Barbara Melotti

Randomized Trial of Low-Dose Morphine Versus Weak Opioids in Moderate Cancer Pain.

PURPOSE The WHO guidelines on cancer pain management recommend a sequential three-step analgesic ladder. However, conclusive data are lacking as to whether moderate pain should be treated with either step II weak opioids or low-dose step III strong opioids. PATIENTS AND METHODS In a multicenter, 28-day, open-label randomized controlled study, adults with moderate cancer pain were assigned to receive either a weak opioid or low-dose morphine. The primary outcome was the number of responder patients, defined as patients with a 20% reduction in pain intensity on the numerical rating scale. RESULTS A total of 240 patients with cancer (118 in the low-dose morphine and 122 in the weak-opioid group) were included in the study. The primary outcome occurred in 88.2% of the low-dose morphine and in 57.7% of the weak-opioid group (odds risk, 6.18; 95% CI, 3.12 to 12.24; P < .001). The percentage of responder patients was higher in the low-dose morphine group, as early as at 1 week. Clinically meaningful (≥ 30%) and highly meaningful (≥ 50%) pain reduction from baseline was significantly higher in the low-dose morphine group (P < .001). A change in the assigned treatment occurred more frequently in the weak-opioid group, because of inadequate analgesia. The general condition of patients, which was based on the Edmonton Symptom Assessment System overall symptom score, was better in the morphine group. Adverse effects were similar in both groups. CONCLUSION In patients with cancer and moderate pain, low-dose morphine reduced pain intensity significantly compared with weak opioids, with a similarly good tolerability and an earlier effect.

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 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.

Cutaneous adverse effects during ipilimumab treatment for metastatic melanoma: a prospective study.

BackgroundIpilimumab is an immunomodulatory antibody directed against cytotoxicT-lymphocyte-associated antigen 4 (CTLA-4), which is administered to patients with advanced melanoma, with a proven positive effect on overall survival. The cutaneous adverse effects (AEs) of ipilimumab are relatively frequent, although described as usually mild and rarely life threatening.ObjectivesTo describe a three-year experience of a single institute in detecting and managing cutaneous AEs.Materials & MethodsA cohort of patients (n = 41) treated with ipilimumab (3 mg/kg/three weeks) for metastatic melanoma, from 2013 to 2016,was investigated for adverse cutaneous events.ResultsOn dermatological evaluation, 34.1% of the patients in our series developed cutaneous AEs: rash (7.3%; n = 3), folliculitis (7.3%; n = 3), mucositis (2.4%; n = 1), rosacea (2.4%; n = 1), eczema (2.4%; n = 1), acneiform eruption (2.4%; n = 1), syringometaplasia mucinosa (2.4%; n = 1), Stevens-Johnson syndrome (2.4%; n = 1), and vitiligo (4.9%; n = 2). These were all Grade 1 and 2 AEs, except for the case of Stevens-Johnson syndrome (Grade 4). On a patient-reported scale, 4.9% (n = 2) and 9.8% (n = 4) of the patients complained of severe xerosis and pruritus, respectively.ConclusionIpilimumab was relatively well tolerated in our series, mainly causing mild cutaneous AEs, which, in our experience, responded satisfactorily to conventional therapies. Only in one case was the treatment discontinued, due to Grade 4 side effects.

Human papillomavirus evaluation of vemurafenib‐induced skin epithelial tumors: a case series

apoptosis. Off-label uses include pemphigus vulgaris (PV), mucosal membrane pemphigoid, paraneoplastic pemphigus and chronic graft-versus-host disease. Mucosal membrane diseases can be devastatingly destructive and in some cases fatal. PV of the epiglottis treated with rituximab was recently reported. The mechanism by which rituximab improves T cell-mediated LP is difficult to explain as it suggests B cells are implicated in the pathogenesis of LP. The majority of intraepithelial lymphocytes in oral LP are CD8 cytotoxic T cells, but most lymphocytes in the lamina propria are CD4 helper T (Th) cells. CD8 cytotoxic T cells may be activated by the combination of antigen associated with major histocompatibility complex class I on basal keratinocytes and Th1 CD4 T cellderived interleukin (IL)-2 and interferon-c. In RA, Melet et al. found rituximab caused a durable, reversible depletion of peripheral CD4 and CD8 T cells. Rituximab efficacy in PV is probably due to B-cell depletion resulting in decreased desmoglein (Dsg)-specific autoantibodies. PV pathogenesis likely involves both autoreactive Th1 and Th2 cells to promote autoantibody secretion by Dsg3-reactive B cells. Dsg3-specific T cells have also been demonstrated to release IL-4, IL-6 and IL-10. Rituximab may also affect autoreactive T cells and the production of T cell-modulating cytokines, autoantigen processing and the presentation of B cells. Rituximab may exhibit a dual effect in PV by depleting CD20 autoreactive B cells as progenitors of autoantibody secreting plasma cells and indirectly by decreasing the frequency of autoreactive CD4 T cells via depletion of B cells. It was hypothesized that regulatory B cells observed postrituximab could be responsible for the downregulation of Dsg-specific CD4 T cells through the secretion of IL-10. We report two cases of erosive LP successfully treated with the RA rituximab protocol. Conversely, cases of rituximabinduced LP are reported. Further investigation in prospective clinical trials is warranted.

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, smokers 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.

Hair and nail adverse events during treatment with targeted therapies for metastatic melanoma

BackgroundTargeted therapies for melanoma have shown clinical benefit in increasing the survival of metastatic patients. Cutaneous adverse events have been reported, but hair and nail data have been rarely detailed.Materials and methodsPatients treated with BRAF andMEKinhibitors for metastatic melanoma underwent dermatological evaluation before the start of each treatment and after every four weeks. Pull test, global photography, dermoscopy/trichoscopy and scalp biopsy were performed. Appendages adverse events were graded using the National Cancer Institute’s Common Terminology Criteria.ResultsOf the 24 patients included, 14 underwent treatment with a selective BRAF inhibitor; 10 received a combined treatment (dabrafenib/trametinib). Adnexal adverse events were common in the group of patients receiving vemurafenib, and included hair kinking, acute hair loss, and hair colour changes, often present in association, classified as G2 in three patients and G1 in eight. Dabrafenib alone induced hair kinking and colour changes in 60% of the patients. Combined treatment with dabrafenib/trametinib did not induce hair changes. Onycholysis was the most common nail side effect, and the unique side effect of dabrafenib (alone or in combination). Vemurafenib also induced acute paronychia and brittle nails. All nail side effects were graded as G1.ConclusionHair and nail side effects during targeted therapy for melanoma are not rare. The early recognition and cure of such side effects by dermatologists is of benefit to ensure the need for dose reduction or drug discontinuation.

Pembrolizumab in the treatment of metastatic non-small cell lung cancer: a review of current evidence:

Immune checkpoint inhibitors (ICPIs) are considered one of the most important breakthroughs in cancer treatment of the past decade; notably, different studies of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have reported impressive clinical activity and durable responses in patients with advanced non-small cell lung cancer (NSCLC). These findings have led to the changing of the current therapeutic algorithm of advanced NSCLC, adding a new standard first-line treatment option for patients with PD-L1-positive tumors. Pembrolizumab, a highly selective anti-PD-1 humanized monoclonal antibody, was approved by the United States Food and Drug Administration (US FDA) in October 2016 for previously untreated metastatic NSCLC patients whose tumors have high PD-L1 expression, tumor proportion score (TPS) ⩾ 50%, as well as for metastatic NSCLC patients whose tumors express PD-L1 with TPS ⩾ 1% progressing on or after platinum-based chemotherapy. However, many issues remain outstanding, mainly regarding the identification of an optimal biomarker which can help selecting patients more likely to respond to ICPIs. In this review, we discuss the clinical results obtained so far with the anti-PD-1 pembrolizumab in advanced NSCLC, commenting on the role of PD-L1 as a predictive factor and providing an update of the future perspectives.

Chemotherapy treatment in malignant pleural mesothelioma: a difficult history

Malignant pleural mesothelioma (MPM) is a rare neoplasm that typically arises from mesothelial surfaces of the pleural cavity. Despite treatment improvements, it carries a dismal prognosis. The majority of patients either have unresectable disease or are not candidates for surgery due to medical comorbidities or old age. For such patients, chemotherapy (CT) represents the gold-standard treatment. To date, combination CT with cisplatin plus pemetrexed represents the most widely used regimen in first-line setting for patients with unresectable MPM. Other first-line options are currently available, including the use of raltitrexed instead of pemetrexed combined with platinum. In this review, we discuss the role of CT in MPM mainly focusing on the results of the trials conducted in first-line setting.

Immune checkpoint inhibition in small cell lung cancer: a key to reach an unmet need?

Small cell lung cancer (SCLC), accounting for 13–15% of all lung cancers, is strongly correlated with smoking and it is associated with a poor overall survival (OS) (2-year OS rate: 5%), particularly in patients with extensive disease (1,2).