Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study.

BACKGROUND: In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination. PATIENTS AND METHODS: This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3(+)CD4(+)ICOS(+)CD45RO(+) or CD45RA(+) T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status. RESULTS: Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in 'memory' but not in 'naïve' T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points. BRAF status did not correlate with clinical outcome. CONCLUSIONS: Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab. EUDRACT NUMBER: 2010-019356-50. CINICALTRIALSGOV: NCT01654692.

Efficacy and safety of ipilimumab in patients with pre-treated, uveal melanoma.

BACKGROUND: Patients with advanced uveal melanoma have a poor prognosis and limited treatment options. Ipilimumab is approved for pre-treated adult patients with advanced melanoma. However, because previous clinical trials with ipilimumab have excluded patients with uveal melanoma, data in this patient population are limited. PATIENTS AND METHODS: Pre-treated patients with advanced uveal melanoma received ipilimumab 3 mg/kg through an expanded access programme, every 3 weeks for four doses. Tumour assessments were conducted at baseline and after completion of treatment and patients were monitored throughout for adverse events. RESULTS: Among 82 assessable patients, 4 (5%) had an immune-related objective response and 24 (29%) had immune-related stable disease lasting ≥3 months for an immune-related disease control rate of 34%. With a median follow-up of 5.6 months, median overall survival (OS) was 6.0 months and median progression-free survival (PFS) was 3.6 months. The 1-year rates of OS and PFS were 31% and 11%, respectively. The safety profile of ipilimumab was similar to that in patients with cutaneous melanoma. CONCLUSIONS: These data suggest ipilimumab 3 mg/kg is a feasible option in pre-treated patients with metastatic uveal melanoma. Evidence of disease control and a 1-year survival rate of 31% indicate the need for further investigation in randomised, controlled trials to determine the optimal timing and use of ipilimumab in this patient population.

Central nervous system failure in melanoma patients: results of a randomised, multicentre phase 3 study of temozolomide- and dacarbazine- based regimens.

BACKGROUND: This study compared the central nervous system (CNS) metastasis incidence between a temozolomide- and a dacarbazine-based regimen in untreated stage IV melanoma patients. METHODS: A total of 150 patients were randomly assigned to receive either oral temozolomide (200 mg m(-2) per day; days 1-5) or intravenous dacarbazine (800 mg m(-2); day 1), in combination with intravenous cisplatin (75 mg m(-2); day 1) and subcutaneous interleukin-2 (3 MU twice daily; days 9-18), every 28 days (CTI and CDI). RESULTS: A total of 149 patients were eligible for an intention-to-treat analysis (CTI: n=74, CDI: n=75). The 1-year cumulative CNS incidence failure was 20.6% for CTI and 31.1% for CDI (P=0.22). In all 24 patients in CTI (32%) and 34 (45%) in CDI developed CNS metastases; 31 patients died of early systemic progression, before CNS evaluation. Median survival time was 8.4 months in the CTI and 8.7 in the CDI arm; in patients with CNS metastases the median survival time was 13.5 months in the CTI and 11.5 in the CDI arm. No difference in toxicity was observed between the two arms. CONCLUSION: The incidence of CNS failures in metastatic melanoma was not significantly reduced and the clinical course was not modified substituting a dacarbazine-based regimen with a temozolomide-based regimen. Patients who developed CNS metastases did not have a worse prognosis than patients progressing in other sites and should not be excluded from new investigational studies.

An environmental analysis for comparing waste management options and strategies.

The debate on different waste management practices has become an issue of utmost importance as human activities have overloaded the assimilative capacity of the biosphere. Recent Italian law on solid waste management recommends an increase in material recycling and energy recovery, and only foresees landfill disposal for inert materials and residues from recovery and recycling. A correct waste management policy should be based on the principles of sustainable development, according to which our refuse is not simply regarded as something to eliminate but rather as a potential resource. This requires the creation of an integrated waste management plan that makes full use of all available technologies. In this context, eMergy analysis is applied to evaluate three different forms of waste treatment and construct an approach capable of assessing the whole strategy of waste management. The evaluation included how much investment is needed for each type of waste management and how much "utility" is extracted from wastes, through the use of two indicators: Environmental yield ratio (EYR) and Net eMergy. Our results show that landfill is the worst system in terms of eMergy costs and eMergy benefits. Composting is the most efficient system in recovering eMergy (highest EYR) from municipal solid waste (MSW) while incineration is capable of saving the greatest quantity of eMergy per gram of MSW (highest net eMergy). This analysis has made it possible to assess the sustainability and the efficiency of individual options but could also be used to assess a greater environmental strategy for waste management, considering a system that might include landfills, incineration, composting, etc.

Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study.

PURPOSE: The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. PATIENTS AND METHODS: Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. RESULTS: 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. CONCLUSIONS: The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. TRIAL REGISTRATION NUMBER: NCT01149343, Results.

Quality of life evaluation in a randomised trial of chemotherapy versus bio-chemotherapy in advanced melanoma patients.

This study analyses the health related quality of life (HRQOL) of advanced melanoma patients, in a randomised trial comparing bio-chemotherapy (bio-CT) versus chemotherapy (CT). The trial enrolled 178 patients and the median survival was not statistically different between the two arms. HRQOL was assessed at baseline and before each cycle of therapy, using the Rotterdam Symptom Checklist (RSCL) questionnaire completed with 140 patients. At baseline, overall quality of life and psychological distress scores were the most impaired, compared with the normal population. During treatment, the difference between the two arms in the changes from baseline was statistically significant (P=0.03) only in the overall quality of life score, with a decrease of 6.28 points in the bio-CT arm. The mean values decreased significantly in all domains in bio-CT arm, but only in activity level and physical symptom distress scores in the CT arm. Testing HRQOL variables and prognostic clinical factors in a Cox model, only the serum level of lactic dehydrogenase, baseline overall quality of life and the physical symptom distress scores remained significant independent prognostic factors for survival. A score of less than 75 points in the overall quality of life and in the physical symptom distress domains was associated with a Hazard Ratio (HR) of 2.31 (95% Confidence Interval (CI): 1.09-4.90) and 1.92 (95% CI: 1.10-3.36), respectively.

The cardiac conduction system in progressive systemic sclerosis. Clinical and pathologic features of 35 patients.

Progressive systemic sclerosis may be associated with focal myocardial fibrosis. Electrocardiographic abnormalities including conduction block are common in progressive systemic sclerosis but whether they are due to direct destruction of the specialized conduction tissue of the heart is uncertain. The conduction systems of 35 patients with progressive systemic sclerosis were studied. Of these 35 patients, 17 (50 per cent) had myocardial fibrosis of the type seen in progressive systemic sclerosis. In 10 of the 17, it was severe. Sinus node fibrosis was present in 13 patients and was nearly as frequent in those with as in those without the progressive systemic sclerosis myocardial lesion. Overlying pericarditis may have contributed to the fibrotic changes within the sinoatrial nodes in seven of the 13 patients. The atrioventricular node and main His bundles were normal. However, fibrotic changes were found in the proximal bundle systems in six patients. In three of the six, severe myocardial progressive systemic sclerosis was present, two had focal fibrous atrophy of the left bundle, and one had complete interruption of the right bundle. In only the latter patient was this reflected in the electrocardiogram which showed a right bundle branch block. Three patients without progressive systemic sclerosis myocardial lesions also had fibrous atrophy of a portion of the proximal left bundle branch, and in one the electrocardiogram showed an isolated left anterior hemiblock. Thus, morphologic abnormalities within the conduction system in our patients are difficult to attribute to progressive systemic sclerosis per se. Furthermore, although conduction abnormalities were more frequent in patients with myocardial disease, specific conduction system disease was not the cause in most patients. As has been noted in ischemic heart disease, the conduction system appears to be relatively spared from the myocardial changes of progressive systemic sclerosis, and the high incidence of conduction disturbances in this condition may be a consequence, rather, of damage to working myocardium.

The conduction system in cardiac amyloidosis. Clinical and pathologic features of 23 patients.

Cardiac amyliodosis is frequently associated with major electrocardiographic conduction disturbances; but that these disturbances are due to infiltrative destruction of the conduction system by amyloid is unclear. We studied the conduction systems in 23 autopsy patients with cardiac amyloidosis (group 1) (mild in seven, moderate in five and severe in 11), 21 (91 per cent) of whom had had abnormalities of conduction or rhythm during life. For comparison, we examined the conduction system in 23 control subjects matched in age and heart weight (group 2). Of the 23 patients in group 1, only three had extensive amyloidosis of the conduction system; in all three, electrocardiograms showed first degree atrioventricular block and left anterior hemiblock. A more common morphologic abnormality of the conduction system was severe sinoatrial node fibrosis present in seven (30 per cent) patients, and idiopathic atrophy and fibrosis of the bundle branches present in six (26 per cent) patients. None of the patients in group 2 had severe sinoatrial node fibrosis, but two (9 per cent) had idiopathic atrophy and fibrosis of the left bundle branch. Marked fibrosis of the sinus node was more frequent in patients with severe or moderate amyloid, but fibrosis of the bundle branch did not appear to be related to the amount of amyloid elsewhere in the heart. Varying degrees of atrioventricular and bundle branch block were also present in six patients with no morphologic abnormalities of the conduction system. Thus, conduction and rhythm disturbances are frequent in cardiac amyloidosis, but direct amyloid infiltration of the specialized conduction tissue of the heart does not account for the majority of these disturbances. Whether the increased incidence of fibrosis of the conduction system in group 1 compared to that in group 2 relates to the infiltrative myocardiopathy is uncertain.

Unusual cardiac, renal and pulmonary involvement in Gaucher's disease. Intersitial glucocerebroside accumulation, pulmonary hypertension and fatal bone marrow embolization.

A 25 year old black woman who had manifestations of Gaucher's disease since one year of age is described. This patient had clinically significant cardiac, renal and pulmonary involvement with Gaucher's disease. Interstitial infiltration of the myocardium by Gaucher cells caused decreased left ventricular compliance and decreased cardiac output. In the kidney, Gaucher cells were present in the mesangium of the glomeruli and the interstitium of the cortex. Also, electron dense, intramembranous granular deposits were seen in glomeruli on electron microscopy. The pulmonary findings included pulmonary arterial hypertension, accentuated basilar deposition of glucocerebroside in the interstitium of alveolar septums and fatal bone marrow embolization.

Schneiderian papillomas: a clinicopathologic study of 30 cases.

Schneiderian papillomas are tumors involving the nasal cavity and paranasal sinuses that tend to recur. A long-term clinical follow-up of 30 patients revealed histologically confirmed recurrences in 20 of the 30 patients (67%) and probable recurrences in two additional patients (combined recurrence percentage 73%). Recurrences were most frequent within 1-2 years following primary thrapy and were generally more frequent in patients with more extensive disease and involvement of paranasal sinuses. Histologic features were not helpful in predicting recurrence. One patient in the study (1/30 = 3%) developed a carcinoma at the site of a histologically confirmed benign Schneiderian papilloma after four recurrences over a period of 9 years. No patients died from the tumor. Twenty patients were alive and free of disease at last follow-up; four patients died of unrelated causes and without evidence of disease; four patients are alive with evidence of disease; and two patients died with disease but of unrelated causes. These tumors often pursue a relentless local course requiring multiple surgical excisions but are rarely responsible for death of the patient and seldon undergo a malignant "transformation" (less than 5%).

Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients.

Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1-9 and 9-12 months; mesothelioma-related pleural effusion severely impairs the patients' quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40-84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9000000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3000000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5-39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and active both in palliation of pleural effusion and on primary tumor, with manageable toxicity. The overall survival observed in nonprogressing patients warrants further randomized studies with IL-2 aimed to the patient outcome.

The perilobular hemangioma. A benign microscopic vascular lesion of the breast.

Vascular tumors of the breast are rare, and reports in the literature suggest that most are malignant. The present study is concerned with a benign vascular tumor of the breast, a lesion generally known as perilobular hemangioma. This microscopic lesion consists of a meshwork of thin-walled, dilated vascular channels that may be situated within a breast lobule or in the extralobular mammary stroma. Hemangiomas of this type were found in seven or 1.2% or 555 mastectomies performed in 1974 in female patients who had mammary carcinoma. There was no association with a specific type of mammary carcinoma. Similar hemangiomas were observed as often in a series of breast biopsies performed for benign conditions. None of the angiomas showed any significant atypia or anaplasia.

Tn-polyagglutinability associated with acute myelomonocytic leukemia.

A case of Tn polyagglutinability in a patient with acute myelomonocytic leukemia is described. This represents the third report in which Tn polyagglutination has been associated with a leukemic state. Serologic recognition of Tn polyagglutination and probable causes are discussed. Known cases of Tn-polyagglutinability are reviewed.

Spontaneous calcific emboli from calcific mitral annulus fibrosus.

Clinically important complications resulting from calcific mitral annulus fibrosus (CMAF) are unusual. They include mitral regurgitation, mitral stenosis, and complete heart block. In one patient with massive CMAF associated with multiple systemic calcific emboli originating from the mitral valve, the emboli were the cause of multiple brain infarcts and a clinical course of unexplained neurological deterioration. We believe that this is the first report of such a complication occurring with CMAF.

Evaluation of toxicity in 22 patients treated with subcutaneous interleukin-2, alpha-interferon with and without chemotherapy.

Biological response modifiers (BRMs) have greatly modified the immunotherapy of tumors. Interleukin-2 (IL-2) has brought about metastasis regression in some cases of malignant tumors, however, when given systemically, it results in high toxicity. More recently, the subcutaneous administration of IL-2 (combined with alpha-interferon, alpha-IFN) seems to be capable of offering the same chances of therapeutic response, but this time with a lower level of toxicity. The Authors report an evaluation of toxicity in 22 patients treated with a combination of IL-2 + alpha-IFN i.m. with or without chemotherapy. The side-effects present in the majority of cases were: fever, diarrhea and asthenia. Approximately 50% of the patients had nausea/vomiting, mucositis, skin rashes, and slight leukopenia. The following side-effects were noted to a much lesser degree, thrombocytopenia, alterations in hepatic and dizziness and cystitis. Only one patient reached 4th degree toxicity, with mucositis, asthenia and skin rash. All the other patients received the treatment without suspensions for toxicity. Biological evaluations will enable us to determine in the future, the cases which can benefit from therapeutic intensification and thus it would seem opportune at this time to use therapy with acceptable toxicity.

Chemotherapy and bio-chemotherapy in patients with advanced melanoma: combination therapy with a nitrosourea.

The treatment of advanced melanoma is still disappointing. In a multicenter randomized clinical trial to compare a chemotherapy (CT) with or without low doses of IL-2 and IFN (Bio-CT), the participating centers chose whether or not to add a nitrosourea, carmustine (BCNU) to the therapy. The aim of the present paper is to report the clinical results of the patients (pts) treated in both arms with BCNU. One hundred and seventy-six pts with advanced melanoma were enrolled in the study from 27 centers and a total of 18 pts also received BCNU in 3 centers. No further changes to the protocol criteria were allowed. One patient refused the treatment. No complete responses were observed. Irrespectively of the treatment arm, 9/17 pts showed a partial response to therapy (53%) (5/9 in the CT and 4/8 in the BioCT arm). The most important adverse events observed were hematological: 12 pts presented grade 3 (6 pts) or grade 4 (6 pts) leukocytopenia and 9 pts had grade 4 thrombocytopenia, all of which resolved spontaneously. The addition of a nitrosourea to CT or Bio-CT appears to improve response rates compared to the same regimens without nitrosourea. Patient tolerability is acceptable. Further studies using this combination are warranted.

Chemotherapy with 5-fluorouracil and streptozotocin in carcinoid tumors of gastrointestinal origin: experiences with 13 patients.

The Authors report their experiences on the treatment of 13 consecutive cases of gastro-intestinal carcinoid tumors observed over the last 11 years. The primary sites were as follows: intestine (5 cases), appendix (3 cases), colon (1 case) and peritoneum (4 cases); only 3 patients presented systemic signs. Ten patients in advanced phase were treated with a chemotherapeutic regimen containing 5-fluorouracil (5-Fu) and streptozotocin (STZ). One case was excluded from the study because of a concomitant gastric carcinoma. Of the 9 evaluable patients, two achieved partial remission (22%) with a duration of 18+ and 66 months respectively; 4 (44.5%) had stable disease for periods ranging from 7 to 40 months and 3 cases progressed. Severe toxicity (thrombocytopenia and diarrhea) occurred in 2 cases and disappeared with the suspension of therapy. The systemic signs disappeared with treatment and did not appear in 2 cases out of 3. The prospective of the employment of new drugs such as alpha-interferon and, above all, somatostatin provides hope that this uncommon disease may have an improved response rate to treatment in the future.

A phase II study of advanced colorectal cancer patients treated with combination 5-fluorouracil plus leucovorin and subcutaneous interleukin-2 plus alpha interferon.

Twenty-one patients with advanced, pretreated colorectal cancer in disease progression were entered in a phase II study to investigate the use of 5-fluorouracil (5FU) + leucovorin with subcutaneous Interleukin-2 + alpha interferon (alpha-IFN). Eighteen of these patients were evaluable for response to treatment: 1 partial response (PR) (duration 8 months), 9 stable disease (SD) (median duration of 6.5 months, range 2-15) and 8 progressive disease (PD). The PR patient survived for 15 months, the SD patients for a median of 11 months and 8 months for PD patients. Toxicity evaluated in the 21 patients reached grade 4 for mucositis in two cases. Grade 3 toxicity was observed more frequently for fever (52.3%) and diarrhea (33.3%) and was most probably the result of the combined side-effect of chemotherapy and the biological response modifiers (BRMs). Treatment was, for the most part, carried out on an out-patient basis as originally planned. In 15 patients tests were carried out to verify whether any immuno-activation had taken place. Significant increases were found during the course of therapy regarding cluster of differentiation activation (HLA-DR, CD71, CS25). Different curves were observed during the course of treatment with respect to the CD8 value, which proved higher in SD patients than in PD patients. Our study would seem to suggest that the addition of BRMs to 5FU + leucovorin could increase survival. The next step, however, must be to determine lower doses of IL-2 for subcutaneous administration in order to reduce toxicity but maintain the same immunostimulation.

N-nitroso compound precursors and gastric cancer: preliminary data of a study on a group of farm workers.

An epidemiological research on gstric cancer mortality rates carried out in the town of Forì is reported. The results are significant as regards the relation between the urban and rural areas, and show a higher risk for gastric cancer in the rural area. Salivary nitrite measurement in 92 farm workers showed particularly high values (over 30 ppm in 4 individuals). Analysis of histological findings in biopsies performed during endoscopy in 46 persons of the group studied showed a great number of CAG and CAG + IM in asymptomatic individuals.

A retrospective study of FAM regimen in 38 patients with advanced gastric cancer.

Gastric carcinoma has a very poor prognosis, with a survival rate at 5 years of 13%. Various chemotherapy regimens have been used in the advanced stages of the disease. The best results were obtained using the FAM combination. We treated 38 patients with advanced measurable gastric cancer using the FAM combination and obtained 23.67% complete plus partial remission (CR + PR) (32% with more restrictive criteria for eligible patients) and 34% no change. The median length of response was 30 weeks in CR patients (range 20-100) and 26 weeks (range 12-34) in PR patients. Responsive patients (CR + PR) had a median survival of 12.3 months (range 5-22) compared to nearly 4 months (range 2-8) for unresponsive patients.