ovariectomized rabbits. Although non-muscle myosin immunoreactivity for NM-A9 is detectable under all the experimental conditions, it can assume different patterns of intracellular distribution in vitro (punctate vs filamentous), depending on culture conditions and the presence of estrogens.

Oestrogen-dependent expression of the SM2 smooth muscle-type myosin isoform in rabbit myometrium.

Ovarectomized rabbits displayed a decreased SM1 to SM2 ratio of smooth muscle-type myosin heavy chain isoforms compared to unoperated, virgin females which was reversed after 17beta-oestradiol administration to a value similar to that of control animals. When this steroid was given to sexually immature animals or to adult virgin rabbits, SM2 expression was not induced, as also happened with proliferating myometrial smooth muscle cells grown in vitro. In growing rabbit, the 17beta-oestradiol administration induced the formation of the circular and the longitudinal muscle layers, characteristics of sexually competent females. The SM2 isoform was up-regulated during postnatal development and the SM1 to SM2 ratio changed during pregnancy and post-partum period but not with human gonadotropin treatment which increases the level of circulating progesterone. Immunofluorescence staining of adult myometrium with anti-SM2 antibody indicated that this isoform is localized to the longitudinal layer exclusively and, in contrast to the circular layer, its expression was independent of oestrogen level. Difference in oestrogen sensitivity between the two layers was also detected for the expression of the intermediate filament protein vimentin and the thin filament protein calponin. Changes of SM2 expression in the myometrium correlated with variations in the oestrogen receptor density as also confirmed by decreased SM2 content/oestrogen receptor density in the circular layer when ovarectomized females were treated with the oestrogen antagonist ICI 182,780. Our results indicate that: (1) a specific distribution of myosin heavy chain exists within rabbit myometrium, and (2) SM2 myosin expression in this smooth muscle is under oestrogen control.