Giuseppe Gullo

Expression of multidrug resistance markers ABCB1 (MDR-1/P-gp) and ABCC1 (MRP-1) in renal cell carcinoma

BackgroundRenal cell carcinoma patients respond poorly to conventional chemotherapy, this unresponsiveness may be attributable to multidrug resistance (MDR). The mechanisms of MDR in renal cancer are not fully understood and the specific contribution of ABC transporter proteins which have been implicated in the chemoresistance of various cancers has not been fully defined in this disease.MethodsIn this retrospective study the expression of two of these transporter efflux pumps, namely MDR-1 P-gp (ABCB1) and MRP-1 (ABCC1) were studied by immunohistochemistry in archival material from 95 renal cell carcinoma patients.ResultsIn the first study investigating MDR-1 P-gp and MRP-1 protein expression patterns in renal cell carcinoma patients, high levels of expression of both efflux pumps are observed with 100% of tumours studied showing MDR-1 P-gp and MRP-1 positivity.ConclusionAlthough these findings do not prove a causal role, the high frequency of tumours expressing these efflux pumps suggests that they may be important contributors to the chemoresistance of this tumour type.

BRAF mutations in melanoma and colorectal cancer: A single oncogenic mutation with different tumour phenotypes and clinical implications

BRAF is an oncogene encoding a serine-threonine protein kinase involved in the MAPK signalling cascade. BRAF acts as direct effector of RAS and through the activation of MEK, promotes tumour growth and survival. Approximately, 8% of cancers carry a BRAF mutation. However, the prevalence of this mutation varies significantly across different tumour types. There has been increasing interest in the specific role of BRAF mutations in cancer growth and progression over the last few years, especially since the clinical introduction of therapeutic BRAF inhibitors. In this paper we review the published literature on the role of BRAF mutations in melanoma and colorectal cancer, focusing on similarities and differences of BRAF mutations with respect to frequency, demographics, risk factors, mutation-associated clinico-pathologic and molecular features and clinical implications between these two diseases.

High Incidence of Hypocalcemia and Serum Creatinine Increase in Patients with Bone Metastases Treated with Zoledronic Acid

BACKGROUND Zoledronic acid belongs to the new generation of bisphosphonates with demonstrated clinical benefit for the treatment of bone metastases from different kinds of neoplasms. Hypocalcemia and serum creatinine elevation are expected adverse events during this therapy. The monitoring of serum calcium and creatinine is therefore recommended. The primary aim of this study was to establish the actual incidence of hypocalcemia and serum creatinine elevation during treatment with zoledronic acid. Skeletal-related events and side effects were also assessed. METHODS Serum creatinine and calcium levels were evaluated in 240 consecutive patients (83 males, 157 females; mean age, 62 years) with metastatic bone lesions from different solid tumors treated with zoledronic acid. RESULTS Overall, 93 of 240 patients (38.8%) developed hypocalcemia, which was grade (G)1 in 45 patients (48.4%), G2 in 37 patients (39.8%), G3 in 10 patients (10.8%), and G4 in one patient (1.1%). The median time to occurrence of hypocalcemia (any grade) was 2.3 months after the beginning of the treatment (range, 0-34.9 months). Increased serum creatinine was observed in 33 of 240 patients (13.7%), of whom 19 had G1 (57.6%), 11 had G2 (33.3%), and three had G3 (9.1%). The median time to serum creatinine increase (for any grade) was 4.7 months (range, 0-29.2 months). CONCLUSIONS Our analysis shows a high incidence of hypocalcemia and increased serum creatinine level during treatment with zoledronic acid. These results strongly support the need for accurate monitoring of plasma calcium and creatinine levels.

Membrane transport proteins in human melanoma: associations with tumour aggressiveness and metastasis.

Background:Malignant melanoma, generally described as incurable, is notoriously refractory to chemotherapy. The mechanisms contributing to this have not yet been defined and the contributions of drug efflux pumps, implicated in chemo-resistance of many other cancer types, have not been extensively investigated in melanoma.Methods:In this study, expression of multi-drug resistant (MDR1/P-gp and MRP-1) proteins was examined, by immunohistochemistry, in archival specimens from 134 melanoma patients. This included 92 primary tumours and 42 metastases.Results:On assessing all specimens, MRP-1 and MDR1/P-gp expression was found to be common, with the majority (81%) of melanomas expressing at least one of these efflux pumps. Although there is significant association between expression of these pumps (P=0.007), MRP-1 was found to be the predominant (67% of cases) form detected. χ2 analysis showed significant associations between expression of MRP-1 and/or MDR1/P-gp and the aggressive nature of this disease specifically increased Breslows depth, Clarks level and spread to lymph nodes. This association with aggressiveness and spread is further supported by the observation that a significantly higher percentage of metastases, than primary tumours, express MRP-1 (91% vs 57%; P<0.0001) and MDR1/P-gp (74% vs 50%; P=0.010).Conclusion:The predominant expression of these pumps and, in particular, MRP-1 suggests that they may be important contributors to the inherent aggressive and resistant nature of malignant melanoma.

Level of HER2/neu gene amplification as a predictive factor of response to trastuzumab-based therapy in patients with HER2-positive metastatic breast cancer

SummaryTo explore the clinical significance of the level of HER2/neu gene amplification in a homogenous cohort of 33 patients with HER2-positive metastatic breast cancer (MBC) and available tumor samples treated with a trastuzumab-based regimen, we retrospectively performed dual-color fluorescence in-situ hybridization test and correlated them for each patient with time-to-progression (TTP) and overall survival (OS). We obtained values of HER2/chromosome 17 centromere (CEP17) ratio ranging from 2.5 to 21 (median 7.2). At the Cox model there is indication that patients whose tumors have high-level HER2/CEP17 ratio have shorter TTP and OS than those with lower ratio, when treated with a trastuzumab-based regimen. Correlations do not reach the limits of statistical significance but no formal sample size calculation was performed due to the explorative nature of the study. If confirmed in larger cohorts of patients, HER2/CEP17 ratio could represent a reliable and economical predictor of response to trastuzumab-based therapy in MBC.

Herpes Infections in Breast Cancer Patients Treated with Adjuvant Chemotherapy

Objective: There is little information on Herpes zoster infection in breast cancer patients as a complication during adjuvant chemotherapy. The aim of this study is to evaluate the incidence of Herpes zoster and simplex infections in this patients setting. Methods: We analyzed 623 early-stage breast cancer patients in our Institute over a period of 7 years (1998–2005). Four-hundred and sixty-onepatients were treated with anthracycline-based chemotherapy, 116 with CMF and 46 with taxane-containing regimens. Results: Twelve (1.9%) developed herpes zoster; 9 patients, receiving anthracycline-based chemotherapy, two taxane-containing regimens, and one CMF regimen. Herpes zoster infection required treatment delay in 6 patients. Adjuvant chemotherapy was delayed for 1 week in 2 patients, while in 4 patients with more severe symptoms chemotherapy was delayed for 2 weeks. One patient, despite i.v. acyclovir, had severe postherpetic motor neuropathy with a permanent ambulation impairment, and chemotherapy was stopped. In our study, herpes zoster occurred in 55/1,000 cases/year. The reported incidence in the general population varies between 2.2 and 4.1 per 1,000 patients/year; therefore, the risk of developing herpes zoster in these patients may be 13- to 25-fold higher compared to the incidence in the general population. In addition, 13 of 623 patients developed herpes simplex. Conclusion: Our findings suggest that adjuvant chemotherapy can facilitate reactivation of herpes infection.

Unexpected Low Efficacy of Stealth Liposomal Doxorubicin (Caelyx) and Vinorelbine in Metastatic Breast Cancer

In this phase II study, 23 patients with metastatic breast cancer were treated with a combination of Caelyx (40 mg/m2 on day 1) and vinorelbine (20 mg/m2 on days 1 and 8) every 4 weeks. According to the statistical design, enrollment was closed after the first stage due to the low response rate observed (four partial remissions, 12 stabilizations). Toxicity was acceptable, however, grade 3–4 neutropenia was not negligible. Our study does not support the development of this combination in advanced breast cancer.

Transferrin-bound proteins as potential biomarkers for advanced breast cancer patients

Background Serum profiling using mass spectrometry-based proteomic techniques has great potential to detect biomarkers that might improve the management for advanced breast cancer patients. The albuminome has previously been investigated as a tool in biomarker discovery, however other high abundant blood proteins are also likely to sequester potentially interesting molecules. Methods Affinity resin purified and isolated Transferrin and associated bound proteins from normal control and breast cancer patient serum samples were analysed by label-free mass spectrometry during the discovery phase. Results 21 significant proteins were identified with Fibrinogen and Fibronectin selected for further analysis in an independent sample set, with significant difference found when comparing the controls groups (normal healthy control, inflammatory bowel disease and benign breast disease) to stage IV breast cancer. Conclusions The area under the curve value for Fibrinogen compared favourably with cancer antigen 15-3, an established breast cancer tumour marker. A combination of all three biomarkers improved accuracy when comparing control/benign to stage IV breast cancer patient groups. General significance Mass spectrometry profiling of Transferrin-bound proteins has revealed serum proteins that can distinguish between serum from advanced breast cancer patients and healthy control subjects with high confidence.

Chemotherapy with mitomycin C and capecitabine in patients with advanced colorectal cancer pretreated with irinotecan and oxaliplatin

Aims and background To assess the activity and tolerability of the combination of mitomycin C and capecitabine in patients with metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens. Methods We retrospectively reviewed 28 patients with pretreated advanced colorectal cancer who had been treated with mitomycin C, 6 mg/m2 on day 1, and capecitabine, 1,900 mg/m2 on days 1–14, every 3 weeks. Tumor assessment was performed every 3 cycles, toxicity assessed at each cycle. Results Main patient characteristics were median age, 61 years (range, 35–73); male/female ratio, 16/12; single metastatic site involvement, 5/28 (18%); ≥3 metastatic sites, 10/28 (36%). Ninety-six courses of therapy were given (median number, 3; range, 1–9). Twenty-six patients were assessable for response, and all were assessable for toxicity. There was 1 partial response (4%) and 12 had stable disease (43%). Median time to progression was 2 months (range, 1–9) and median overall survival was 6 months (range, 1–29+), with a 1-year overall survival rate of 25%. The regimen was very well tolerated without significant hematological toxicity. Conclusions Our results are disappointing. Despite the good safety profile, they do not support further investigation or the routine use of this regimen in this setting.

Controversies in clinicopathological characteristics and treatment strategies of male breast cancer: A review of the literature

Male breast cancer (MaBC) is a rare disease, accounting for less than 1% of malignancies in men. For this reason, literature data on its clinicopathological characteristics are very heterogeneous and treatment strategies have mostly been extrapolated from the female counterpart. However, immunohistochemical peculiarities of MaBC have recently emerged, defining it as a distinct entity from female breast cancer (FBC), thus requiring a tailored clinical approach. MaBC appears to be more often hormone receptor positive than FBC, while data on HER2 status still remain inconclusive, indicating a possible higher incidence of HER2 alterations. Treatment strategies for MaBC have evolved and less invasive local treatments such as lumpectomy and sentinel lymph node biopsy have become part of everyday clinical practice, while there are still controversies on the indication of radiotherapy, especially after mastectomy. Similarly, differences between male and female hormonal status have raised some concerns in the use of aromatase inhibitors in male patients and the choice of best endocrine therapy is still controversial.