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Background: The reason why some multiple sclerosis (MS) patients show disease activity after alemtuzumab (ALM) is still unclear, but ocrelizumab (OCR) could represent an interesting sequential therapeutic approach., Objectives: To investigate safety and efficacy of OCR in MS patients with disease activity after two ALM courses., Methods: Observational retrospective multi-centers Italian cohort study., Results: Seventy-two subjects were included. Mean follow-up (FU) was 2.4 (±1) years. Forty-five patients (62.5%) experienced at least one adverse event (AE), with infections accounting for 96.7% of cases. A reduction in total lymphocytes was observed between OCR start and 6 months FU, driven by BCD19+ lymphocytes depletion ( p < 0.001). Immunoglobulin M (IgM) levels decreased between OCR start and 6 months FU ( p < 0.001). At 2-year FU, relapse, magnetic resonance imaging (MRI) activity and disability worsening-free survival were 92.1%, 90.8%, and 89.2%. The evidence of inflammatory activity between the two ALM courses was associated with higher risk of relapse, MRI activity, and NEDA-3 status loss in relapsing-remitting multiple sclerosis (RRMS; p = 0.02, p = 0.05, p = 0.01, respectively)., Conclusions: OCR after two ALM courses seemed to be safe and effective. Early IgM hypogammaglobulinemia occurred in a high proportion of patients. The evidence of inflammatory activity between ALM courses seemed to increase the risk of MS re-activation on OCR treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C. Lapucci has received honoraria for speaking, travel grants, and for participating in the advisory board from Merck, Sanofi, Novartis, Roche, Alexion. J. Frau served on scientific advisory boards for Biogen and Genzyme, and has received honoraria as a speaker from Merck Serono, Genzyme, Biogen, and Teva. E. Cocco reported grants, personal fees, and non-financial support from Biogen and Merck; personal fees and non-financial support from Novartis; grants from Roche; and personal fees from Genzyme. G. Coghe received honoraria for consultancy or speaking from Biogen, Novartis, Sanofi, Genzyme, Serono, Teva, and Almirall. M. Petracca has received travel/meeting expenses from Novartis, Janssen, Roche, and Merck; speaking honoraria from HEALTH&LIFE S.r.l., AIM Education S.r.l., Biogen, Novartis, and FARECOMUNICAZIONE E20; honoraria for consulting services and advisory board participation from Biogen; research grants from Baroni Foundation and the Italian Ministry of University and Research. R. Lanzillo has received honoraria from Biogen, Merck, Novartis, Roche, and Teva. V. Brescia Morra has received research grants from the Italian MS Society and Roche, and honoraria from Bayer, Biogen, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme, and Teva. C.G. Nicoletti received travel funding from Biogen, Merck Serono, Sanofi-Genzyme, Roche, Teva, Novartis, Bristol Mayer Squibb, Janssen, Almirall and consultation fees from Sanofi, Almirall, Merck- Serono, Roche, Novartis, and Biogen. She is a sub-investigator in clinical trials being conducted for Biogen, Merck Serono, Roche, Biogen, Sanofi, Novartis, Teva, Bristol Mayer Squibb. D. Landi has received travel funding from Biogen, Merck Serono, Sanofi, Teva, Bristol Myers Squibb, Mylan; speaking or consultations fees from Sanofi, Merck Serono, Teva, Biogen, Roche, Novartis, Bristol Myers Squibb, BayerSchering. G. Marfia has received travel funding, speaking or consultation fees from Almirall, Bayer-Schering, Biogen, Sanofi, Merck Serono, Novartis, Teva, Mylan, Bristol Mayers Squibb and research grants from Roche and Biogen. M. Vercellino has received congress grants, speaker fees and advisory board fees from Merck-Serono, Novartis, Roche, Biogen, Sanofi Genzyme. P. Cavalla has received honoraria as speaker or travel grants to attend national and international conferences or consultation for advisory boards from Alexion, Almirall, Bayer Schering, Biogen, Cellgene-BMS, Merck-Serono, Teva, Roche, Novartis, Sanof-Genzyme, and Janssen. A. Bianco has received honoraria for speaking, advisory board/consulting from Biogen, Novartis, Merck Serono, Roche, Sanofi Genzyme. M. Mirabella has received honoraria for speaking, advisory board/consulting from Biogen, Novartis, Merck Serono, Roche, Almirall, Sanofi Genzyme, Janssen, Bristol-Myers Squibb, Viatris, Alexion. He is principal investigator in clinical trials for Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, CSL Behring, Ultragenix, Argenx. V. Torri Clerici acted as an Advisory Board member of Biogen Idec, Novartis, Merck Serono, Roche, Sanofi Genzyme, Almirall, Lundbeck and Bristol Myers Squibb; she received funding for traveling and honoraria for speaking or writing from Novartis, Sanofi Genzyme, Horizon, Merck Serono, Roche, Bristol Myers Squibb, Janssen and Almirall. She received support for research project by Almirall. E. Tomas received funding for work contract from Roche. M.T. Ferrò has received consultancy fees or speaker compensation from Sanofi, Bristol, Biogen Idec, and Novartis. L. Moiola has received honoraria for speaking and for participating in advisory board from Merck, Celgene, Biogen, Sanofi, Novartis, Roche, Alexion. M. Zaffaroni has received advisory board membership, speakers honoraria, travel support, research grants, consulting fees or clinical trial support from Actelion, Almirall, Bayer Schering, Biogen, Celgene, Excemed, Genzyme, Merck, Novartis, Sanofi, Roche, Teva. M. Ronzoni has received travel grants for congresses participation from Biogen, Genzyme, Novartis e Merck. G. Novi has received speaker honoraria from Merck, Novartis, Roche, Alexion. M. Cellerino has received consulting fees from Novartis, Genzyme, Teva and Zambon. A. Uccelli has received grants (to his institution) from FISM, Biogen, Roche, Alexion, and Merck Serono and has participated on a data safety monitoring board or advisory board (to his institution) for BD, Biogen, Iqvia, Sanofi, Roche, Alexion, and Bristol Myers Squibb. M. Inglese received grants from NIH, NMSS, and FISM; received fees for consultation from BMS, Janssen, Roche, Genzyme, Merck, Biogen and Novartis. P. Grossi, A. Nozzolillo, and F. Pinardi have nothing to disclose.

Background: Pleural mesothelioma is a rare cancer with a dismal prognosis and few therapeutic options, especially in the pretreated setting. Immunotherapy with checkpoint inhibitors as single agents yielded interesting results in refractory pleural mesothelioma, achieving a response rate between 10-20%, median progression-free survival of 2-5 months and median overall survival of 7-13 months., Patients and Methods: A retrospective, multi-institutional study of pleural mesothelioma patients treated with nivolumab in second and further line was performed. The endpoints of the study are response rate, disease control rate, progression free survival and overall survival., Results: Sixty-five patients with pleural mesothelioma treated with nivolumab in second and further line were enrolled at seven Italian institutions. The response rate was 8%, disease control rate was 37%, median progression free survival was 5.7 months (95% CI: 2.9-9.0) and median overall survival was 11.1 (95% CI 6.2-19.9) months. A higher neutrophils and neutrophils to lymphocytes ratio at baseline were associated with worse prognosis., Conclusion: Nivolumab as a single agent is fairly active in a cohort of unselected pretreated pleural mesothelioma patients. Further investigations on clinical and translational factors are needed to define which patient might benefit most from nivolumab treatment in pleural mesothelioma., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Little is known about COVID-19 course and outcomes after a third booster dose of mRNA vaccine against SARS-CoV-2 (mRNA-Vax) in patients with multiple sclerosis (pwMS) treated with ocrelizumab (OCR) and fingolimod (FNG), which showed a weakened immune response to mRNA-vax., Objectives: The aim of this study was to evaluate COVID-19 course and outcomes in pwMS on OCR and FNG after receiving the third dose of mRNA-Vax and to compare it with pwMS on natalizumab (NTZ)., Methods: Inclusion criteria: >18 years of age, being treated with OCR/FNG/NTZ since the first mRNA-Vax dose; COVID-19 after a third booster dose of mRNA-Vax; no steroids use., Results: Overall, 290 pwMS (79 NTZ, 126 OCR, and 85 FNG) from 17 Italian MS centers were included. Age, Expanded Disability Status Scale (EDSS) score, MS phenotype, disease, and treatment duration were significantly different across groups. PwMS who had COVID-19 on OCR and FNG compared with those on NTZ were slightly more symptomatic with higher hospitalization rates (11.1% vs 7.1% vs 1.3%, respectively). Regression models showed that the majority of the differences observed were not related to the disease-modifying treatments (DMTs) used. No fatal cases were observed., Conclusion: Our results support the effectiveness of the third booster dose of mRNA-Vax against severe forms of COVID-19 in pwMS treated with OCR and FNG.

When conducting randomised clinical trials, the choice of methodology and statistical analyses will influence the results. If the planned methodology is not of optimal quality and predefined in detail, there is a risk of biased trial results and interpretation. Even though clinical trial methodology is already at a very high standard, there are many trials that deliver biased results due to the implementation of inadequate methodology, poor data quality and erroneous or biased analyses. To increase the internal and external validity of randomised clinical trial results, several international institutions within clinical intervention research have formed The Centre for Statistical and Methodological Excellence (CESAME). Based on international consensus, the CESAME initiative will develop recommendations for the proper methodological planning, conduct and analysis of clinical intervention research. CESAME aims to increase the validity of randomised clinical trial results which will ultimately benefit patients worldwide across medical specialities. The work of CESAME will be performed within 3 closely interconnected pillars: (1) planning randomised clinical trials; (2) conducting randomised clinical trials; and (3) analysing randomised clinical trials., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Cerebrospinal fluid (CSF) free light chains (FLCs) can be an alternative assay to oligoclonal bands (OCBs) in inflammatory neurological disorders, but threshold has no consensus., Objective: To assess the diagnostic accuracy of CSF FLCs in multiple sclerosis (MS) and other neurological diseases., Methods: A total of 406 patients from five Italian centers. FLCs were measured in CSF and serum using Freelite MX assays on Optilite., Results: A total of 171 patients were diagnosed as MS, 154 non-inflammatory neurological diseases, 48 inflammatory central nervous system (CNS) diseases, and 33 peripheral neurological diseases. Both kFLC and λFLC indices were significantly higher in patients with MS compared to other groups ( p  < 0.0001). The kFLC index ⩾ 6.4 is comparable to OCB for MS diagnosis (area under the receiver operating characteristic curve (AUC) = 0.876; sensitivity 83.6% vs 84.2%; specificity 88.5% vs 90.6%). λFLC index ⩾ 5 showed an AUC of 0.616, sensitivity of 33.3% and specificity of 90.6%. In all, 12/27 (44.4%) MS patients with negative OCB had kFLC index ⩾ 6.4. Interestingly, 37.5% of 24 patients with a single CSF IgG band showed high kFLC index and 12.5% positive λFLC index., Conclusion: Our findings support the diagnostic utility of FLC indices in MS and other CNS inflammatory disorders, suggesting a combined use of FLC and OCB to help clinicians with complementary information.

Background: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences., Objectives: To identify prognostic factors for early switch after first therapy choice., Methods: Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models., Results: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p  = 0.009), natalizumab (HR = 0.13; p  < 0.001), dimethyl-fumarate (HR = 0.60; p  = 0.037), teriflunomide (HR = 0.21; p  = 0.031) as compared to interferons. Younger age (HR = 0.96; p  < 0.001), diagnosis delay (HR = 1.23; p  = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p  = 0.001), and spinal cord lesions (HR = 1.46; p  = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p  = 0.001), fingolimod (HR = 0.35; p  = 0.002), and dimethyl-fumarate (HR = 0.57; p  = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p  = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p  = 0.047)., Conclusion: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.

Purpose: Elderly patients with metastatic breast cancer are expected to derive similar benefits from chemotherapy as younger patients, but are more likely to experience therapy-related toxicity. Data from the VICTOR-1 study showed that metronomic therapy with vinorelbine and capecitabine was effective and well tolerated in patients with metastatic breast cancer. This analysis determined the efficacy and safety of the metronomic combination of oral vinorelbine and capecitabine in a subgroup of VICTOR-1 study patients aged ≥70 years., Methods: Eighteen of the 32 patients enrolled in VICTOR-1 were aged ≥70 years. Objective response and clinical benefit rates were calculated and toxicity was determined using the NCI-CTCAE criteria., Results: All patients had at least 1 comorbidity (4 had 2 comorbidities), and 77.7% were taking concomitant medication. Eight patients (44%) had received ≥1 chemotherapy regimens for metastatic disease and most (78%) had ≥2 metastatic sites. Grade 1-2 adverse events occurred in 45.8% of cycles, whereas the incidence of grade 3 and grade 4 events was very low (1.5% and 0.7%, respectively). Median time to progression was 10.5 months (range 1-40). The objective response rate was 33% and the clinical benefit rate was 67%., Conclusions: The all-oral metronomic combination of vinorelbine and capecitabine had an acceptable efficacy profile and appears to be better tolerated than standard treatment schedules in elderly metastatic breast cancer patients (age ≥70 years).

Aim: To assess patient perception toward oral chemotherapy for solid tumors, the Italian Association of Medical Oncology performed a large multi-institutional national survey., Methods: A 17-item anonymous questionnaire including 7 general and 10 investigational questions with free-text, single-choice, or multiple-choice answers was administered. Analysis of response distribution according to predefined factors was described by summary measures and conducted by χ2 test and other nonparametric tests., Results: From January to June 2010, 581 patients completed the questionnaire; data of 404 patients constituted the final study sample. Three groups could be distinguished according to treatment: IV chemotherapy (IV group, n = 313), oral chemotherapy (oral group, n = 48), or combined therapy (combined group, n = 43). Thirty-one (72%) patients in the combined group and 187 (60%) in the IV group expressed preference for oral therapy (p = 0.028). Limitations in family and work commitment were more frequently perceived by patients on IV than oral chemotherapy (147 (47%) vs 14 (29%) patients, p&lt;0.05, and 134 (43%) vs 11 (23%) patients, p&lt;0.05). A total of 134 (43%) patients on IV chemotherapy versus 15 (31%) patients in the oral group did not point out any limitation for number of tablets per day (p = 0.004)., Conclusions: We observed a propensity from the patient perspective in favor of oral chemotherapy that was considered to have a lower impact on family and work commitments than IV chemotherapy. The treatment that patients were taking when the questionnaire was administered likely influenced their perception and related results.

Aims and Background: The addition of trastuzumab to chemotherapy for HER2-positive metastatic breast cancer has significantly improved progression-free survival and overall survival, although most patients develop resistance or have a primarily resistant disease. The aim of the study was to describe the efficacy and safety of a first-line treatment in unselected metastatic HER2-positive breast cancer patients, treated according to clinical practice., Methods: From 2000 to 2009, we conducted a retrospective multi-institutional analysis of 182 consecutive patients with HER2-positive metastatic breast cancer who underwent first-line treatment with trastuzumab. The primary end points were progression-free survival and overall survival; the secondary end points were survival after progression in patients treated with second-line chemotherapy with or without trastuzumab and safety. A total of 172 patients were analyzed., Results: Median progression-free survival and overall survival were 1.2 (95% CI, 1.1-1.4) and 4.4 years (95% CI, 3.6-5.4), respectively. For 100 patients who received second-line chemotherapy, median survival after progression was significantly longer in those who also received trastuzumab: 2.8 (95% CI, 2.1-4.0) versus 1.2 years (95% CI, 0.6-1.9)., Conclusions: Although based on retrospective data, the study confirms the role of trastuzumab as first-line treatment in metastatic breast cancer outside of a controlled trial. Moreover, information obtained on the use of trastuzumab beyond disease progression supports its use in this setting.

Aims and Background: The purpose of the study was to evaluate the outcome of metastatic colorectal cancer patients treated, as first line, with 5-fluorouracil bolus/leucovorin + oxaliplatin, in terms of response, progression-free and overall survival., Materials and Methods: A retrospective cohort of consecutive metastatic colorectal cancer patients, treated from 2003 to 2006, was identified and analyzed. All patients, without a central venous device, were treated with oxaliplatin + 5-fluorouracil and leucovorin., Results: Twenty-five metastatic colorectal cancer patients were treated. No 3-4 grade toxicity was observed. Five of 23 patients achieved a partial response: one of them resulted in a complete response after radiofrequency and another one after surgery. Fifteen of 23 patients had stable disease (one underwent radical surgery after chemotherapy, obtaining a complete remission) and 3 had progressive disease. Median progression-free survival was 7.2 months, and median overall survival was 30 months., Conclusions: Based on this case-series study, the regimen seems to offer a good control of disease (86.9%) and can be considered as an alternative choice for patients who cannot receive continuous infusion.

Background: Only 10% to 25% of patients with liver metastases from colorectal cancer are suitable for resection. Methods for increasing the resectability of liver metastases are based on specific surgical techniques and neoadjuvant chemotherapy., Methods: We collected retrospective data on patients from various Italian hospitals from 1996 to 2002. Data from colorectal cancer patients with liver metastases treated with oxaliplatin-based neoadjuvant chemotherapy were considered. Analysis focused on patients and treatment description and on longterm survival. We considered 107 patients from 36 Italian hospitals., Results: Of the 105 patients assessable for response, 8.4% achieved a complete response, 70.1% a partial response and 19.6% stable disease. Ninety-nine patients were treated with surgery for liver metastases. A radical resection was achieved in 79% of patients. Median survival time was 42 months. Thirteen patients experienced grade 3-4 hematologic toxicity, and 10 patients had grade 3-4 nonhematologic toxicity. Neurologic toxicity of grade >1 was observed in 21% of patients., Conclusions: Neoadjuvant chemotherapy can be useful to increase the number of liver resections for metastatic colorectal cancer patients. Nevertheless, randomized trials are necessary to confirm this retrospective survey as well as the few single-institution experiences reported so far in the medical literature.

Background: Clinical trials with non-profit promoters are frequently performed in oncology and represent a highly valuable source of information., Methods: To describe the costs of insurance policies and their determinants, data were collected from 12 Italian non-profit promoters of cancer trials. The cost of policies was expressed as per-patient premium., Results: Sixty-two quotations issued by only two companies were collected, relative to 44 trials proposed for quotation between December 1998 and February 2003. Only the date of quotation was significantly associated with the cost (P = 0.0003) of quotations by Company A for policies with a deductible, with cost increasing over time. Date of quotation (P = 0.0002), sample size (P = 0.008) and number of study arms (P = 0.02) were independently associated with the cost of no-deductible policies quoted by Company A. Only the number of study arms was significantly associated with cost (P = 0.0001) in no-deductible policies quoted by Company B., Conclusion: There is insufficient competition among companies for insurance of cancer trials with non-profit promoters. Many variables that affect the trial risk profile from a clinical perspective are not associated with insurance cost. Date of quotation is among the strongest determinants of the cost, which has sharply increased over time. This trend may become a serious problem for non-profit promoters of cancer clinical trials.

Background: Transferring results derived from clinical research into practice is particularly difficult in lung cancer where clear indications for treatment are defined only for selected subgroups of patients. Studies on hospital-based lung cancer population could provide data for quantifying this issue., Patients and Methods: This was a follow-up study of consecutive, first-diagnosis cases referred to the in-and outpatient cancer clinics of a large italian general hospital between January 1975 and December 1990. Data were collected from medical records and recorded on ad hoc standardized forms. Analysis focused on changes in distribution over time of patient-related characteristics, prevalence of specific treatment strategies and survival of the study population., Results: 1345 primary non small cell lung cancer cases were reviewed and 1125 were fully evaluable. In early stages (510/1125, 45%) only 237 patients actually underwent surgery. In this group surgery increased from 36 to 69% whereas chemotherapy decreased from 58 to 15%. In the advanced group (615/1125, 55%) chemotherapy was the preferred treatment but combined modalities tripled over time (from 4 to 12%). No significant changes in survival were observed within each group over time., Conclusion: Despite changes in the therapeutic approaches, mortality from lung cancer does not seem reduced over time. Since the proportion of cases that could potentially benefit from "active" treatments is small, for the large majority of patients a switch in clinical research from a cure to a care-oriented strategy should be considered.