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Background We performed a qualitative study to investigate the experiences of participants in a multicentre randomized controlled trial on a home-based palliative approach (HPA) for adults with severe multiple sclerosis (MS) and their caregivers. Our aim was to explore the strengths and challenges of the intervention, and circumstances that may have influenced its efficacy. Methods Participants to the qualitative study were the patients, their caregivers, patient referring physicians, and the teams who delivered the HPA intervention. We performed semi-structured one-on-one interviews with 12 patients and 15 informal caregivers chosen using a maximum variation strategy, two focus group meetings with patient referring physicians (4 participants each), and one with the HPA teams (9 participants). Results From data analysis (framework method) 38 sub-categories emerged, which were grouped into 10 categories and 3 themes: 'expectations,' 'met and unmet needs', and 'barriers’. Intervention benefits were improved control of symptoms and reduced sense of isolation of the patient-caregiver dyads. Limitations were: factors related to experimental design (difficulty of dyads in identifying examiner and team roles, additional burden for caregivers); team issues (insufficient team building /supervision, competing priorities); limitations of the intervention itself (insufficient length, lack of rehabilitation input); and external factors (resource limitations, under-responsive services/professionals). The referring physician focus groups provided little experiential data. Conclusions The HPA reduced patient symptoms and sense of isolation in patients and caregivers. The indirect role of the HPA teams, and insufficient length of the intervention were key limitations. The experimental design imposed additional burdens on the dyads. Key barriers were the paucity of available services, the demanding administrative procedures, and lack of networking facilities. These findings suggest that two major requirements are necessary for home palliative care to be effective in this patient population: HPA teams well-connected with MS rehabilitation services, and care delivered over the long-term, with variable intensity. Trial registration Current Controlled Trials ISRCTN73082124 (Registered 19/06/2014).

Background: Evidence on the efficacy of palliative care in persons with severe multiple sclerosis (MS) is scarce. Objective: To assess the efficacy of a home-based palliative approach (HPA) for adults with severe MS and their carers. Methods: Adults with severe MS-carer dyads were assigned (2:1 ratio) to either HPA or usual care (UC). At each center, a multi-professional team delivered the 6-month intervention. A blind examiner assessed dyads at baseline, 3 months, and 6 months. Primary outcome measures were Palliative care Outcome Scale-Symptoms-MS (POS-S-MS) and Schedule for the Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW, not assessed in severely cognitively compromised patients). Results: Of 78 dyads randomized, 76 (50 HPA, 26 UC) were analyzed. Symptom burden (POS-S-MS) significantly reduced in HPA group compared to UC ( p = 0.047). Effect size was 0.20 at 3 months and 0.32 at 6 months, and statistical significance was borderline in per-protocol analysis ( p = 0.062). Changes in SEIQoL-DW index did not differ in the two groups, as changes in secondary patient and carer outcomes. Conclusion: HPA slightly reduced symptoms burden. We found no evidence of HPA efficacy on patient quality of life and on secondary outcomes.

Background: The SIMS-Trial showed that the ‘Sapere Migliora’ information aid (IA) for newly diagnosed people with multiple sclerosis (PwMS) effectively improved patient knowledge and satisfaction with care. Objectives: The objectives of this paper are to assess the effectiveness of the IA in clinical practice and to compare the whole IA with the take-home booklet/website component alone. Methods: After updating the IA and replacing the CD with a website, a prospective, open-label non-randomised controlled trial compared the whole IA (group A, five SIMS-Trial centres) to take-home (group B, 16 centres). One month after the intervention, participants completed the MS Knowledge Questionnaire (MSKQ), care satisfaction questionnaire (COSM-R) (primary study outcomes), Hospital and Anxiety Depression Scale, and ad hoc questionnaire appraising the IA. Results: We enrolled 159 newly diagnosed PwMS (May 2012–March 2013). Drop-outs were four of 77 (5%, group A) and 11/82 (13%, group B). Primary endpoint (highest tertile both for MSKQ and COSM-R section 2 scores) was achieved by 38/77 (49%) group A and 33/82 (40%) group B ( p = 0.25). Attainment of secondary outcomes was also similar between groups. Conclusions: This study shows that the entire IA is not superior to the booklet/website alone, and that both are comparable in efficacy to the intervention arm of the SIMS-Trial. Trial registration number: ISRCTN78940214.

Background and purpose Charcot−Marie−Tooth disease (CMT) is a very slowly progressive neuropathy which makes it difficult to detect disease progression over time and to assess intervention efficacy. Experience from completed clinical trials with ascorbic acid and natural history studies confirm difficulties in detecting such changes. Consequently, sensitive-to-change outcome measures (OMs) are urgently needed. Methods The relative responsiveness of clinical scales of the Italian−UK ascorbic acid trial (placebo arm) were assessed by using the standardized response mean (SRM), which is the ratio of the paired scores mean change over time to the standard deviation of the score change (0 is worst responsiveness). Results Little worsening of OM scores was found over 2 years. In detail, the primary OM of the trial, the CMT Neuropathy Score version 1 (CMTNSv1), showed low responsiveness (SRM 0.13). Some CMTNS items showed slightly greater responsiveness (CMT Examination Score 0.17; CMTNS Signs 0.19). Myometric assessments of handgrip and foot dorsiflexion strength were the most responsive (SRM −0.31 and −0.38, respectively). Amongst the other measures, the nine-hole peg test, which assesses upper limb functioning, showed the best sensitivity to change (SRM 0.28). Conclusions Overall these OMs showed low or negligible responsiveness, confirming the need to improve current OMs and to develop novel ones for prognostic and interventional studies. However, handgrip and foot dorsiflexion myometry are worth retaining for future trials as they were the most responsive and are likely to be clinically relevant for patients.

There are few studies on patient knowledge in multiple sclerosis (MS), and only two published questionnaires. The objective of this article was to develop and validate the MS Knowledge Questionnaire (MSKQ), a self-assessed instrument for newly diagnosed MS patients. Thirty multiple-choice statements, conceived to test MS knowledge, were produced by a multidisciplinary panel and pre-tested on three MS patients, resulting in an intermediate 26-item version. This was tested on 54 MS patients for internal consistency, content and construct validity (validation sample I). The final (25-item) MSKQ was a primary outcome measure in the SIMS-Trial on an information aid to newly diagnosed MS patients. Postal responses of SIMS-Trial participants to the MSKQ a month after intervention (validation sample II) were analysed. Median MSKQ scores in validation samples I and II were, respectively, 18 (range 9—23) and 17 (range 3—24). Acceptability, internal consistency (Kuder—Richardson-20 formula 0.76) and content validity were good. Educational attainment and receiving the information aid were the main independent predictors of MS knowledge. Other predictors were female sex (positive association) and disease duration (negative association). In conclusion, the MSKQ has good clinimetric properties and is sensitive to an educational intervention. We propose the MSKQ as a brief instrument for clinical practice and research.

Summary Background Ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing peripheral myelin protein 22 ( PMP22 ), a model of Charcot–Marie–Tooth disease type 1A (CMT1A) associated with the PMP22 duplication. However, in three 1-year trials, ascorbic acid had no benefit in human beings. We did a multicentre 2-year trial to test the efficacy and tolerability of ascorbic acid in patients with CMT1A. Methods Adult patients (aged 18–70 years) with symptomatic CMT1A were enrolled from nine centres in Italy and the UK, and were randomly assigned (1:1 ratio) to receive 1·5 g/day oral ascorbic acid or matching placebo for 24 months. The randomisation sequence was computer generated by block randomisation, stratified by centre and disease severity, and patients were allocated to treatment by telephone. The primary outcome was change in the CMT neuropathy score (CMTNS) at 24 months. Secondary outcomes were timed 10 m walk test, nine-hole peg test, overall neuropathy limitations scale, distal maximal voluntary isometric contraction, visual analogue scales for pain and fatigue, 36-item short-form questionnaire, and electrophysiological measurements. Patients, treating physicians, and physicians assessing outcome measures were masked to treatment allocation. Analysis of the primary outcome was done on all randomised patients who received at least one dose of study drug. This study is registered, numbers ISRCTN61074476 (CMT-TRAUK) and EudraCT 2006-000032-27 (CMT-TRIAAL). Findings We enrolled and randomly assigned 277 patients, of whom six (four assigned to receive ascorbic acid) withdrew consent before receiving treatment; 138 receiving ascorbic acid and 133 receiving placebo were eligible for analysis. Treatment was well tolerated: 241 of 271 patients (89% in each group) completed the study; 20 patients (nine receiving ascorbic acid) dropped out because of adverse events. Mean CMTNS at baseline with missing data imputed was 14·7 (SD 4·8) in the ascorbic acid group and 13·9 (4·2) in the placebo group. Mean worsening of CMTNS was 0·2 (SD 2·8, 95% CI −0·3 to 0·7) in the ascorbic acid group and 0·2 (2·7, −0·2 to 0·7) in the placebo group (mean difference 0·0, 95% CI −0·6 to 0·7; p=0·93). We recorded no differences between the groups for the secondary outcomes at 24 months. 21 serious adverse events occurred in 20 patients, eight in the ascorbic acid group and 13 in the placebo group. Interpretation Ascorbic acid supplementation had no significant effect on neuropathy compared with placebo after 2 years, suggesting that no evidence is available to support treatment with ascorbic acid in adults with CMT1A. Funding Telethon-UILDM and AIFA (Italian Medicines Agency) for CMT-TRI AA L, and Muscular Dystrophy Campaign for CMT-TRAUK.

BACKGROUND: In overwork weakness (OW), muscles are increasingly weakened by exercise, work or daily activities. Although it is a well-established phenomenon in several neuromuscular disorders, it is debated whether it occurs in Charcot-Marie-Tooth disease (CMT). Dominant limb muscles undergo a heavier overload than non-dominant and therefore if OW occurs we would expect them to become weaker. Four previous studies, comparing dominant and non-dominant hand strength in CMT series employing manual testing or myometry, gave contradictory results. Moreover, none of them examined the behaviour of lower limb muscles. METHODS: We tested the OW hypothesis in 271 CMT1A adult patients by comparing bilateral intrinsic hand and leg muscle strength with manual testing as well as manual dexterity. RESULTS: We found no significant difference between sides for the strength of first dorsal interosseous, abductor pollicis brevis, anterior tibialis and triceps surae. Dominant side muscles did not become weaker than non-dominant with increasing age and disease severity (assessed with the CMT Neuropathy Score); in fact, the dominant triceps surae was slightly stronger than the non-dominant with increasing age and disease severity. DISCUSSION: Our data does not support the OW hypothesis and the consequent harmful effect of exercise in patients with CMT1A. Physical activity should be encouraged, and rehabilitation remains the most effective treatment for CMT patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

We assessed inter- and intra-rater reliability of outcome measures in Charcot-Marie-Tooth disease (CMT) patients. In 40 CMT patients, we assessed reliability of Overall Neuropathy Limitations Scale (ONLS), 10-m timed walk (T10MW), 9-hole-peg test (9-HPT), maximal voluntary isometric contraction (MVIC) of arm (elbow flexion, hand-grip, and three-point pinch) and leg (knee extension, foot dorsiflexion/plantar flexion). Reliability was substantial for ONLS, excellent for T10MW and 9-HPT. For MVIC, inter and intra-rater reliability was excellent for hand contractions; for leg contractions, intra-rater agreement was moderate to substantial, whereas inter-rater agreement was poor. An ad hoc device was produced to immobilize the foot and MVIC reliability was re-assessed in 26 CMT patients, resulting in excellent inter-rater and intra-rater reliability for foot dorsiflexion, and clear inter-rater improvement for foot plantar flexion. All outcome measures appear adequate for CMT assessment. Use of an immobilization device improves foot MVIC reliability, preventing biased findings in patients with greater strength.

Introduction: Breast cancer is the leading cause of cancer death among women in the industrialized countries. The incidence of local recurrences after mastectomy and breast-conserving therapy varies between 5% and 40% depending on risk factors and primary therapy. Methods: From April 1999 to April 2011, 40 patients underwent chest wall resection and reconstruction for locally recurrent breast carcinoma with chest wall invasion. The main goal of surgery was local disease control to palliate clinical symptoms. Results: Local radical resection was achieved in 26 patients (65%). One, 2 and 5 year overall survival rates were 94.4%, 82.0% and 68.5%; 1, 2 and 5 year disease-free survival rates were 94.4%, 73.6% and 45.5% respectively.Univariate analysis indicated age (p = 0.002) and synchronous distant metastases (p = 0.020) as factors having a negative impact on overall survival; multivariate analysis disclosed age (p = 0.052) and synchronous metastases (p = 0.059) as factors with a slight negative impact on overall survival. Older age was associated with improved overall survival.Univariate analysis indicated synchronous distant metastases (p = 0.029) and the need of post resectional additional treatments (p = 0.022) as factors adversely conditioning disease-free survival or time to progression; multivariate analysis disclosed the need of post resectional additional treatments (p = 0.036) as the only factor adversely conditioning disease-free survival or time to progression. Conclusions: Chest wall resection and reconstruction for locally recurrent breast cancer is a feasible and safe procedure providing adequate local disease control and an excellent palliation of very disabling symptoms in a selected group of patients.

Introduction: Available information on perioperative blood transfusion practices in oncologic thoracic surgery is scant and outdated. The purpose of this study was to investigate transfusion requirements in patients undergoing curative resection for lung cancer and to identify possible factors predictive of perioperative blood transfusion in our cohort of patients. Methods: From 1st January 2009 to 31st December 2009, 317 patients underwent anatomic pulmonary resection. Patients who received at least 1 unit of red blood cells comprised the "transfused" group. Each case in this group was matched for surgical procedure with a control subject who did not require blood transfusion and was operated on during the same year; these patients comprised the "not transfused" group. Results: A total of 75 patients (23.6%) received at least 1 unit of red blood cells during the perioperative period. Factors conditioning perioperative blood transfusion were: preoperative hemoglobin level (p < 0.0001); procedure duration (p = 0.017); body mass index (p < 0.001); induction therapies (p = 0.017); redo procedure (p = 0.021). Age, sex, histology, stage, ASA score, side, intraoperative blood loss, and fluid infusion did not affect perioperative blood transfusion practices. Conclusions: Preoperative hemoglobin level is the major risk factor for perioperative blood transfusion practices in oncologic thoracic surgery; procedure duration, body mass index, induction therapies, and redo procedure may condition transfusional needs, although they were actually not predictive on multivariate analysis. © 2011 Society of Surgical Oncology.

The purpose of this study is the evaluation of clinical and surgical impact of the Z0011 trial criteria on the management of breast cancer (BC) patients undergoing breast conservative surgery (BCS) at the European Institute of Oncology (IEO). We studied 1386 patients who underwent BCS and sentinel lymph node biopsy (SLNB) from July 2016 to July 2018. Clinical evaluation, breast ultrasound, mammogram, and cyto/histological examination were performed for all patients at the time of diagnosis. Frozen sections of the sentinel lymph node (SLN) were not performed for any patient. Patients who underwent neo-adjuvant therapy were excluded. To evaluate the results before and after the introduction of Z0011 criteria, a group of 1425 patients with the same characteristics who underwent BCS and SLNB from July 2013 to July 2015 were analyzed. We studied the characteristics of the patients by nodal status, and we observed that T stage, tumor grade, and lymphovascular invasion were statistically related with the highest rate of positive SLN. Of the 1386 patients who underwent surgery after the introduction of the Z011 trial, 1156 patients (83.4%) had negative SLN, 230 patients (16.6%) had positive SLN. Subsequent axillary lymph node dissection (ALND) was performed in only 7 cases (3.0%). Of the 1425 patients operated before the introduction of the Z0011 trial, 216 patients had subsequent ALND (15%). The reduction in the number of ALND performed after the introduction of Z0011 is statistically significant, and this could result in a remarkable reduction of the comorbidities of our patients.

Background: The aim of this work is to evaluate pattern of care and clinical outcome in a large series of patients with in-breast recurrence (IBR), after quadrantectomy and intraoperative radiation therapy with electrons (IOERT) as partial breast irradiation. Patients and Methods: Patients with IBR after IOERT, treated with salvage surgery ± adjuvant reirradiation (re-RT), were selected from a multiinstitution database. Disease-free survival (DFS), overall survival (OS), cumulative incidence of second IBR, and distant metastases (DM) were estimated. Results: A total of 224/267 patients from seven institutions were included. Primary tumors received 21 Gy. Median time to first IBR was 4.3 years (range 2.6–6.1 years). Salvage mastectomy and repeat quadrantectomy were performed in 135 (60.3%) and 89 (39.7%) patients, followed by adjuvant re-RT in 21/135 (15.5%) and 63/89 (70.8%), respectively. Median follow-up after salvage treatment was 4.1 years. Overall, 5- and 8-year outcomes were as follows: cumulative incidence of second IBR: 8.4% and 14.8%; cumulative incidence of DM: 17.1% and 22.5%; DFS: 67.4% and 52.5%; OS: 89.3% and 74.7%. The risk of second IBR was similar in the salvage mastectomy and repeat quadrantectomy + RT groups [hazard ratio (HR) 1.41, p = 0.566], while salvage mastectomy patients had greater risk of DM (HR 3.15, p = 0.019), as well as poorer DFS (HR 2.13, p = 0.016) and a trend towards worse OS (HR 3.27, p = 0.059). Patients who underwent repeat quadrantectomy alone had worse outcomes (second IBR, HR 5.63, p = 0.006; DFS, HR 3.21, p = 0.003; OS, HR 4.38, p = 0.044) than those adding re-RT. Conclusions: Repeat quadrantectomy + RT represents an effective salvage approach and achieved local control comparable to that of salvage mastectomy.

Background and objectives The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that in clinically node-negative women undergoing breast-conserving therapy (BCT) and found to have metastases to 1 or 2 sentinel nodes, sentinel lymph node biopsy (SLNB) alone resulted in rates of local control, disease-free survival, and overall survival equivalent to those seen after axillary lymph node dissection (ALND), but with significantly lower morbidity. Application of the Z0011 guidelines resulted in fewer ALNDs without affecting locoregional recurrence or survival. Changes in practice inevitably affect health care costs. The current study investigated the actual impact of applying the Z0011 guidelines to eligible patients and determined the costs of care at a single institution. Patients and methods We compared axillary nodal management and cost data in breast cancer patients who met the Z0011 criteria and were treated with BCT and SLNB. Patients were allocated into two mutually exclusive cohorts based on the date of surgery: pre-Z0011 (June 2013 to December 2015) and post-Z0011 (June 2016 to December 2018). Results Of 3912 patients, 433 (23%) and 357 (17.6%) patients in the pre- and post-Z0011 era had positive lymph nodes. ALND decreased from 15.3% to 1.57% in the post-Z0011 era. The mean overall cost of SLNB in the pre-Z0011 cohort was €1312 per patient, while that for SLNB with completion ALND was €2613. Intraoperative frozen section (FS) use decreased from 100% to 12%. Omitting the FS decreased mean costs from €247 to €176. The mean total cost in the pre-Z0011 cohort was €1807 per patient, while in the post-Z0011 cohort it was €1498. The application of Z0011 resulted in an overall mean cost savings of €309 for each patient. Conclusions Application of the Z0011 criteria to patients undergoing BCT at our institution results in more than half a million Euro cost savings.

Background Chylothorax following pulmonary resection and lymphadenectomy for cancer is a potential severe complication in thoracic surgery. In the present study, we investigated the efficacy of the nonsurgical approach as well as the need for reoperation after conservative approach failure. Methods Chylothorax was diagnosed when chylous leakage from the chest drainage was observed and confirmed by the presence of triglycerides in the pleural fluid. We initially treated all the patients conservatively with complete oral intake cessation and total parenteral nutrition; if drainage output remained more than 800 mL/d after the first 5 days or major pleural effusion was observed at chest X-ray after chest tube removal, surgical treatment of chylothorax was indicated. Results Between January 1998 and December 2018, 5,072 patients underwent standard anatomical resection and mediastinal lymph node dissection for cancer at our institution. Among them, 30 patients (0.6%) developed chylothorax: 20 patients were effectively treated only by nil per os and low-fat diet, while 10 patients (33.3%) required surgical treatment. Mean age was 63 years; there were 24 male patients (80%); right-sided chylothorax was more frequent than left-sided chylothorax (22 vs. 8, respectively) although not statistically significant (p = 0.38); the only factor that seems to influence the need for reoperation is chylothorax flow rate during conservative treatment (p = 0.06). Conclusion Conservative treatment is effective in the case of low flow-rate chylothorax (< 800 mL/d); in the case of a higher flow rate, surgical exploration is needed and thoracic duct ligation—with or without lymphatic sites clipping—provides definitive lymphostasis.

Background The role of primary tumour surgery in pancreatic neuroendocrine tumours (PNETs) with unresectable liver metastases is controversial and international guidelines do not recommend surgery in such cases. Resectability of the primary tumour has never been considered in outcome comparisons between operated and non-operated patients. Methods From two institutional prospective databases of patients affected by PNET and unresectable liver metastases, 63 patients who underwent a left-pancreatectomy at diagnosis were identified and compared with a group of 30 patients with a potentially resectable but not-resected primary tumour located in the body or tail. The endpoint was overall survival (OS). Results The two groups significantly differed at baseline with regard to liver tumour burden Ki-67 labelling index, site of pancreas, results of the 18FDG PET-CT and age. In the operated patients, surgical morbidity comprised 7 cases of pancreatic fistula. Postoperative mortality was nil. Median OS for patients undergoing left-pancreatectomy was 111 months vs 52 for the non operated patients (p = 0.003). At multivariate analysis after propensity score adjustment, no surgery as well as liver tumour burden>25% and higher Ki-67 index were associated with an increased risk of death during follow-up. In patients with unresectable primary tumour, OS was similar in comparison to that in the resectable but non-resected patients, and significantly worse than that in the resected patients (p = 0.032). Conclusion In PNETs located in the body or tail and diffuse liver metastases distal pancreatectomy may be justified in selected patients. Randomized studies may be safely proposed in future on this topic.

Background The Glasgow prognostic score (GPS) is an inflammation-based score based on albuminemia and C-reactive protein concentration proved to be associated with cancer-specific survival in several neoplasms. The present study explored the immediate postoperative value of the GPS for patients undergoing pneumonectomy for lung cancer. Methods The value of the GPS preoperatively was studied in 250 patients undergoing pneumonectomy fornon-small cell lung cancer (NSCLC). We analyzed overall postoperative complications, pulmonary and cardiac complications, 30-day postoperative death, reoperation for early complications, intensive care unit(ICU) length of stay and total length of hospital stay. Results Patients with a GPS of 0 and 1 had a mean ICU length of stay of 0.8 days, whereas patients with a GPS of 2 had a mean ICU stay of 5.0 days (p= 0.004). The postoperative mortality rate in patients with a GPS of 2 was much higher than in patients with a GPS of 1 and 2, although it was not statistically significant (p= 0.083). Conclusions A preoperative GPS of 2 effectively predicts a prolonged ICU stay in patients who undergo pneumonectomy for cancer. The score may be proposed as an easy-to-determine, economical, and fast preoperative tool to plan and optimize ICU admissions after elective pneumonectomy.

A low burden of disease represents an independent favorable prognostic factor of response to peptide receptor radionuclide therapy (PRRT) in patients affected by gastro-entero-pancreatic neuroendocrine tumors. However, it is not clear whether this is due to a lower diffusion of the disease or thanks to debulking surgery. From 1996 to 2013 those patients diagnosed with G1–G2 pancreatic neuroendocrine tumor (PNET) and synchronous liver metastases who were not deemed eligible for liver radical surgery but were eligible to receive upfront PRRT were prospectively included in the study. Two groups of comparison were identified: those submitted for primary tumor resection before PRRT and those who were not. The outcome was evaluated as: objective response to PRRT (OR), progression-free survival (PFS), and overall survival (OS). Of the 94 subjects, 31 were previously submitted for primary tumor resection. After propensity score adjustments, patients who underwent surgery before PRRT showed higher stabilization or objective responses after PRRT (p = .006), and this translated into a better median PFS (70 vs. 30 months; p = .002) and OS (112 vs. 65 months; p = .011), for operated versus nonoperated patients, respectively. At multivariate analysis, operated patients showed a statistically significantly improved PFS: HR, 5.11 (95 % CI 1.43–18.3); p = .012, whereas Ki-67 in continuous fashion was correlated significantly with OS: 1.13 (95 % CI 1–1.27); p = .048. Primary tumor resection prior to PRRT can be safely proposed in G1–G2 PNETs with diffuse liver metastases because it seems to enhance response to PRRT and to improve significantly PFS.

http://hdl.handle.net/20.500.11768/96439 Background: During the period that randomized clinical trials were establishing the role of adjuvant therapy in tumors larger than 5 cm without lymph-node invasion, which shifted from stage IB (6th TNM) to stage II (7th TNM), we derived the rate of shifted patients in our series and analyzed the relationship between specific patient- and tumor-characteristics, and clinical outcome, to identify putative prognostic factors. Methods: We retrospectively collected data (age, sex, smoking status, type of surgery grading, and histological type) from 467 patients who underwent radical surgery for primary 6th TNM-T2N0 non-small cell lung cancer patients between 1998 and 2009 at our institute. Categorical variables were cross-tabulated by tumor staging according to the 7th TNM edition, and they were tested both for association with stage and survival. Results: One hundred and eighteen patients shifted to stage II, mainly older patients and patients with a sarcomatoid or a poorly differentiated carcinoma. Median overall survival time was significantly different across stages. Among the factors investigated, only the tumor dimension resulted in being statistically significant in multivariate analysis. Conclusions: Nearly a quarter of patients shifted from stage I (6th TNM) to stage II (7th TNM), raising a major need for information on the effects of adjuvant chemotherapy in this group of patients. Our findings suggest that randomized clinical trials aimed at addressing this topic should consider only tumor dimensions as principal selection criteria.

Background Screening-CT is able to discover small peripheral lung nodules. The nature of these nodules is uncertain but it is reasonable that some of them, in particular the non-solid ones, could represent precancerous lesions. A previous trial showed a reduction in size of peripheral nodules by inhaled budesonide in subjects with bronchial dysplasia. Objective The primary objective of the study was the evaluation of the effect of budesonide as a chemopreventive agent for lung lesions. The primary endpoint was the modification of lung lesions at ld-CT scan (according to RECIST criteria) after one year of treatment in a person-specific analysis. Methods We performed a randomized, double-blind, placebo controlled trial to evaluate whether inhaled budesonide was able to reduce size and number of persistent, undetermined CT-detected lung nodules in high-risk asymptomatic subjects currently undergoing a five-year CT scan screening program at the European Institute of Oncology. Results Trial enrollment started in April 2006 and ended in July 2007 with the randomization of 202 current or former smokers with stable CT-detected lung nodules set to receive budesonide 800 μg or placebo twice daily for 12 months. Conclusion Our trial represents the first phase II study of a chemopreventive intervention focusing on the peripheral lung, where the majority of lung cancers arise. The research was nested into a screening project with clear advantages in participant accrual and reduction of costs. This paper describes the rationale and design of the study, thus focusing on the methodology and operational aspects of the clinical trial. ( Clinicaltrials.gov number. NCT00321893 )

Objective Pneumonectomy is not always sufficient for the radical resection of cancer. In the present study, pneumonectomy may be associated with an extended resection of mediastinal or parietal structures. The postoperative risk and the oncologic benefits of such an extended procedure have not been sufficiently demonstrated. Methods We have defined "extended" pneumonectomy (EP) as the removal of the entire lung, associated with one or more of the following structures: superior vena cava, tracheal carina, left atrium, aorta, chest wall, or diaphragm. Our clinical database was retrospectively reviewed to identify patients who underwent EP to assess their postoperative morbidity, mortality, and long-term survival. Results Between 1998 and 2005, 47 EPs were performed. The "extended" procedure included left atrium resection in 15 patients, combined SVC and carinal resection in 9 patients, aortic resection in 8 patients (in 3 patients with prosthetic replacement), chest wall or diaphragmatic resection in 6 patients, SVC resection in 4 patients, and carinal resection in 4 patients. A partial esophageal muscular resection was performed in 1 patient. Overall 60-day mortality was 8.5%. Major postoperative complications occurred in 8 patients (17%). The 2- and 5-year survival rates for the overall population were 42% and 22.8%, respectively. Interestingly, long-term survivors were recorded only in the group of patients who received induction treatment. Conclusions Extended pneumonectomy is a feasible procedure with an acceptable risk factor. To improve the selection of patients, all candidates should undergo preoperative mediastinoscopy and induction chemotherapy. In patients with positive response to chemotherapy or stable disease, extended pneumonectomy may afford a radical resection in more than 80% of cases and may result in a permanent cure in some instances.

Objective: A higher mortality has been reported after pneumonectomy over the age of 70. The aim of the study was to quantify the additional riskduetoageafterstandardpneumonectomyforlungcancerbyacase—controlstudy.Methods:Ourclinicaldatabasewasreviewedtosearchfor patients aged 70 years or more who underwent standard pneumonectomy for lung cancer between 1998 and 2005. A control group of patients younger than 70 (one case/two controls) was matched for sex, cardiovascular disease, American Association of Anaesthetists score, respiratory function, side of pneumonectomy, induction chemotherapy and stage. Overall mortality and morbidity were compared. Long-term survival data were also analysed. Results: During the considered period, 35 patients aged 70 years or more underwent pneumonectomy (30 males, median age 73 years, 15 right-sided procedures). The control group was composed of 70 patients. The two groups were homogeneous in the variables used for matching. Overall mortality and morbidity were 11.4 and 54.2% in the elderly group as compared to 4.3 and 41.6% in controls (p-value not significant). Elderly patients experienced a higher rate of respiratory complications (25.7%) as compared to controls (8.3%, p = 0.01). At univariate analysis, the only risk factor for death was the occurrence of respiratory complications (OR 6.5, CI 1.8—18.2). At multivariate analysis, age 70 years (OR 5.36, CI 1.48—19.3) and preoperative chemotherapy (OR 7.65, CI 2.04—28.6) were confirmed as predictors of respiratory complications. Five-year survival was 17.5% in the elderly group and 53.6% in the control group (p = 0.003). Elderly patients with a better respiratory function (FEV1 > 70%) had a 5-year survival of 45.4%. Conclusions: In the elderly patients, the risk of respiratory complications after pneumonectomy is increased as compared to younger patients with equivalent respiratory function. Age and preoperative chemotherapy are independent risk factors for respiratory complications. A lower mortality and a better long-term survival are obtained in elderly patients with a better respiratory function (FEV1 70%). # 2007 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Background: Anxiety and depression are common in people with multiple sclerosis (MS), but data on emotional communication during MS consultations are lacking. We assessed patient expressions of emotion and neurologist responses during first-ever MS consultations using the Verona Coding Definitions of Emotional Sequences (VR-CoDES). Methods: We applied VR-CoDES to recordings/transcripts of 88 outpatient consultations (10 neurologists, four MS Italian centers). Before consultation, patients completed the Hospital Anxiety and Depression Scale (HADS). Multilevel sequential analysis was performed on the number of cues/concerns expressed by patients, and the proportion of reduce space responses by neurologists. Results: Patients expressed 492 cues and 45 concerns (median 4 cues and 1 concern per consultation). The commonest cues were verbal hints of hidden worries (cue type b, 41%) and references to stressful life events (type d, 26%). Variables independently associated with number of cues/concerns were: anxiety (HADS-Anxiety score >8) (incidence risk ratio, IRR 1.08, 95% CI 1.06-1.09; p Conclusions: Patient emotional expressions varied widely, but VR-CoDES cues b and d were expressed most often. Patient anxiety was directly associated with emotional expressions; older age of patients and neurologists, and second opinion consultations were inversely associated with patient emotional expression. In over 50% of instances, neurologists responded to these expressions by reducing space, more so in anxious patients. These findings suggest that neurologists need to improve their skills in dealing with patient emotions.

Since squamous cell carcinoma antigen (SCC-Ag) testing became commercially available on the Architect platform, the previously established method on the Abbott IMx platform has been progressively replaced. Aim of this work was to compare SCC-Ag values obtained with the 2 methods. Clinical and laboratory data of 188 patients for whom SCC-Ag determination was requested, were reviewed. IMx was used to determine the levels of SCC-Ag from June 2007 to May 2009, while the Architect system was used from June 2009 to April 2011. Only patients consistently diagnosed with no evidence of disease, for whom at least 2 determinations with each analyzer were available were used. Comparison of the results obtained with the 2 systems was then performed. Mean values for SCC-Ag were 0.56 ng/mL (Standard Error (SE): 0.08) with the IMx method, and 1.08 ng/mL (SE 0.10) with Architect (p

Objectives The aim of the study is to evaluate the response to neoadjuvant chemotherapy (NACHT) of patients with recurrent cervical cancer who were poor candidates for pelvic exenteration (PE), and the impact on DFS and OS. Methods A retrospective data collection extracted from medical records of 61 patients submitted to pelvic exenteration was performed: 30 underwent up-front exenterative procedure whereas 31 received NACHT. Results The median tumor size was significantly (P = 0.0006) larger in the NACHT group compared to the up-front PE one (43.9 mm vs 28 mm), and a significant (P = 0.04) higher percentage of patients (45 vs 20%) had lateral pelvic wall invasion in the NACHT group. No statistically significant difference in early and late complications was observed in the two groups. Median overall survival in study population was 42.9 months (95% CI: 22.2, 180.8). Median overall survival times as well as recurrence free survival times were not significantly different between NACHT (42.9 months and 36.1 months for OS and DFS respectively) vs. No NACHT (111.9 months and 48.1 months for OS and DFS respectively). There was an overall significant difference in DFS between negative and positive margins but the curves were similar for NACHT and up-front PE groups stratified by resection margin status. Conclusions In our series, though small and retrospective, NACHT prior to PE represents a feasible therapeutic option without intra-operative and early post-operative mortality or worsening of early and late complication rate and with acceptable long-term survival and DFS for recurrent cervical cancer patients who are poor candidates for up-front pelvic exenteration. © 2013 Elsevier Inc.

The quality of first surgery is one of the most important prognostic factors in ovarian cancer patients. Pre-surgical distinction of benign and malignant pelvic mass plays a critical role in ovarian cancer management and survival. The aim of this study was to evaluate the clinical performance of ROMA algorithm and of CA125 and HE4 in the triage of patients with a pelvic mass undergoing surgery, in order to discriminate benign from malignant disease.Three hundred and forty-nine pre- and post-menopausal women, aged 18 years or older undergoing surgery because of a pelvic mass were enrolled: serum concentrations of CA125 and HE4 were determined and ROMA was calculated for each sample.Median serum CA125 and HE4 levels were higher in patients with EOC compared to subjects with benign disease (p0.0001). The resultant accuracy (using Receiver Operating Characteristics, ROC Area) values for HE4, CA125 and ROMA showed a good performance ranging from 89.8% for CA125 in pre-menopausal patients to 93.3% for ROMA in post-menopausal patients: AUC for ROMA resulted significantly higher in comparison to CA125 alone (93.3% vs 90.3%, p=0.0018) in post menopausal patients. A sub-analysis considering the 40 patients with endometrioid disease showed the highest accuracy of HE4 in these patients.Data presented confirm the accuracy of HE4 and of the ROMA algorithm in the distinction of ovarian carcinoma from benign disease, with a trend towards better performance for ROMA than for CA125 alone, statistically significant in postmenopausal patients.

Background Borderline ovarian tumors are generally diagnosed in young women. Because of the young age of patients at first diagnosis and at recurrence, and given the good prognosis of borderline ovarian tumors, a conservative surgical approach in those women who wish to preserve their fertility is advised. In this scenario, transvaginal ultrasound examination plays a key role in the detection of borderline ovarian tumor recurrence, and in assessment of amount of normal functioning parenchyma remaining. To date, no data are available about the natural history of borderline ovarian tumor recurrence. Objective The aim of the study was to determine growth rate of recurrent ovarian cysts by a scheduled follow-up by ultrasound examination, in women previously treated with fertility-sparing surgery due to borderline ovarian tumors. Study Design In this prospective observational study, we collected data from 34 patients previously treated with fertility-sparing surgery due to borderline ovarian tumors, who had a suspicious recurrent lesion. The patients underwent transvaginal ultrasonographic examination every 3 months, until the clinical setting recommended proceeding with surgery. According to cyst size at study entry, they were categorized into 3 groups: ≤10 mm, 10-20 mm, and >20 mm. Summary statistics for cyst size, growth rate, and the probability of remaining within the same dimension category at first ultrasound during the follow-up were also obtained. For each cyst the growth rate was calculated as the slope of the linear interpolation between 2 consecutive measurements. Results Follow-up timing (P 20 mm. The final histology of all recurrent lesions confirmed the same histotype of primary borderline ovarian tumors. Conclusion This article represents the first observational study that describes the trend in the growth rate of borderline ovarian tumor recurrence in relation to their size detected at the first ultrasound examination. The findings of this study seem to confirm, in selected patients, that a thorough ultrasonographic follow-up of borderline ovarian tumor recurrence has proven to be safe and feasible. The final goal of such management is to maximize the impact on fertility potential of these young women without worsening their prognosis.

Screening CT identifies small peripheral lung nodules, some of which may be pre- or early invasive neoplasia. Secondary end point analysis of a previous chemoprevention trial in individuals with bronchial dysplasia showed reduction in size of peripheral nodules by inhaled budesonide. We performed a randomized, double-blind, placebo-controlled phase IIb trial of inhaled budesonide in current and former smokers with CT-detected lung nodules that were persistent for at least 1 year. A total of 202 individuals received inhaled budesonide, 800 μg twice daily or placebo for 1 year. The primary endpoint was the effect of treatment on target nodule size in a per person analysis after 1 year. The per person analysis showed no significant difference between the budesonide and placebo arms (response rate 2% and 1%, respectively). Although the per lesion analysis revealed a significant effect of budesonide on regression of existing target nodules (P = 0.02), the appearance of new lesions was similar in both groups and thus the significance was lost in the analysis of all lesions. The evaluation by nodule type revealed a nonsignificant trend toward regression of nonsolid and partially solid lesions after budesonide treatment. Budesonide was well tolerated, with no unexpected side effects identified. Treatment with inhaled budesonide for 1 year did not significantly affect peripheral lung nodule size. There was a trend toward regression of nonsolid and partially solid nodules after budesonide treatment. Because a subset of these nodules is more likely to represent precursors of adenocarcinoma, additional follow-up is needed. Cancer Prev Res; 4(1); 34–42. ©2010 AACR.

Objective To determinate the impact of maximal cytoreductive surgery on progression free survival (PFS), overall survival (OS) rates and morbidity, in patients with advanced epithelial ovarian or fallopian tube cancer. Methods We reviewed all medical records of patients with stages IIIC–IV epithelial ovarian and fallopian tube cancer that were managed at our institution between January 2001 and December 2008. The following information was collected: demographics, tumor characteristics, operative information, surgical outcomes and peri-operative complication. Results A total of 288 patients with advanced epithelial ovarian and fallopian tube cancer were referred to our institution between January 2001 and December 2008, 259 consecutive patients were enrolled in the study. After a median follow-up of 29.8 months, the PFS and OS were 19.9 and 57.6 months, respectively. At univariate analysis, factors significantly associated with decreased PFS included: age greater than median (> 60 years), stage IV, presence of ascites > 1000 cc, presence of diffuse peritoneal carcinomatosis and diameter of residual disease. This was confirmed also at multivariate analysis with age greater than 60 years (P = 0.025), stage IV vs IIIC (P = 0.037) and any residual disease (P = 0.032) having an independent association with worse PFS. Conclusions Our study seems to demonstrate that a more extensive surgical approach is associated with prolonged disease-free interval and improved survival in patients with stages IIIC–IV epithelial ovarian and fallopian tube cancer. Moreover all patients with no residual tumor seem to have the best prognosis and in view of these results we believe that the goal of primary surgery should be considered as leaving no macroscopic disease.

http://hdl.handle.net/20.500.11768/96473 Background: Prolonged air leak after pulmonary lobectomy is a common time- and cost-consuming complication. Its prevention may significantly reduce hospitalization length and costs offering patients a standard uneventful postoperative course. The aim of the present study is to identify predictors of prolonged postoperative air leak and to stratify preoperative risk factors. Methods: From July 2004 to December 2007 241 consecutive standard lobectomies were performed with curative intent for lung cancer. After excluding patients not fulfilling the inclusion criterion, 58 patients were enrolled in the "prolonged air leak" group and 63 patients were enrolled in the "standard outcome" group. Results: Total lung capacity (p = 0.0038) and percentage emphysema (p = 0.0050) calculated by computed tomography were both significantly related to prolonged postoperative air leak; the values of 4773 cc and 0.4% showed the highest predictive value in terms of sensitivity (84.5% and 75.9% respectively). Multivariate logistic regression disclosed that male sex (p = 0.0006), right side of operation (p = 0.0010) and age (p = 0.0082) were significantly related to prolonged postoperative air leak. Preoperative chemotherapy (p = 0.0940) did not affect air leak status. Conclusions: Computed tomography quantification of emphysema is the best predictor of prolonged air leak. Age, male sex and right side lobectomy are correlated to this complication. Preoperative chemotherapy is not an additional risk factor. (C) 2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

Introduction Indications and results of salvage surgery in mediastinal tumors are still unclear. This study analyzes a single-center experience to assess its mortality, morbidity, and long-term results. Methods Mediastinal salvage surgery (MSS) was defined as surgical resection of persistent or recurrent primary mediastinal tumors after previous local treatments with curative intent or exclusive chemotherapy in case of bulky tumors. Clinical data of patients undergoing MSS between 1998 and 2005 were analyzed. Overall and disease-specific long-term survival was calculated. Results Twenty-one patients (15 men and 6 women, mean age 41 years) underwent MSS. Eleven patients suffered from thymic tumors (eight thymomas, three thymic carcinoma) whereas 10 patients suffered from nonthymic tumors (one lung adenocarcinoma + thymoma, two mediastinal monophasic sinovial sarcoma, one mediastinal neuroendocrine tumor, one mediastinal teratoblastoma, one mediastinal disgerminoma, one Hodgkin's lymphoma, one mediastinal atypic carcinoid, two medullary thyroid carcinoma). MSS required extended vascular resection in 10 cases and cardiopulmonary bypass in one case. Median operation time was 215 minutes (range 140–720). One postoperative death and four major complications were recorded (overall mortality 4.7%, morbidity 19.0%). With a median follow-up of 30.6 months, overall 1-, 3-, and 5-year Kaplan-Meier survival was 89.7, 71.2, and 56.6%, respectively. Thymic neoplasms had a better prognosis (1-, 3-, and 5-year survival was 100, 87.5, 87.5%, respectively) when compared with others (1-, 3-, and 5-year survival was 77.8, 53.3, 26.7%, respectively—logrank p = 0.0128). Conclusions MSS can offer a chance of curative treatment in selected patients with an acceptable morbidity and mortality. Thymic tumors obtain the best results in term of long-term survival.

Background. The oncologic value of superior vena cava (SVC) resection for lung and mediastinal malignancies remains controversial. In this context, we have reviewed our experience in the treatment of locally advanced lung and mediastinal tumor invading the SVC system, analyzing postoperative outcome and long-term oncologic results. Methods. The clinical data of patients who underwent SVC resection were retrospectively analyzed to assess postoperative mortality, and overall and procedure-specific morbidity. Overall survival was calculated for mediastinal and lung tumor groups. Results. From 1998 to 2004, 70 consecutive patients (52 with lung cancer and 18 with mediastinal tumors) underwent SVC system resection. There were 25 replacements (36%) of the SVC system by prosthesis, whereas the remaining underwent partial resection. Major postoperative morbidity and mortality rates in lung cancer patients were 23% and 7.7%, respectively (50% and 5.6% in mediastinal tumors). In the lung cancer group, 5-year survival probability was 31%, and it was affected by mediastinal nodal status (5-year survival in N0‐N1 patients 52%, 21% in N2 patients, 0 in N3 patients). Median survival for mediastinal tumors was 49 months. Conclusions. In conclusion, SVC resection may achieve permanent cure in patients who would have been defined as inoperable 10 years ago. In the case of mediastinal tumors, the need for SVC resection alone should not be considered a contraindication for surgery when prosthetic replacement is feasible. In the case of lung tumors, infiltration of SVC can achieve satisfactory long-term results after neoadjuvant chemotherapy, only when pathologic N2 disease is excluded by preoperative mediastinoscopy.

Background An antimicrobial dressing containing ionic silver was found effective in reducing surgical-site infection in a preliminary study of colorectal cancer elective surgery. We decided to test this finding in a randomized, double-blind trial. Methods Adults undergoing elective colorectal cancer surgery at two university-affiliated hospitals were randomly assigned to have the surgical incision dressed with Aquacel® Ag Hydrofiber dressing or a common dressing. To blind the patient and the nursing and medical staff to the nature of the dressing used, scrub nurses covered Aquacel® Ag Hydrofiber with a common wound dressing in the experimental arm, whereas a double common dressing was applied to patients of control group. The primary end-point of the study was the occurrence of any surgical-site infection within 30 days of surgery. Results A total of 112 patients (58 in the experimental arm and 54 in the control group) qualified for primary end-point analysis. The characteristics of the patient population and their surgical procedures were similar. The overall rate of surgical-site infection was lower in the experimental group (11.1% center 1, 17.5% center 2; overall 15.5%) than in controls (14.3% center 1, 24.2% center 2, overall 20.4%), but the observed difference was not statistically significant (P = 0.451), even with respect to surgical-site infection grade 1 (superficial) versus grades 2 and 3, or grade 1 and 2 versus grade 3. Conclusions This randomized trial did not confirm a statistically significant superiority of Aquacel® Ag Hydrofiber dressing in reducing surgical-site infection after elective colorectal cancer surgery. Trial registration Clinicaltrials.gov: NCT00981110

Objective The impact of induction chemotherapy on postoperative complications after pneumonectomy remains unclear. The aim of the study was to test the hypothesis that chemotherapy may increase the risk of postoperative respiratory complications. Methods Data from 202 consecutive standard pneumonectomies performed for lung cancer were collected and analyzed. Postoperative and 90-day mortality, overall morbidity, and respiratory complication rates were evaluated in patients who had no induction treatment (group A, n = 103) as well as in those who received it (n = 99, group B). Preoperative chemotherapy was inserted as a variable together with 12 other variables (age, sex, smoking status, body mass index, previous cardiac event, American Society of Anesthesiologists score, preoperative forced expiratory volume in 1 second [percent], diffusion capacity for carbon monoxide adjusted for alveolar volume [percent], side of pneumonectomy, perfusion of the removed lung, operating time, and blood transfusion) into univariate and multivariate logistic regression. Results No difference in terms of mortality was recorded between group A (4.9%) and group B (3%, P > .05). Respiratory complications were more frequent in group B than in group A (19 cases, 19.2%, vs 7 cases, 6.8%, P = .008). Univariate logistic regression has demonstrated that pulmonary complications were more frequent in patients over the age of 70 than in those aged 70 or less (25.7% vs 10.2, P = .02), in those with a lower diffusion capacity adjusted for alveolar volume (18.3% vs 5.95%, P = .06), and in patients who received preoperative chemotherapy (19.2% vs 6.8, P = .008). Logistic regression confirmed the role of age (odds ratio = 6.3), preoperative chemotherapy (odds ratio = 4.4), and diffusion capacity adjusted for alveolar volume (odds ratio = 0.33) as risk factors of respiratory complications. Conclusions Standard pneumonectomy is a safe procedure even after induction chemotherapy, with a mortality rate in the order of 5%, but this increases in patients over the age of 70 years. In the case of induction chemotherapy, the risk of respiratory complications is significantly increased, apparently not affecting the overall mortality rate.