Oral melanoma and other pigmentations: when to biopsy?

Oral pigmentations (OPs) are often neglected, although a meticulous examination of the oral cavity is important not only in the diagnosis of oral melanoma, but also for the detection of important clinical findings that may indicate the presence of a systemic disease. OPs may be classified into two major groups on the basis of their clinical appearance: focal and diffuse pigmentations, even though this distinction may not appear so limpid in some cases. The former include amalgam tattoo, melanocytic nevi, melanoacanthoma and melanosis, while the latter include physiological/racial pigmentations, smoker's melanosis, drug-induced hyperpigmentations, postinflammatory hyperpigmentations and OPs associated with systemic diseases. We will discuss the most frequent OPs and the differential diagnosis with oral mucosal melanoma (OMM), underlining the most frequent lesions that need to undergo a bioptic examination and lesions that could be proposed for a sequential follow-up.

Liver metastases from prostate cancer at 11C-Choline PET/CT: a multicenter, retrospective analysis.

AIM: During our daily clinical practice using 11C-Choline PET/CT for restaging patients affected by relapsing prostate cancer (rPCa) we noticed an unusual but significant occurrence of hypodense hepatic lesions with a different tracer uptake. Thus, we decided to evaluate the possible correlation between rPCa and these lesions as possible hepatic metastases. MATERIALS AND METHODS: We retrospectively enrolled 542 patients diagnosed with rPCa in biochemical relapse after a radical treatment (surgery and/or radiotherapy). Among these, patients with a second tumor or other benign hepatic diseases were excluded. All patients underwent 11C-Choline PET/CT during the standard restaging workup of their disease. We analyzed CT images to evaluate the presence of hypodense lesions and PET images to identify the relative tracer uptake. In accordance to the subsequent oncological history, five clinical scenarios were recognized [Table 1]: normal low dose CT (ldCT) and normal tracer distribution (Group A); evidence of previously unknown hepatic round hypodense areas at ldCT with normal rim uptake (Group B); evidence of previously known hepatic round hypodense areas at ldCT stable over time and with normal rim uptake (Group C); evidence of previously known hepatic round hypodense areas at ldCT, in a previous PET/CT scan, with or without rim uptake and significantly changing over time in terms of size and/or uptake (Group D); evidence of hepatic round hypodense areas at ldCT with or without rim uptake confirmed as prostate liver metastases by histopathology, triple phase ceCT, ce-ultra sound (CEUS) and clinical/biochemical evaluation (Group E). We evaluated the correlation with PSA level at time of scan, rim SUVmax and association with local relapse or non-hepatic metastases (lymph nodes, bone, other parenchyma). RESULTS: Five hundred and forty-two consecutive patients were retrospectively enrolled. In 140 of the 542 patients more than one 11C-choline PET/CT had been performed. A total of 742 11C-Choline PET/CT scans were analyzed. Of the 542 patients enrolled, 456 (84.1%) had a normal appearance of the liver both at ldCT and PET (Group A). 19/542 (3,5%) belonged to Group B, 13/542 (2.4%) to Group C, 37/542 (6.8%) to Group D and 18/542 (3.3%) to Group E. Mean SUVmax of the rim was: 4.5 for Group B; 4.2 for Group C; 4.8 for Group D; 5.9 for Group E. Mean PSA level was 5.27 for Group A, 7.9 for Group B, 10.04 for Group C, 10.01 for Group D, 9.36 for Group E. Presence of positive findings at 11C-Choline PET/CT in any further anatomical area (local relapse, lymph node, bone, other extra hepatic sites) correlated with an higher PSA (p = 0.0285). In both the univariate and multivariate binary logistic regression analyses. PSA, SUVmax of the rim, local relapse, positive nodes were not associated to liver mets (Groups D-E) (p > 0.05). On the contrary, a significant correlation was found between the presence of liver metG (group D-E) and bone lesions (p= 0.00193). CONCLUSION: Our results indicate that liver metastases in relapsing prostate cancer may occur frequently. The real incidence evaluation needs more investigations. In this case and despite technical limitations, Choline PET/CT shows alterations of tracer distribution within the liver that could eventually be mistaken for simple cysts but can be suspected when associated to high trigger PSA, concomitant bone lesions or modification over time. In this clinical setting an accurate analysis of liver tracer distribution (increased or decreased uptake) by the nuclear medicine physician is, therefore, mandatory.

Hybrid (intravenous and oral) administration of vinorelbine plus cisplatinum followed by oral vinorelbine as first-line therapy of advanced non-small cell lung cancer: a phase II study.

BACKGROUND: The combination of alternate i.v./oral (hybrid) administration of vinorelbine (VNR) plus cisplatin (CDDP), followed by oral VNR, could result in a more suitable first-line regimen for patients (pts) with advanced non-small cell lung cancer (aNSCLC) in the outpatient setting. METHODS: The induction treatment consisted of CDDP 80 mg/m(2) i.v. and VNR 25 mg/m(2) i.v. day 1 and VNR 60 mg/m(2) oral day 8, every 3 weeks for 4 courses. A dose escalation of VNR to 80 mg/m(2) oral from day 8 of the second course and to 30 mg/m(2) i.v. from day 1 of the third course was planned in the absence of G3-4 toxicity. Pts with disease control after 4 courses underwent consolidation treatment with oral VNR 80 mg/m(2) days 1 and 8 every 3 weeks up to intolerance or progression. RESULTS: Fifty-three pts entered the study: 80% males; median age 63 years (range 43-71); median ECOG PS 0 (range 0-1); histotype: adenocarcinoma 59%, epidermoid 31%, undifferentiated 10%; disease stage: IIIB 22%, IV 70%, recurrent disease 8%. The objective response was as follows: 1 (2%) CR, 20 (38%) PR, 16 (30%) SD, 11 (21%) PD and 5 (9%) pts were not assessable. Median TTP and OS were 6 and 10 months, respectively. G3-4 neutropenia was observed in 23 and 24% of pts in the induction and in the consolidation phases, respectively, with febrile neutropenia in 6 pts (11%) and 2 (8%), respectively. G3-4 non-haematological toxicity was rare, being represented by nausea-vomiting and neurotoxicity in 3 pts (6%) in the induction phase. CONCLUSIONS: This combination regimen including hybrid administration of VNR plus CDDP is feasible, tolerable and effective as a first-line treatment in pts with aNSCLC.

Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer.

This study compares two cytotoxic regimens comprising the same dose and schedule of cisplatin (CP) plus vinorelbine (VNR) or gemcitabine (GEM) administered under the same schedule to patients with advanced non-small cell lung cancers (NSCLC). From April 1998 to February 2003, 285 patients were randomised to receive either VNR 25 mg/m(2) on days 1 and 8 as an intravenous (i.v.) bolus plus CP 75 mg/m(2) on day 1 (regimen A) or GEM 1200 mg/m(2) on days 1 and 8 as an i.v. 30-min infusion plus CP 75 mg/m(2) on day 1 (regimen B). Both treatments were recycled every 21 days. If no progression had occurred after six cycles, the patients continued to receive VNR or GEM monochemotherapy weekly. Cross-over of the two single agents was considered if disease progression occurred. Objective response (OR), time to progression (TTP) and overall survival (OS) were analysed according to the intention-to-treat principle. 272 patients were ultimately eligible (137 on A and 135 on B). Their main characteristics were: male/female ratio 214/58; median age 63 (range 32-77) years; median Karnofsky Performance Status (PS) 80 (range 70-100); stage IIIB 34%, stage IV 61%, recurrent disease 5%; histology - epidermoid 29%, adenocarcinoma 53%, other NSCLC 18%. The characteristics of the patients in the two arms were well matched. The following response rates were observed in regimens A and B, respectively: complete response (CR) 0.7% and 3.7%, partial response (PR) 31.9% and 22.2% (P = 0.321). Median CR+PR duration was 8 months in both arms. Clinical benefit represented by an improvement in symptoms was evident in 25.7% and 28.1%, respectively. Median TTP was 5 months in both arms and median OS 11 months in both arms. Grade III-IV neutropenia occurred in 30.7% and 17.7% of the patients in arms A and B, respectively (P = 0.017); thrombocytopenia occurred in 0% and 9.3% (P = 0.004), respectively. No difference in the incidence of anaemia was observed. Non-haematological toxicity was generally mild: a higher incidence of grade 1-2 peripheral neurotoxicity and grade 1-2 local toxicity with regimen A and grade 1-2 liver toxicity with regimen B was reported. A pharmaco-economic comparison showed a difference between the two doublets, principally due to the different costs of VNR and GEM. Under the study conditions the combination of VNR or GEM with the same dose and schedule of CP produced similar OR, clinical benefits, TTP and OS in advanced NSCLC, and only mild toxicological differences were observed. Pharmaco-economic evaluation favoured the CP + VNR doublet.

Combination chemotherapy with mitoxantrone, methotrexate, and mitomycin (MMM regimen) in malignant pleural mesothelioma: a phase II study.

The prognosis of malignant pleural mesothelioma is poor, with a median survival time from diagnosis of 7 to 17 months. At present there is no standardized treatment of this neoplasia. Between July 1995 and January 1999, 22 patients with malignant pleural mesothelioma were enrolled in our study. The characteristics of patients were: 16 men and 6 women; median age 61 years (range, 49-77 years); stage (according to Butchart): 8 patients stage I, 10 stage II, 2 stage III, and 2 stage IV; cytologic diagnosis in 5 cases and histologic diagnosis in 17 cases. The treatment consisted of mitoxantrone 10 mg/m2 intravenous (IV) or intrapleural (IPL), methotrexate 35 mg/m2 IV, and mitomycin 7 mg/m2 IV on day 1 and repeated every 3 weeks, with mitomycin in alternate cycles (MMM regimen). One complete response (4.5%) (42 months of duration) and 6 partial responses (27.3%) (5, 5, 7, 9, 14, and 19 months of duration) were achieved; the overall response rate (ORR) was 31.8% (95% CI, 12.4-51.3%); 7 patients were stable under this treatment (31.8%). According to the pathologic type, ORR for the only epithelial type was 39.9% (95% CI, 15.2-64.8%). Median time to progression was 6 months (range, 1-22). The overall median survival time was 13.5 months (range, 1-50); the median survival time of responders significantly differed from that of nonresponders (18.0 versus 8.5 months; p = 0.017). This treatment produced a considerable clinical benefit, with improvement of dyspnea (68.4%) and pain (33.3%); 15 of 19 patients (78.9%) with pleural effusion at the time of diagnosis showed an important reduction in pleural fluid during chemotherapy. Hematologic toxicity was the main side effect; World Health Organization grade III to IV of neutropenia, anemia, and thrombocytopenia were observed in 81.8%, 13.6%, and 22.7% of patients, respectively. From the data presented here, this regimen can be considered active in the treatment of malignant pleural mesothelioma.

A new regimen of cisplatin, epirubicin and methotrexate (PEM-3) as primary chemotherapy for locally advanced bladder cancer.

In this phase II study, 41 patients with locally advanced urothelial bladder cancer (T2-4, N0, M0) were treated with primary chemotherapy (cisplatin, epirubicin, methotrexate: PEM-3). All the patients were assessable for response and toxicity. Clinical monitoring was performed with computerized tomography and cystoscopy. Nineteen clinical complete remissions (46%) and 10 partial remissions (24.5%) were obtained (CR + PR, 70.5%; 95% confidence interval, 57%-85%). Ten patients were considered to have clinically stable disease (24.5%), and 2 patients progressed (5%). Surgery after chemotherapy was performed in 22 cases: in 6 patients (27%) a pathologic complete response was achieved. The pathologic stage was lower than the initial clinical stage in 13 patients (59%). After a median follow-up of 3 years (range, 1-4), the median time to progression was 104 weeks. At this writing, 20 patients, 12 of which were submitted to surgery and 8 were not operated, are disease-free. The 3-year survival rate is 52%. No one had to interrupt the treatment because of toxicity. In conclusion, the PEM-3 regimen is a very active and well-tolerated regimen in locally advanced bladder cancer.

A phase II study of carboplatin and cyclophosphamide in advanced ovarian carcinoma.

Forty-two patients affected by either stage III and IV ovarian cancer with residual tumor after surgery or recurrent ovarian cancer entered a phase II study of the combination carboplatin 300 mg/m2 and cyclophosphamide 600 mg/m2 every 28 days. Thirty-eight patients were evaluable for response and of these 27 obtained complete or partial remission with a 71% overall remission (clinical complete remission 45%; partial remission 26%). Treatment tolerability was on the whole good. The most frequent side effects were leukopenia (76%), anemia (67%) and nausea/vomiting (60%). Thrombocytopenia was present in 31% of the patients, but nearly always to a mild degree except for one grade 4 case. No other grade 4 side effect was observed. We did not observe any cases of nephrotoxicity and only two patients complained of paresthesia. This carboplatin-cyclophosphamide combination in advanced ovarian carcinoma produces comparable results, in terms of objective responses, to those obtained with standard cisplatin-based regimens, with suggestion of a better toxicological profile.

Folinic acid plus 5-FU based chemotherapy in squamous cell carcinoma of the head and neck: Bologna experience.

BACKGROUND: The principal aim of our policy in the cytotoxic treatment of advanced squamous cell carcinoma of the head and neck (SCCHN) is to reduce toxicity, to maintain or increase the response rate and consequently to improve the quality of life for these patients. In locally advanced disease the aim is to reduce the volume of the tumor and to treat micrometastases in order to achieve a better outcome of the subsequent local treatment (i.e., surgery and/or radiotherapy). In these patients the aim is to prolong survival. PATIENT AND METHOD: We have employed 3 different multi-drug regimens with 5-FU+FA combination in 87 consecutive patients with SCCHN. Two regimens (B1, C) have been used for recurrent and/or metastatic disease and only one (B2) for previously untreated patients with locally advanced SCCHN. Regimen B1: cisplatin (P) 30 mg/m2 i.v., 5-fluorouracil (5-FU) 500 mg/m2 i.v., folinic acid racemic form (d, 1-FA) 200 mg/m2 i.v., bleomycin (B) 15 mg im 1st and 2nd day; Regimen C: P 60 mg/m2 1st day, 5-FU 500-750 mg/m2 continuous infusion, FA 50 mg po every 4 hours, B 15 mg im 2nd and 3rd day; Regimen B2 is similar to the B1 but lasts 3 consecutive days (instead of 2) and for every 3 weeks (instead of 4). It consists of 3 cycles before surgical treatment or radiotherapy. RESULTS: There are no statistical differences in the Objective Response (OR) for the regimens B1 (39%) and C (34%). Grade 3-4 toxicity is higher in regimen B1 (50%) than in regimen C (< or = 8%). CONCLUSION: Regimen C is less toxic regimen B1 with no significant difference in the OR. The primary treatment study is still ongoing but the preliminary results are promising: the remission rate is 92% (22/24, 1CR + 21 PR) and the median survival is 18 months (range 3-38+).

Epirubicin metabolism and pharmacokinetics after conventional- and high-dose intravenous administration: a cross-over study.

In a pharmacokinetics study, six patients were treated i.v. with epirubicin (EPI) at the two dose levels of 60 and 120 mg/m2, whereas a further six patients were treated at 75 and 150 mg/m2. Both groups were studied according to a balanced cross-over design; the aim of the study was to assess the pharmacokinetic linearity of epirubicin given at high doses. Both the absolute goodness of fit and the Akaike Information Criterion (AIC) point to a linear, tricompartmental open model as the choice framework for discussing EPI plasma disposition after 16/24 administrations, independent of the delivered dose. After 8 treatments, the minimal AIC value corresponded to a nonlinear tissue-binding model. However, even in these cases, second-order effects were present only during the early minutes following treatment. In a model-independent framework, mean EPI plasma clearance was identical at the two dose levels of 60 and 120 mg/m2 (65.4 +/- 8.0 vs 65.3 +/- 13.4 l/h, P = 0.92). Both the mean residence time (MRT) and the volume of distribution at steady-state (VSS) were similar as well (MRT: 22.6 +/- 2.9 vs 24.2 +/- 3.7 h; P = 0.46; VSS: 21.3 +/- 1.5 vs 22.6 +/- 6.5 l/kg, P = 0.46). No statistically significant difference could be found in mean statistical-moment-theory parameters determined after 75- and 150-mg/m2 EPI doses (plasma clearance, PlCl: 83.4 +/- 13.5 vs 68.5 +/- 12.8 l/h, P = 0.12; MRT: 22.6 +/- 4.8 vs 21.9 +/- 3.9 h, P = 0.60; VSS: 26.7 +/- 10.5 vs 21.2 +/- 7.0 l/kg, P = 0.17). Analysis of variance also failed to reveal any significant correlation between dose and plasma clearance. However, when data relative to single patients were examined, a trend toward nonlinear drug distribution as well as a consequent increase in peripheral bioavailability could be observed in 4/6 patients of the 75-mg/m2 vs the 150-mg/m2 group.(ABSTRACT TRUNCATED AT 400 WORDS)

Chemotherapy with cisplatin, epirubicin, methotrexate in the treatment of locally advanced or metastatic transitional cell cancer of the bladder (TCC).

Forty patients with advanced transitional cell cancer (TCC) of the bladder were treated with cisplatin, epirubicin, methotrexate (PEM, every 3-4 weeks). If creatinine clearance was reduced to 40 ml/min, the usual full doses of cisplatin and methotrexate, 50 mg/m2, were proportionally reduced. 23 patients had full-dose (FD) therapy, 17 had reduced dose (RD) (40-20 mg/m2). Two patients achieved complete response and 17 partial response. The overall response rate was 19/40 (47.5%), 11/23 (48%) for FD and 8/17 (47%) for RD (p = 1.000). 17/40 pts (42.5%) had no-change and 4/40 (10%) had disease progression. The median duration of CR and PR was 32 weeks, range 4-82 (22 weeks, range 12-52 for FD; 32 weeks, range 4-82 for RD, cisplatin p = .7362). The main side effect was vomiting (35/40 pts, 87.5%, 20/23 = 87% for FD, 15/17 = 90% for RD, p = 1.000). Leukopenia was observed in 12 patients (30%, nadir 3,240 range 900-3,800, 6/23 = 26% for FD, 6/17 = 35% for RD, p = .7285), alopecia in 18 patients (45%, 15/23 = 65% for FD, 3/17 = 18% for RD, p = .004). The results of this study show that a dose escalation to 50 mg/m2 for cisplatin, epirubicin and methotrexate in the PEM regimen results in an increase in overall response (OR) (19/40 = 47.5%) with respect to a historical control using the same drugs at doses of 40 mg/m2 (12/35 = 34%). In patients with normal renal function the escalated dose was tolerated without a corresponding increase in toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Activity of high-dose epirubicin in advanced non-small cell lung cancer.

24 patients with unresectable non-small cell lung cancer (NSCLC) (14 stage IIIB and 10 stage IV) with a performance status of 70% or higher and without liver metastases received 120-165 mg/m2 epirubicin as an intravenous bolus every 21-28 days up to the maximum cumulative dose of 900 mg/m2. 6 patients (25%) (95% confidence limits 9.8-46.7%) achieved partial remission for a median duration of 7.5 months (range: 3-13+). The median dose actually administered per course was 120 mg/m2 in responsive and non-responsive patients. The dose-limiting side-effect was neutropenia. 1 patient receiving the higher dose died of drug-related infection. Other non-dose-related grade 3 side-effects were alopecia (100%) and vomiting (17%). In 4 patients, the treatment was interrupted because of a greater than 10% reduction in the left ventricular ejection fraction as calculated by radionuclide angiocardiography. None of these patients suffered from cardiac symptoms. The median survival was 10 months (range 1-16). These data suggest that epirubicin at 120-135 mg/m2 may have higher antitumour activity than standard doses in patients with NSCLC. Further studies are needed to clarify whether or not high-dose epirubicin increases, the risk of cardiotoxicity compared to standard doses.

High-dose epirubicin for untreated patients with advanced tumours: a phase I study.

In a phase I study, epirubicin was administered as an intravenous bolus at an initial dose of 105 mg/m2 in untreated patients with advanced tumours considered resistant to antineoplastic treatment. A 15 mg/m2 dose escalation was done every 3 patients if toxicity was below grade 3 or every 6 patients if at least 1 patient had grade 3 toxicity. 18 patients entered the study. The dose was (mg/m2): 105 (3 patients), 120 (3), 135 (3), 150 (6) and 165 (3). The maximally tolerated dose was 165 mg/m2. The dose-limiting toxicity was neutropenia. Other side-effects were nausea/vomiting (78%) and alopecia (100%). 4 patients stopped treatment because of a decrease in left ventricular ejection function, without clinical signs of cardiotoxicity. A complete response was observed in a patient with abdominal metastases from unknown origin at 105 mg/m2 and a partial response in 2 out of 7 patients with non-operable non-small cell lung cancer, at 135 and 150 mg/m2, respectively. The recommended dose for phase II trial is 135-150 mg/m2.

Pharmacokinetics of PTT-119 in man.

The pharmacokinetics of PTT-119, a new alkylating agent, was studied in 8 advanced cancer patients. PTT-119 disappeared rapidly from plasma after administration at a dose of 3 mg/kg by i.v. bolus injection. The HPLC method shows plasma levels of m-bis (dichloroethyl)amino-phenyl-L-alanine which is the major metabolite of PPT-119. Elimination of the drug from plasma can be described by a one-compartment model. Mean values of 77.8 min for the half-life, 510.8 ml/min for the total plasma clearance and 0.69 l/kg for the volume of distribution were found.