Salvatore Berretta

CD200 expression may help in differential diagnosis between mantle cell lymphoma and B-cell chronic lymphocytic leukemia

Chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) share many features and their differential diagnosis may be challenging, especially when a leukemic picture alone is present. Monoclonal antibody panels are often useful, with CD23 being the most reliable. However, MCL diagnosis should be confirmed by immunohistochemical cyclin D1 detection, sometimes with equivocal or even negative results. Other cytofluorimetric, cytogenetics or molecular techniques are reliable but not widely available. B-CLL leukemic cells express CD200, a membrane glycoprotein belonging to the immunoglobulin superfamily. We investigated its expression on fresh neoplastic cells of 93 patients with a CD5+ lymphoproliferative disease (79 selected B-CLL and 14 MCL in leukemic phase). Although these data cannot be generalized, all B-CLL samples we examined were positive, with CD200 present on the vast majority of the cells while, in MCL patients, CD200 was expressed by a small minority of CD5+ cells in three subjects and totally absent in the remaining 11. We then examined CD200 expression on paraffin-embedded lymphoid tissues and bone marrow (BM) trephine biopsies from 23 B-CLL and 44 MCL patients. Again, all B-CLL cells were CD200+ both in lymph nodes and in BM while all MCL cells were negative. Adding CD200 in routine panels could be of diagnostic utility in excluding MCL diagnosis.

Hepatocellular Carcinoma in HIV-Infected Patients: Check Early, Treat Hard

PURPOSE Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-infected patients in the highly active antiretroviral therapy (HAART) era. The aims of this study were to describe HCC tumor characteristics and different therapeutic approaches, to evaluate patient survival time from HCC diagnosis, and to identify clinical prognostic predictors in patients with and without HIV infection. PATIENTS AND METHODS A multicenter observational retrospective comparison of 104 HIV-infected patients and 484 uninfected patients was performed in four Italian centers. HCC was staged according to the Barcelona Clinic Liver Cancer (BCLC) criteria. RESULTS Tumor characteristics of patients with and without HIV were significantly different for age, Eastern Cooperative Oncology Group performance status (PS) score ≤1, and etiology of chronic liver disease. Despite the similar potentially curative option rate and better BCLC stage at diagnosis, the median survival time was significantly shorter in HIV(+) patients. HIV(+) patients were less frequently retreated at relapse. Independent predictors of survival were: BCLC stage, potentially effective HCC therapy, tumor dimension ≤3 cm, HCC diagnosis under a screening program, HCC recurrence, and portal vein thrombosis. Restricting the analysis to HIV(+) patients only, all positive prognostic factors were confirmed together with HAART exposure. CONCLUSION This study confirms a significantly shorter survival time in HIV(+) HCC patients. The less aggressive retreatment at recurrence approach does not balance the benefit of younger age and better BCLC stage and PS score of HIV(+) patients. Thus, considering the prognosis of HIV(+) HCC patients, effective screening techniques, programs, and specific management guidelines are urgently needed.

Solid pseudopapillary tumour of the pancreas.

Solid pseudopapillary tumour (Frantz’s tumour) is a rare benign or low-grade neoplasm of the pancreas with distinct clinicopathological features. The diagnosis may be difficult, but should be considered as a possibility in young women who present with a large abdominal mass involving the pancreas. In this report we describe the clinical and pathological characteristics of these lesions and discuss therapeutic options. A 27-year-old woman was admitted to our hospital in October 1999 with a 3-month history of mild asthenia, weight loss, and a feeling of heaviness localised to the left lumbar region. Routine laboratory analyses were all within the normal range; however, abdominal ultrasound revealed the presence of a mass in the superior abdomen, which was composed of high and low echoic areas. Computed tomography showed the mass to be solid, encapsulated, and about 9 cm in diameter (figure 1). It was composed of high and low density areas and was located close to the splenic hilum—above the pancreatic tail, behind the stomach, and between the spleen and the aorta (Albarran-Chatelin’s anatomosurgical quadrilateral). Nuclear magnetic resonance imaging revealed a posterior anastomosis between the mass drainage vessels and the diaphragmatic veins. The patient underwent a complete surgical resection of the tumour (enucleation) and a resection of the pancreatic tail. The spleen was removed because of vascular damage consisting of large patches of venous stasis and ischaemia which did not resolve over time or after application of warm, moist dressings. The pathological diagnosis was epithelial solid papillary cystic neoplasm with signs of incipient pseudocapsular invasion. Immunohistochemical studies established that the tumour cells were positive for cytokeratins and vimentin, and negative for S100 protein, CD34, chromogranin, neurone-specific enolase (NSE), and glial fibrillary acid protein. The postoperative course was uneventful and the patient was discharged from hospital on day 7 and referred to the Centro di Riferimento Oncologico di Aviano for counselling. No residual tumour or metastases were found with clinical imaging, so no adjuvant therapy was recommended. In November 2001, routine work-up identified no signs of tumour relapse. This case is a typical example of solid pseudopapillary tumour of the pancreas or Frantz’s tumour. The diagnostic imaging techniques used were effective in defining the location of the tumour, although a nonfunctioning neoplasm of the left adrenal gland was initially suspected. In 1959, Frantz 1

Effects of imatinib mesylate in osteoblastogenesis.

Imatinib mesylate (IM), a tyrosine kinase inhibitor currently used in chronic myeloid leukemia (CML), may also affect the growth of other cellular systems besides CML cells. Because it has been reported that IM may affect bone tissue remodeling, we evaluated the effects of IM on osteoblastic differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs). After 21 days of culture, hBM-MSCs treated with IM (1 microM) alone or osteogenic medium (OM) + IM showed changes in morphology with evidence of extracellular mineralization and increased mRNA expression of osteogenic markers, such as RUNX2, osteocalcin (OCN), and bone morphogenetic protein (BMP-2). We also observed that levels of OCN and the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL) ratio (OPG/RANKL ratio) were increased in the surnatant of the 21-day culture with IM or OM + IM compared to controls (p<0.005). In addition, we found that in 46 serum samples collected from CML patients treated with IM for 3 to 24 months, the OPG/RANKL ratio increased after 3 and 6 months (p<0.004) returning back to the basal level after 24 months of IM treatment. In these patients, OCN levels were low at diagnosis but they increased throughout the IM treatment, approaching normal levels at 24 months of IM therapy. In summary, our data show that IM increases mRNA expression of osteogenic markers in hBM-MSCs and increases the OPG/RANKL ratio and the OCN levels both in surnatant of hBM-MSCs cultured with IM and in serum of patients treated with IM, thus indicating that IM potentially favors osteoblastogenesis.

Pancreatic cancer in HIV-positive patients: a clinical case-control study.

Objectives Pancreatic cancer (PC) is the fourth and fifth most common cause of cancer-related death among men in United States and in Europe, respectively. No data are available for HIV-positive patients. The aim of this study was to investigate and to compare clinical presentation and outcome between HIV-positive and HIV-negative PC patients. Methods From April 1988 to June 2010, the Italian Cooperative Group on AIDS and Tumors identified 16 cases of HIV-positive PC patients. Each HIV-positive patient from our institution was randomly matched (ratio 1:2) with HIV-negative patients (32 controls) based on sex and year of PC diagnosis. Differences in clinical presentation, treatment, and overall survival were assessed. Results At multivariate analysis, HIV-positive patients compared with HIV-negative patients had a higher risk of an unfavorable performance status (PS ≥2) and a younger age (<50 years) at cancer diagnosis. At multivariate analysis, HIV-positive status and PS of 2 or greater were the only 2 features that significantly reduced PC patients’ survival. Conclusions Our data show, for the first time, that HIV-positive PC patients, compared with HIV-negative patients, are younger at cancer diagnosis. Furthermore, they share a more unfavorable PS and a shorter survival.

Clinical Presentation and Outcome of Colorectal Cancer in HIV-Positive Patients: A Clinical Case-Control Study

Background: Data on colorectal cancer (CRC) in HIV-positive patients are limited. The study objective was to investigate and compare clinical presentation and outcome between HIV-positive and HIV-negative CRC patients. Patients and Methods: Between September 1985 and November 2003 we identified 27 cases of HIV-positive CRC patients from the cancer registry database – Italian Cooperative Group AIDS and Tumours (GICAT); the clinical presentation/outcome information was retrieved. Each HIV-positive patient from our institution was randomly matched (ratio 1:2) with HIV-negative patients (54 controls) based on age, sex, and year of diagnosis in the same time period. Differences in clinical presentation, treatment, and overall survival were assessed. Results: Of 1130 HIV-negative CRC patients, 54 were identified and matched with 27 HIV-positive patients. Compared with the HIV-negative patients, the HIV-positive patients had a higher risk of lower performance status (PS: ≥2) (odds ratio (OR) = 14.4; 95% confidence interval (CI): 3.6–57.7), a higher risk of unfavorable Dukes’ stage (D) (OR = 4.9; 95% CI: 1.8–13.5), and a higher risk of poor grading (G3–G4) (OR = 5.0; 95% CI: 1.9–13.4). Median overall follow-up was 27 months (range: 2–212). At multivariate analysis, the only characteristics that significantly reduced the survival of the CRC patients were: HIV-positive status (hazard ratio (HR): 2.4; 95% CI: 1.1–5.2) and Dukes’ stage D (HR: 3.7; 95% CI: 1.9–7.1). Conclusion: Our data show that HIV-positive CRC patients compared to HIV-negative patients have a poorer PS, an unfavorable Dukes’ stage, higher grading and shorter survival.

Anal Cancer: Focus on HIV-Positive Patients in the HAART Era

Anal cancer represents an increasing health problem, especially in immune-compromised patients, as HIV-positive patients. Notably, a significant higher incidence rate is reported among HIV infected patients with the advent of highly active antiretroviral therapy (HAART). To date, no randomised trial supports the correlation between existing screening strategies and reduced progression of anal intraepithelial neoplasia (AIN) to anal cancer or improved survival. Nevertheless, screening and treatment of AIN by topical agents should be implemented in high risk population. Data on invasive anal cancer treatment show that combined modality treatment (CMT) is the treatment of choice. Early reports on HIV-positive patients describe higher treatment toxicity and a relation with lower CD4 count and higher HIV viral load. More recently, reported outcomes seem to be similar in HIV-positive population and general population. Reports on a rise in local recurrence rates and in acute side effects along with a correlation with pre-treatment CD4 counts in HIV-positive patients, are not confirmed by all authors. The development of the first approved vaccine is a milestone in the field of anogenital cancers. However, many questions are still unresolved especially as concerns immunization in the setting of HIV infection.

Adjuvant radiotherapy on older and oldest elderly rectal cancer patients

The purpose of this study was to evaluate the impact of radiotherapy in terms of feasibility and activity in the patients aged > or = 75 with advanced rectal cancer. From January 2002 to December 2006, 41 consecutive patients (27 men and 14 women) aged > or = 75 received radiotherapy for local advanced rectal cancer, 9 in a pre-operative and 22 in a post-operative setting. Sixteen patients received concomitant chemotherapy. Variables considered were age, co-morbidities, evaluated according to the adult co-morbidity evaluation index (ACE-27), surgery versus no surgery, and timing of radiotherapy. The median age was 80.5 years (range 75-90). A total of 19.5% of the patients had no co-morbidity, 48.8% mild, 17.1% moderate, and 14.6% had severe co-morbidities. Thirty-nine subjects (95.1%) were submitted to surgery. All patients but one completed the planned radiation schedule. At a median follow-up of 23.1 months, the 2- and 4-year overall survival rates were 71.8% and 61.6%, respectively. There was a better survival for patients with no or mild co-morbidities (p=0.002) and a good performance status (p=0.003). The cancer-free survival at 2 and 4 years was 78.9% and 26.4%, respectively. No difference in acute and late toxicity rates was found between patients with different ACE-27 indexes. We conclude that compliance with radiotherapy is good and rate of toxicity is acceptable in elderly patients. Patients with no or mild co-morbidities have a significantly better survival. Increasing severity of co-morbidity may sufficiently shorten remaining life expectancy to cancel gains with adjuvant radiotherapy. Further prospective trials are needed to confirm these results.

Oxaliplatin Based Chemotherapy and Concomitant Highly Active Antiretroviral Therapy in the Treatment of 24 Patients with Colorectal Cancer and HIV Infection

BACKGROUND Although FOLFOX4 is considered the standard chemotherapy regimen for colorectal cancer (CRC), few data are available on its results in human immunodeficiency (HIV)-related CRC. The results were analyzed to evaluate feasibility and activity of FOLFOX4 plus highly active antiretroviral therapy (HAART) in metastatic CRC (mCRC) HIV-seropositive patients. PATIENTS AND METHODS From January 2002 to March 2007, 24 patients were selected among the CRC HIV-seropositive patients treated with FOLFOX4 and concomitant HAART within the Italian Cooperative Group on AIDS and Tumors (GICAT). RESULTS Four median cycles of chemotherapy were administered; the most common severe toxicity was neutropenia (37.5%). An overall response rate of 50% was observed; 4.2% of patients achieved complete response and 45.8% partial response. No opportunistic infections occurred during or immediately after chemotherapy. The median CD4+ count was 380 (range 220-570) at diagnosis. CONCLUSIONS To our knowledge, this is the largest study describing activity and tolerability of FOLFOX4 and HAART, in this setting. FOLFOX4 plus concomitant HAART resulted feasible and active also in HIV-seropositive patients. Moreover, the concomitant use of HAART did not to seem to increase the FOLFOX4 toxicity. This study suggests the good tolerability of the FOLFOX4, making it a reasonable option for combination with HAART.

FOLFOX4 in the treatment of metastatic colorectal cancer in elderly patients: A prospective study

Elderly patients constitute a subpopulation with special characteristics that differ from those of the general population and have been under-represented in clinical trials. We, prospectively, analyzed the toxicity and efficacy of the original FOLFOX4-regimen in the treatment of elderly patients affected by metastatic (m) colorectal cancer (CRC). Thirty-six consecutive patients aged 67-82 years (median age 72 years), 22 males and 14 females, with mCRC and measurable disease, were enrolled in the study. The primary site of metastases was the liver (36.1% of patients). The median ECOG Performance Status (PS) was 1. The main hematological and extra-hematological (grade 3 or 4) toxicities were neutropenia (38.9%) and neurological (13.9%), respectively. A total of 36 patients, aged 67-82 years were included. Twenty-two and 14 patients were male and female, respectively. The median age was 72 years (range 67-82). The primary site of metastases was the liver (36.1% of patients). The median ECOG Performance Status (PS) was 1. The overall response rate (ORR) was 44.4% and similar to original study. Median progression-free survival (PFS) was 7.5 months and median overall survival (OS) was 16 months. The main hematological and extra-hematological (grade 3 or 4) toxicities were neutropenia (38.9%) and neurological (13.9%), respectively. Tolerability, however, was manageable and no toxic death occurred. FOLFOX4-regimen maintains its efficacy, and safety ratio in elderly patients with mCRC and good performance status. It would be considered the treatment of choice in the treatment of this particular setting of patients.