Raffaele Ardito

Anomalous dystroglycan in carcinoma cell lines

Dystroglycan is a receptor responsible for crucial interactions between extracellular matrix and cytoplasmic space. We provide the first evidence that dystroglycan is truncated. In HC11 normal murine and the 184B5 non‐tumorigenic mammary human cell lines, the expected β‐dystroglycan 43 kDa band was found but human breast T47D, BT549, MCF7, colon HT29, HCT116, SW620, prostate DU145 and cervical HeLa cancer cells expressed an anomalous ≈31 kDa β‐dystroglycan band. α‐Dystroglycan was udetectable in most of the cell lines in which β‐dystroglycan was found as a ≈31 kDa species. An anomalous ≈31 kDa β‐dystroglycan band was also observed in N‐methyl‐N‐nitrosurea‐induced primary rat mammary tumours. Reverse transcriptase polymerase chain reaction experiments confirmed the absence of alternative splicing events and/or expression of eventual dystroglycan isoforms. Using protein extraction procedures at low‐ and high‐ionic strength, we demonstrated that both the 43 kDa and ≈31 kDa β‐dystroglycan bands harbour their transmembrane segment.

Targeted inhibition of the epidermal growth factor receptor‐tyrosine kinase by ZD1839 (‘Iressa’) induces cell‐cycle arrest and inhibits proliferation in prostate cancer cells

The epidermal growth factor (EGF) plays a role in the development of prostate cancer, which becomes essential after androgen resistance has emerged. The EGF receptor (EGFR) is therefore a potential target for anticancer therapy. We evaluated the effects of ZD1839 (‘Iressa’), an orally active EGFR—tyrosine kinase inhibitor, on prostate cancer cell lines. The effects of ZD1839 were evaluated on the anchorage dependent and independent growth of androgen‐responsive (LNCaP) and androgen‐independent (DU145 and PC3) cells by a cell proliferation assay, cell counting, and soft agar analysis. Flow cytometric analysis and Western blotting were used to assess the effects on the cell‐cycle and on protein expression levels, respectively. ZD1839 caused a dose‐ and time‐dependent growth inhibition in all three cell lines. A dose‐dependent supra‐additive increase in growth inhibition was observed when ZD1839 was combined with the antiandrogen flutamide or ionizing radiation (IR). The antiproliferative effect of ZD1839 was mainly cytostatic and associated with a block in the G0/G1 phase of the cell‐cycle, evident after about 12 h of treatment. In the DU145 cells this block was associated with an increase in expression of the CDK inhibitor p27Kip1, both in the cytoplasmic and nuclear fractions. The increase in p27Kip1 was not evident in the LNCaP and PC3 cells. No changes were observed in the expression of cyclin D1 protein. These results demonstrate the antiproliferative effects of ZD1839 on the growth of prostate cancer cells and suggest that inhibition of EGFR‐associated signal transduction pathway might represent a promising novel therapeutic strategy for the treatment of prostate cancer. J. Cell. Physiol. 201: 97–105, 2004.

Metabolic Syndrome as a Peculiar Target for Management of Prostate Cancer Patients

An interesting and reciprocal association between the metabolic syndrome and prostate cancer has been identified. Metabolic alterations, such as hyperinsulinemia, increased levels of insulin growth factor-1, and insulin resistance could be on the basis of development and progression of many tumors, including prostate cancer, and changes in body composition, in turn, can represent some side effects of androgen deprivation therapy and novel drugs, such as mammalian target of rapamycin inhibitors. This review evaluates this interrelation between metabolic syndrome and prostate tumor scanning in many clinical and preclinical epidemiological studies and describes possible pathogenetic biological mechanisms. Finally, this article discusses feasible clinical implications for the management, prevention, diagnosis, prognosis, and treatment of patients affected by metabolic syndrome and prostate cancer, with particular attention to the metformin action.

Long-term survival in small cell lung cancer: a case report and review of the literature

Small cell lung cancer (SCLC) represents approximately 13% of all newly diagnosed lung cancers. SCLC is a very aggressive disease characterized by early locoregional and distant metastases. The median survival is 14-16 months for patients with limited disease and 8-11 months for those with extensive disease, with 20-40% of patients with limited disease and 5% of patients with extensive disease alive at 2 years. This report discusses the case of a long-term SCLC survivor treated with radiotherapy, several lines of chemotherapy and long-acting somatostatin analogs who is alive 7 years after diagnosis, with no evidence of further relapse. In the near future, better identification of prognostic and predictive factors based on models that integrate clinical data and multiple gene expression profiles and the use of novel treatments could increase the number of long-term SCLC survivors.

The evolving landscape in advanced penile cancer

Penile carcinoma is a rare malignancy with incidence rates which vary in the range of 1–10 cases per 100,000 men according to ethnicity, cultural background, geographic area and social habits [1]. Keratinizing squamous cell carcinomas, similar to carcinomas of nongenital skin, and verrucous carcinoma are the most common histologic variants, while basaloid and warty carcinomas are less prevalent [1]. Prognosis of penile cancer is mainly dependent on stage, with patients with noninvasive disease showing a 5-year cause-specific survival rate approximating 100% [1]. In published series, cancer-specific survival of patients with invasive tumors has ranged from 75 to 93% in patients with cN0 disease, 40 to 70% in those with cN1 disease, 33 to 50% in those with cN2 disease and 20 to 34% in those with cN3 disease [2]. The rarity of penile cancer poses a great challenge for researchers, and improvements in prognosis have been mostly seen in patients with localized cancer. In one cohort study involving 1000 men treated over the course of six decades, the 5-year cancer-specific survival of patients with clinically negative lymphnode improved by 9% in the last 20 years, increasing from 82% of the period from 1956 to 1993 to 91% of the period from 1994 to 2012. This result paralleled the introduction of sentinal node biopsy, and was maintained after adjustment for grade and T stage [3]. While in patients with N0/1 disease surgery is the mainstay of treatment, N2/3 penile carcinoma requires a multidisciplinary approach involving surgery, radiation therapy and chemotherapy, as recurrence has been observed in up to 90% of cases, and it is especially frequent in patients with extranodal extension and involvement of pelvic lymphnodes [2]. In a Phase II trial by Pagliaro et al. [4] conducted in 30 men receiving neoadjuvant chemotherapy based on paclitaxel, ifosfamide and cisplatin, 15 patients (50%) had an objective response and 22 (73.3%) subsequently underwent surgery. Of note, three patients (10%) had no remaining tumor on histopathology. Chemotherapy was very well tolerated, with grade 3–4 side effects, including anemia, neutropenia, febrile neutropenia and peripheral neuropathy, occurring each in less than 5% of patients. Surgery, which included inguinal and pelvic lymphadenectomy, was also well tolerated, with perioperative side effects such as noninfectious wound separation, skin breakdown, hemorrhage, skin infection, lower extremity edema and soft tissue necrosis, each occurring in less than 10% of patients. The estimated median time to progression in 20 patients who died during the follow-up was 8.1 months (95% CI: 5.4–50+), with an overall survival of 17.1 months (95% CI,: 10.3–60), while the median duration of follow-up for the 10 surviving patients was 34 months (range, 14–59 months). These findings appear encouraging if compared with existing data [1,2]. As the greatest majority of patients with relapsing disease show inguinal/pelvic recurrence [1], adjuvant radiation therapy may further improve these results. One retrospective study showed that regional failure rates after inguinal lymphnode dissection in 14 men with pathological inguinal lymphnode metastasis after lymphadenectomy Carlo Buonerba*,1, Giuseppe Di Lorenzo2, Giuseppe Calderoni1, Matteo Ferro3, Francesco Perri4, Lucia Lombardi1, Raffaele Ardito1, Piera Federico5, Sabino De Placido2 & Michele Aieta1 Division of Medical Oncology, Centro di Riferimento Oncologico di Basilicata, I.R.C.C.S, Via Padre Pio 1, 85028 Rionero in Vulture, PZ, Italy Medical Oncology Unit, Department of Clinical Medicine, Federico II University, Naples, Italy Divisione di Urologia, Istituto Europeo di Oncologia, Milano, Italy Medical Oncology Department POC SS Annunziata Taranto, Italy IOS SrL e Coleman SPA, Naples, Italy *Author for correspondence: Tel.: +39 972 726 111 Fax: +39 972 723 509 carbuone@hotmail.com The evolving landscape in advanced penile cancer

Role of parenteral nutrition in cancer patients undergoing high-dose chemotherapy followed by autologous peripheral blood progenitor cell transplantation.

High-dose chemotherapy followed by autologous bone marrow or peripheral blood progenitor cell transplantation represents a recognized option in the treatment of solid tumors and hematologic diseases. Patients receiving high-dose chemotherapy are traditionally supported with parenteral nutrition with the aim to prevent malnutrition secondary to gastrointestinal toxicity and metabolic alterations induced by the conditioning regimens. Nevertheless, well-defined guidelines for its use in this clinical setting are lacking and there are several areas of controversy.

Evaluation of molecular prognostic and predictive factors: an important step towards personalised treatment in non small cell lung cancer

Treatment for patients with advanced NSCLC generally consists of chemotherapy, but response rates are modest and recurrence occurs for most patients after standard first-line platinum-based doublet therapy. Tailoring therapy to individual patient according to certain prognostic and predictive factors has the potential to improve outcome in NSCLC. This review focuses on the most important molecular prognostic and/or predictive factors in the treatment of advanced NSCLC; considering these molecular features, we also suggest a molecular-based treatment algorithm.

836PTREATMENT AND OUTCOME(S) OF A LARGE COHORT OF POOR RISK METASTATIC RENAL CELL CARCINOMA (PRRCC) PATIENTS (PTS)

ABSTRACT Aim: With the exception of the Temsirolimus (Tem) registration trial, prRCC is grossly underrepresented in clinical trials. Methods: We collected information on a large cohort of prRCC (239 pts) from 20 Italian and 2 Spanish centers. Results: Three prognostic models (MSKCC, modified MSKCC - mMSKCC, International Metastatic RCC Database Consortium - DC) and 8 individual risk factors (RF) were considered: multiple metastatic sites (89%), time from diagnosis to treatment (82%), and anaemia (77%) were the most frequent individual RF. Eighty-nine percent, 63%, and 61% of pts had at least 3 RF according to mMSKCC, MSKCC, and DC, respectively; mMSKCC had the best discriminating power between intermediate and prRCC (median OS: 28 vs 8 mos, respectively; p 6 mos) was 44% and was significantly higher for pts receiving first-line TKI versus Tem (50% vs 26%, p = 0.002). Age, nephrectomy status, mMSKCC, and total number of RF, but not the type of treatment received (Tem vs VEGFR-TKI), were independently associated with OS at multivariate analysis. Thirty seven percent of prRCC pts survived >12 mos (29% and 40% in pts receiving Tem and VEGFR-TKI, respectively). Basal Hb and calcium levels within normal limits were significantly associated with higher chances of achieving long-term survival upon VEGFR-TKI treatment, while a non-significant trend towards a higher proportion of long-term survivors upon Tem treatment was observed for longer time from diagnosis to treatment and normal LDH levels, in an exploratory analysis of predictive factors. Conclusions: Despite heterogeneity, prRCC may benefit from systemic treatment across multiple lines of therapy. Further prognostic/predictive stratification within the prRCC group is clearly necessary (see also the abstract by Guida et al. at this Meeting). Disclosure: All authors have declared no conflicts of interest.