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Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, improved outcomes compared with crizotinib in patients with previously untreated ALK-positive advanced NSCLC in the phase 3 CROWN study. Here, we investigated response correlates using plasma circulating tumor DNA (ctDNA) and tumor tissue profiling.

Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor approved for treatment-naive and crizotinib-refractory advanced ALK-positive (ALK+) NSCLC. We evaluated brigatinib after other next-generation ALK tyrosine kinase inhibitors.

Background: Sunitinib is still a recommended treatment option for metastatic renal cell carcinoma (RCC) patients; lack of cross-resistance to sequential antiangiogenic drugs has been postulated.Objective: The possibility of a successful rechallenge with sunitinib was tested in this prospective phase II trial.Methods: Main inclusion criteria were: histologically proven RCC with clear cell component, previous first-line sunitinib with a Disease Control Rate lasting ⩾10 months, and second-line everolimus. The primary end-point was 6-months progression-free survival (PFS). A Simon’s 2-stage design was used; after testing sunitinib on 12 patients, the trial would have been terminated if ⩽5 had a PFS <6 months. Otherwise, the trial would have proceeded enrolling a total of 38 patients. If the total number of patients free of progression at 6 months would have been ⩽18, sunitinib would have been rejected.Results: A total of 39 patients (30 males, 9 females) were enrolled. The study reached the second stage, and ultimately succeeded; indeed, 6-months PFS was 64.1%, median PFS being 14.9 months (95% confidence interval: 9.06–20.91). Treatment-related grade 3–4 adverse events observed in ⩾5% of the patients were: hand-foot skin reaction, fatigue, nausea, hypertriglyceridemia, hypophosphatemia, hypocalcemia, hyperglycemia, and neutropenia. One case each of myocardial infarction, atrial flutter, and spontaneous pneumothorax, were also reported.Conclusions: Despite an ineluctable time-lead-bias, median PFS on sunitinib rechallenge was high, clearly showing that many patients may become sensitive again to antiangiogenic treatment. In countries where treatment options are still limited, sunitinib rechallenge could represent an option. EudraCT number: 2012-000473-23.

Introduction: The immune checkpoint inhibitors (ICPIs) agents anti-T lymphocytes-associated antigen 4 (CTLA-4) and anti-programmed cell death protein-1 (PD-1) and its ligands (PD-L1/PD-L2) have opened a new scenario in the treatment of cancer. These agents can induce immuno-related adverse events (irAEs), which may affect the endocrine system. Purpose: The aim of this study was to analyze the occurrence and the course of endocrine irAEs in cancer patients treated with anti-PD-1 immunotherapy. Methods: This was a retrospective, multicentre study, involving cancer patients treated with the PD-1 inhibitors nivolumab or pembrolizumab at reference Oncology Centres. One hundred and seventy-nine consecutive patients with different types of cancer (mostly non-small cell lung cancer, melanoma, kidney cancer) were included in the study. Patients had received nivolumab (70.9%) or pembrolizumab (29.1%) for 2–33 months. The study evaluated clinical data records until the established date of July 15, 2018. The primary end point was the assessment of endocrine toxicity and possible predictive factors. Results: Endocrine toxicity occurred in 54 out of 179 patients (30.2%) and was related to thyroid dysfunction, with the exception of one case of diabetes mellitus. Thyroid toxicity occurred mostly within 2 months from the initiation of immunotherapy (83% of cases). A pre-existing thyroid dysfunction was a significant predictor of disease flare. Conclusions: Thyroid alterations are frequently associated with anti PD-1 treatment in cancer patients. Regular thyroid assessment should be performed, particularly in the first months of treatment and in patients with a pre-existing thyroid disease.

In selected metastatic renal cell carcinoma (mRCC) patients, radical metastasectomy followed by observation is a potential strategy. It is still to be defined whether systemic therapy should be administered following metastasectomy.

Background: Lung cancer is the most frequent cause of cancer-related death. In the last decades, the introduction of targeted therapies and more recently, of immunotherapy, has led to significant improvements in different outcomes of this malignant neoplasm. Objective: The present review provides a balanced overview of most recent targeted therapies and immunotherapies patented for the treatment of lung cancer. Methods: An extensive scientific literature and patent databases search were performed to identify peerreviewed studies containing information on recently patented drugs for the treatment of lung cancer, with a particular focus on their safety data and recently patented combinations. Results: The development of therapies directed to different pathways involved in the tumor angiogenesis, proliferation, and metastasis has transformed the clinical practice of lung malignancies. Several clinical trials have shown an improvement in terms of progression-free survival and overall survival in patients with advanced/metastatic lung cancer. Safety data, extracted from clinical trials and from the WHO global database of adverse drug reactions (VigiAccessTM database), show that recently patented drugs for the treatment of lung cancer are well-tolerated and most of the adverse events reported are mild to moderate. Conclusion: Currently, a consistent number of new drugs and combinations have been introduced for the treatment of patients with advanced-stage lung cancer. Safety data remain essential to better assess the long-term risk/benefit ratio of these valuable emerging therapies. The new patents’ development could provide further significant improvements for lung cancer treatment.

In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted.

Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure.

Purpose: Elderly patients with metastatic colorectal cancer (mCRC) differ from the general population and are underrepresented in clinical trials. We, retrospectively, analyzed the safety and efficacy of XELOX regimen in the treatment of elderly patients affected by mCRC. Patients and methods: One-hundred-eleven consecutive patients, aged 70 years or older, were enrolled in the study. Results: All patients were evaluated for safety and efficacy (male/female, 63/48). Median age was 75 years (range 71-85 years). Median Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0 (range 0-2). Metastatic sites distribution is as follows: liver (44.1%), lung (13.5%), liver plus lung (12.6%) and other (29.7%). A total of 584 cycles were administered (median 6 cycles/patient, range 2-10). Median follow-up time was 14.5 months (range 1-41 months). In an intent-to-treat analysis, objective responses and stable disease were recorded in 41 (40.4%) and 29 (26.6%) patients, respectively. The median response duration was 5.9 months (range 0.5-28.8). The median progression free-survival (PFS) was 7.5 months (range 1-26 months). The median overall survival (OS) was 15 months (range 1-64 months). The grade 3 toxicities were: neutropenia (8.1%), diarrhea and neurotoxicity (5.4% respectively). Most adverse events were mild to moderate; the most common was acute sensory neuropathy (57.6%). Conclusion: XELOX is a highly effective first-line treatment for mCRC elderly patients. Response rates, PFS and OS are similar to those observed with fluorouracil/leucovorin/oxaliplatin combinations. XELOX is a convenient regimen, likely to be preferred by both patient and healthcare providers.

In the recent years many advances have been achieved in the field of the treatment of lung cancer; with the development of novel therapeutic pathways due to the knowledge of oncologic drivers involved in the carcinogenesis of the lung, as well as the involvement of new radiotherapic and surgical techniques. Nevertheless, the standard treatment for elderly is still debated, mainly because of an underrepresentation of elderly patients in clinical trials. Herein we try to summarize the main guidelines for the treatment of lung cancer, with particular attention for the elderly patients, what we know and what has changed.

Lorlatinib, a potent, selective third-generation ALK tyrosine kinase inhibitor (TKI), exhibited overall and intracranial antitumor activity in patients with ALK-positive NSCLC.

Few data are available on the safety and efficacy of sorafenib in HIV-infected patients with unresectable hepatocellular carcinoma (HIV-u-HCC) and concomitant highly active antiretroviral therapy (HAART). Between July 2007 and October 2010, 27 consecutive HIV-u-HCC patients were treated with sorafenib and concomitant HAART within the Gruppo Italiano Cooperativo AIDS e Tumori (GICAT). Three patients achieved a partial response, 12 achieved a stable disease, and 12 showed progression. The median time to progression and overall survival was 5.1 (range 0.5–13.3) and 12.8 (range 1.1–23.5) months, respectively. Grades 3–4 toxicities included diarrhea (four patients, 14.8), hypertension (three patients, 11), and hand-and-foot skin reaction (four patients, 14.9). Most drug-related side effects were low grade and manageable. This retrospective study shows favorable survival data among HIV-u-HCC patients treated with sorafenib together with a reasonable safety profile.

This study aimed to assess the safety of high doses of radiation delivered with tomotherapy to the intact lung after radical pleurectomy/decortication or biopsy for malignant pleural mesothelioma (MPM).

Cancer is the second leading cause of death during the reproductive years complicating between 0.02% and 0.1% of pregnancies. The incidence is expected to rise with the increase in age of childbearing. The most common types of pregnancy-associated cancers are: cervical cancer, breast cancer, malignant melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma and ovarian cancer. The relatively rare occurrence of pregnancy-associated cancer precludes conducting large, prospective studies to examine diagnostic, management and outcome issues. The treatment of pregnancy-associated cancer is complex since it may be associated with adverse fatal effects. In pregnant patients diagnosed with cancer during the first trimester, treatment with multidrug anti-cancer chemotherapy is associated with an increased risk of congenital malformations, spontaneous abortions or fetal death, and therefore, should follow a strong recommendation for pregnancy termination. Second and third trimester exposure is not associated with teratogenic effect but increases the risk of intrauterine growth retardation and low birth weight. There are no sufficient data regarding the teratogenicity of most cytotoxic drugs. Almost all chemotherapeutic agents were found to be teratogenic in animals and for some drugs only experimental data exist. Moreover, no pharmacokinetic studies have been conducted in pregnant women receiving chemotherapy in order to understand whether pregnant women should be treated with different doses of chemotherapy. This article reviews the available data regarding the different aspects of the treatment of cancer during pregnancy.

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 medi 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 seem to increase the FOLFOX4 toxicity. This study suggests the good tolerability of the FOLFOX4, making it a reasonable option for combination with HAART.

Background Bronchioloalveolar carcinoma (BAC) is a histological subtype of non-small cell lung cancer (NSCLC), particularly of adenocarcinoma. Given its multifocality and the poor activity of chemotherapy, there is no established treatment for BAC, although promising results have been achieved with inhibitors of the epidermal growth factor receptor (EGFR). No tumor marker has been validated in the diagnosis and follow-up of lung cancer, in particular to predict the outcome of treatment with EGFR inhibitors.Purpose As CA 15–3 antigen serum levels are reported to be pathologically abnormal in adenocarcinoma of the lung, we chose this tumor marker to monitor treatment with EGFR inhibitors of patients affected by adenocarcinoma with BAC features or pure BAC.Patients and methods We collected data from 26 consecutive Caucasian patients with BAC, mostly women and never smokers, who received EGFR inhibitors.Results We noticed that all patients with normal CA 15–3 serum levels at baseline (15/26, 57.7%) showed a response to EGFR inhibitors, whereas all patients with abnormal CA 15–3 serum levels (11/26, 42.3%) did not.Conclusion Our data suggest that CA 15–3 levels might be a predictive factor for the response to EGFR inhibitors in patients with BAC.

Chemotherapy of non-small-cell lung cancer (NSCLC) has been improved by the use of cis-platin (P) and the pyrimidine antimetabolite gemcitabine (G) (2′,2′-difluorodeoxycytidine). GP regimens currently used in Italy for NSCLC were and are mainly based on G day 1, 8 and 15; P on day 2, every 28 days (4 Day-Hospital admissions per cycle). However, the third G dose is frequently omitted because of myelo-toxicity, with a consistent dose decrease of both G and P in comparison with the intended dose. The 24-h lag time from 1stG and P has not reasonable clinical pharmacology base.

AbstractSeventeen elderly patients with advanced progressive non small cell lung cancer (NSCLC) were treated with oral etoposide at the daily dose of 100 mg for 14 days every 3-4 weeks with pharmacokinetic monitoring. One partial response and 6 stabilizations were documented with a median overall duration of 13 weeks (range 8-32). The median survival was 24 weeks with an apparent advantage for non-progressive patients (40 weeks vs. 18 weeks). The treatment was well tolerated especially by those patients without concomitant illness, suggesting the crucial role of a careful selection of the geriatric population. Toxicity was not related to the etoposide plasma level, but was clearly dependent on comorbidity. A geriatric assessment rather than chronological age therefore appears to be more reliable in the selection of elderly patients for clinical trials. The easy self-management, favorable toxicity profile and synergy with other compounds makes oral etoposide suitable for further clinical-pharmacological studies in elderly patients.

AbstractAngiosarcomas are rare soft tissue malignancies. Typically they originate from the skin of the scalp or face, whereas visceral sarcomas are very rare. We report the case of a 67-year-old man affected by a large angiosarcoma of the kidney. After surgical removal, a rapid peritoneal, visceral and cutaneous diffusion developed. Palliative chemotherapy, based on anthracycline and ifosfamide, which are normally used to treat all other high-grade spindle cell sarcomas, was totally inactive. On the basis of these results and of the biological characteristics of these rare neoplasms it is mandatory to develop other therapeutic approaches. Antiangiogenetic agents are of interest for this disease due to the peculiar origin of the cells of these sarcomas.

Lymphangioleiomyomatosis, a rare disease of unknown etiology that is seen almost exclusively in women of childbearing age, generally presents with features of pulmonary involvement. It may be associated with tuberous sclerosis. Its clinical pulmonary manifestations vary from simple cough to the development of recurrent pneumothorax, hemoptysis, and even complicated pleural effusions. Progressive dyspnea develops as the disease evolves. Most patients eventually require lung transplant. This wide array of symptoms and signs makes the differential diagnosis extensive, and the clinician must be familiar with this disorder to arrive promptly to the correct diagnosis. Here we report a case of a 35-year-old woman with a history of pleuritic effusion with associated dyspnea before being diagnosed with lymphangioleiomyomatosis. A review of the literature pertinent to this case is also provided.

We report a case of a 28-year-old man with angiosarcoma of the spleen and liver metastases. The aim of this paper is to underline the importance of planned splenectomy in these patients even if they have metastatic disease, and to propose an intensive chemotherapy regimen consisting of anthracyclines, ifosfamide and mesna with G-CSF support.

Cancer is often associated with paraneoplastic syndromes, which may be misinterpreted. We report a case of a patient with occult small cell lung cancer that was initially compounded by clinical features of a paraneoplastic neurologic syndrome. The presence of antineuronal antibodies and positron emission tomography scan guided the search for the underlying tumor.Following chemo-radiotherapy the patient showed no evidence of disease for the next 18 months, whereas only a slight improvement in the neurologic disorders was observed. The course of the small cell lung cancer was very indolent and the paraneoplastic neurologic syndrome did not worsen with the use of cisplatin.

The primary amino acid sequence of the carboxyl-terminal portion of the α3 chain of chicken type VI collagen (K-VI) presents a 58-residue motif with a high degree of homology with members of the Kunitz serine-proteinase inhibitors family. This module was cloned, expressed in E. coli, purified and compared to the bovine pancreatic trypsin inhibitor (BPTI) in an inhibition profile assay of two serine proteases, trypsin and plasmin. We found that recombinant K-VI is not endowed with inhibitory activity but it slightly activates both plasmin and trypsin, differently from other members of the family. Moreover, the ability to inhibit the serine protease activity is also lacking in the intact type VI collagen molecule.Copyright 1995, 1999 Academic Press, Inc.

The regulation of NF-κB activation following the triggering of HLA-DR antigens by mAb L243 has been studied at various time in Raji cells. Electrophoretic mobility shift assays demonstrated a strong increase of NF-κB DNA binding after triggering of HLA-DR antigens. Using TNF-α-activity neutralizing antibodies, the authors demonstrated that the upregulation of NF-κB was found to depend, at later time point, on an autocrine effect of TNF-α secreted following triggering of HLA-DR antigens. In contrast, it was found to be TNF-α independent in the early time point. Moreover, the upregulation of NF-κB binding activity is regulated by the triggering of selected epitopes of HLA-DR antigens. In fact, mAb L243 but not the staphylococcal superantigens, staphylococcal exotoxin toxic shock syndrome toxin-1 or staphylococcal enterotoxin B, regulate the NF-κB binding activity.

NF-κB was identified as one of the transcription factors leading to antigen-independent stimulation through activation of integrin receptors. This effect was dependent upon stimulation of α4β1and α5β1integrins, the major fibronectin-binding integrins of Jurkat T cells, since either RGD or CS-1 peptides at 10−4M could prevent NF-κB activation. At variance with fibroblasts and smooth muscle cells, in which only p50 and p65 components of the NF-κB complex are induced, adhesion of T cells to fibronectin resulted in a strong upregulation of p50 and c-Rel and in a partial increase in p65 activity. The upregulation of NF-κB activity was abrogated by calphostin C, an inhibitor of protein kinase C. Cell adhesion determined a strong reduction in the cytoplasmic levels of the NF-κB inhibitor IκBα, reduction that was prevented after treatment with calphostin C, suggesting that PKC-dependent IκBα phosphorylation might be involved in the upregulation of NF-κB.

Hepatocellular carcinoma (HCC) is an increasing cause of mortality in human immunodeficiency virus (HIV) seropositive patients. Concurrent infection with HIV may accelerate the progression from cirrhosis to HCC. Viral hepatitis and alcohol abuse are the main risk factors for HCC in developed countries. Exposure to these risk factors is common among HIV-infected patients. We report the case of a 43-year-old woman affected by HCC, with unusual soft tissue metastases (left masseter muscle) and HIV/HCV coinfection. The usual route of metastatic spread from classic HCC is hematogenous, with the most common extrahepatic site being the lung. Our case, besides the unusual distant metastatic site, showed very rapid clinical progression, as has been commonly observed in HIV-infected patients with HCC. The case series of HCC in HIV-positive individuals published to date does not cumulatively exceed 70 subjects.