MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.

BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.

Pegylated liposomal doxorubicin and gemcitabine in the front-line treatment of recurrent/metastatic breast cancer: a multicentre phase II study.

This multicentre phase II study was aimed at investigating the activity and safety of pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) as front-line therapy in a large series of chemotherapy-naïve recurrent/metastatic breast cancer patients. From June 2003 to December 2006, a total of 71 recurrent/metastatic breast cancer patients were enrolled. Median age was 63 years (range=37-79), and 31 patients (43.7%) were > or =65 years old. Patients received PLD, 25 mg m(-2), day 1, followed by GEM, 800 mg m(-2), days 1 and 8, q21. Response was evaluable in 64 cases. Eight complete (12.5%) and 17 partial responses (26.6%) were registered, with an overall response rate of 39.1%. Thirty patients (46.9%) experienced stable disease, with an overall clinical benefit of 85.9%. Median time to progression (TTP) was 11 months, whereas median overall survival (OS) was not reached. The rate of 1- and 2-year OS was 79 and 61%, respectively. A total of 443 courses were evaluable for toxicity: grade 3 and 4 neutropaenia affected 14 patients (20.3%) and 3 patients (4.3%), respectively. Grade 3 and 4 palmar-plantar erythrodysesthesia syndrome was documented in five cases (7.2%) and one case (1.4%), whereas grade 3 and 4 mucositis occurred in six cases (8.7%) and two cases (2.9%), respectively. Grade 2 cardiac toxicity was observed in only one case. Interestingly enough, there was no difference in the percentage and severity of either haematological or non-haematological toxicity according to the age of the patients (<65 vs > or =65 years). We confirmed in a large, very homogenous study sample of chemotherapy-naïve recurrent/metastatic breast cancer patients the efficacy and safety of PLD/GEM combination, providing response rates, median TTP and OS values comparable with those achieved with more toxic combinations.

Weekly gemcitabine and cisplatin chemotherapy: a well-tolerated but ineffective chemotherapeutic regimen in advanced pancreatic cancer patients. A report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

BACKGROUND: This phase II study was initiated to determine the activity and toxicity of a combination of gemcitabine (GEM) and cisplatin (CDDP) in patients with pancreatic cancer. PATIENTS AND METHODS: CDDP 35 mg/m(2) was given as a 30-min infusion and GEM 1000 mg/m(2) as a 30-min infusion. Both drugs were administered once weekly for 2 consecutive weeks out of every 3 weeks to chemonaive patients with locally advanced or metastatic pancreatic cancer. RESULTS: Forty-five advanced pancreatic cancer patients received this regimen for a total of 180 cycles of chemotherapy. One complete and four partial responses have been observed for an overall response rate of 9% (95% confidence interval 10% to 11%). Twenty-one patients (46%) had stable disease and 19 progressed on therapy. The median time to progression was 3.6 months, with a median survival of 5.6 months. A clinical benefit was obtained in nine of 37 patients (24%). Side-effects were mainly represented by hematological toxicity. Grade 3/4 WHO toxicities included neutropenia (6% of the patients) and thrombocytopenia (11%). The dose of GEM and CDDP was reduced in 14 patients (31%) and treatment was delayed in 10 patients (22%). CONCLUSIONS: Our results in terms of response rate, clinical benefit and survival do not support an advantage for the combination of GEM and CDDP given by this schedule.

[Prevention and treatment of mucositis from cytotoxic chemotherapy]. / Prevenzione e trattamento della mucosite da chemioterapici antiblastici.

The administration of several chemotherapeutic regimens could be conditioned by the onset of mucositis. The characteristic lesions of the mucositis affect whole buccal mucosa. That derives from rapid turnover of the oropharyngeal epithelial surfaces. The mucosa can suffer from direct damage of antiblastic drugs or be susceptible of microbic infections. Moreover, other factors correlated to the patients as age, nutritional status, tumor type, oral hygiene and neutrophil count. Up to date, there is not a standard therapy for the cure or mucositis prevention. Some formalities can be employed in order to reduce chemo-induced damage: 1) altering the distribution and the excretion of drugs on the mucosa; 2) stimulating the basal cells of the mucosa; 3) trying to modify the infectious or inflammatory risks. The effective oral care, dietary changes and the use of protective topical and the careful use of topical and systemic anesthetic drugs are the cornerstones of mucositis care.

Raltitrexed plus oxaliplatin (TOMOX) as first-line chemotherapy for metastatic colorectal cancer. A phase II study of the Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD).

BACKGROUND: To evaluate the safety and efficacy of the novel raltitrexed/oxaliplatin combination (TOMOX) as first-line chemotherapy for patients with advanced colorectal cancer. MATERIALS AND METHODS: Previously untreated patients with metastatic colorectal cancer received raltitrexed 3 mg/m2 plus oxaliplatin 100 mg/m2, both intravenously, on day 1 every 3 weeks. Patients were re-evaluated after every third cycle and chemotherapy was continued up to tolerance or disease progression. RESULTS: Fifty-eight patients from 13 Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD) centers were accrued from September 1999 to November 2000. According to the intention-to-treat analysis from 58 patients, the overall response rate was 50% [95% confidence interval (CI) 38% to 62%], with three complete responses and 26 partial responses. The median overall survival (44 patients currently alive) was >9 months and the median time to disease progression was 6.5 months (range 1-15 months). The main hematological toxicity was grade III/IV neutropenia, which occurred in 17% of patients, while anemia and thrombocytopenia were uncommon. Grade III/IV non-hematological toxicities were transient transaminitis (17% of patients); asthenia (16% of patients); neurotoxicity (10% of patients) and diarrhea (7% of patients). No toxic death was observed, one patient with grade IV asthenia after the first cycle refused chemotherapy. CONCLUSIONS: The results of this study suggest that the TOMOX combination is an effective and well tolerated regimen for the treatment of advanced colorectal cancer. Its ease of administration and patient tolerance warrant further investigation as an alternative to fluoropyrimidine-based regimens with repeated and prolonged fluorouracil infusions.

[Second-line chemotherapy and new drugs for ovarian carcinoma]. / Chemioterapia di seconda linea e nuovi farmaci nel carcinoma ovarico.

Epithelial ovarian carcinoma represents a prototypic example of neoplastic disease sharing at the same time good chemosensitivity as well as marked propensity to relapse. If in one hand the definition of almost clear-cut guidelines has been reached in the setting of first-line therapy (i.e., cytoreductive surgery followed by first-line chemotherapy), more difficult to discern for the oncologist remains the choice of treatment in the occasion(s) of relapse(s). This article focuses on this particular setting of disease, analyzing the specific criteria of choice of drug or their combinations; the definite criteria followed for the use of platinum compounds in the second line of treatment, even if already utilized in the front line therapy, are also analyzed. Specific attention has also been paid in the definition of the role of single parameter as a "prognosticator" and/or as "predictor" of response. The Authors emphasize how clinical definitions remain the more reliable, simple, reproducible tools in therapeutical decision making.

[Medullary carcinoma of the thyroid: diagnosis and therapy]. / Il carcinoma midollare della tiroide: diagnosi e terapia.

Medullary thyroid carcinoma (MTC) originates in the thyroid C cells, or parafollicular cells, secreting calcitonin. It may be either sporadic or familial. Familial form can be isolated or expression of a multiple endocrine neoplasia type II. Mutations of the RET proto-oncogene have been identified in the germline DNA of patients with familial MTC syndromes. Genetic testing can identify patients affected by multiple endocrine neoplasia and familial MTC, allowing early diagnosis and possible cure. The initial treatment is surgical and the adequate surgery consists of total thyroidectomy. The treatment of occult or minimal disease can be curative. Plasma calcitonin measurements are excellent markers for post-operative follow-up. Imaging study can help to discover recurrent or metastatic disease. Adjunctive therapy includes radiotherapy and chemotherapy. Radiotherapy is reserved for bone metastases or for non resectable neck recurrences. Chemotherapy is reserved for patients with progressive MTC. Many chemotherapeutic regimens have been tried, results are controversial.

Fludarabine phosphate as an active and well tolerated salvage therapy in an elderly heavily pretreated Hodgkin's disease patient: a case report.

Up to two thirds of all patients affected by advanced Hodgkin's disease will be cured by chemotherapy alone or by combined chemoradiation modalities. High-dose chemotherapy with autologous stem cell rescue may be potentially curative for patients progressing under frontline chemotherapy or developing early relapse of disease. In spite of this, an unacceptably high percentage of these high-risk patients will relapse after salvage treatments and die of their disease. Fludarabine phosphate is an adenosine nucleoside analog highly active in chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphomas. There are only few data in the literature concerning its use in the management of Hodgkin's disease. We report the case of an elderly, heavily pretreated Hodgkin's disease patient in progression under third-line chemotherapy who experienced good palliation of her B symptoms and a major clinical response of her refractory bone lesions with the administration of fludarabine as monotherapy. The treatment was well tolerated, without grade 4 hematological toxicity or opportunistic infections. The duration of clinical remission and systemic symptom palliation was 9 and 11 months, respectively. Further evaluation of fludarabine phosphate as salvage therapy in relapsed/refractory elderly Hodgkin's disease patients is needed.

Return to jeopardy: the fate of pediatric burn patients who are victims of abuse and neglect.

Child abuse and neglect continue to account for a significant number of pediatric burn injuries. Although the epidemiology of intentional burn injuries has been studied, this report compares victims of abuse with victims of neglect. Furthermore, we investigate the long-term fate of both victim and perpetrator. A retrospective search of the North Carolina Jaycee Burn Center database identified 21 abuse and 21 neglect patients among 238 pediatric admissions (mean age, 5.4 years, mean surface area 14%) from 1992 to 1994. The medical, social, and legal records of each patients were examined by two independent reviewers. History, hospital course, and disposition were compared between groups by chi-square analysis and Student's t test. Compared with victims of neglect, abused children were slightly younger (2.1 vs 2.7 years), had somewhat larger burns (12.3% vs 9.05 total body surface area), had inconsistent mechanisms of injury (90% vs 33%, p < 0.002) that were bathroom related (81% vs 29%, p < 0.001), were likely to have a history of abuse (57% vs 24%, p < 0.05) or stigmata of abuse on exam (43% vs 14%, p < 0.05), had longer lengths of stay (23.8 vs 14.1 days, p < 0.05), had similar complication rates, and were place more often in foster care (65% vs 15%, p < 0.01). Inpatient mortality was 5%. Mean follow-up was 108 days, during which time two children were readmitted for repeat abuse. Regarding the caregivers, 57% were single mothers, 36% had been investigated for abuse or neglect, and 12% had lost custody of other children. Of the perpetrators involved in abuse, 71% were charged with a felony, 43% were convicted, and 19% were incarcerated longer than 30 days. Victims of burn abuse and neglect differ considerably in terms of history and disposition but not hospital course. Children in both groups, however, remain at risk for abuse and neglect after discharge. We recommend that more aggressive efforts be made to secure safe environments for these children and that the perpetrator, if clearly identified, be dealt with in a fashion to prevent recurrence of the offense.