Impact of Hormone Receptor Status and Tumor Subtypes of Breast Cancer in Young BRCA Carriers.

BACKGROUND: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its impact on prognosis of young patients harboring BRCA pathogenic variant (PV). PATIENTS AND METHODS: This international, multicenter, retrospective cohort study included young patients (≤40 years) diagnosed with invasive breast cancer and harboring germline PV in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest (disease-free survival [DFS], breast cancer specific survival [BCSS] and overall survival [OS]) were first investigated according to hormone receptors expression (positive vs. negative), and then according to breast cancer subtype (luminal A-like vs. luminal B-like vs. triple-negative vs. HER2-positive breast cancer). RESULTS: From 78 centers worldwide, 4,709 BRCA carriers were included, of whom 2,143 (45.5%) had hormone receptor-positive and 2,566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% vs. 9.6%, p<0.001), while the rate of second primary breast cancer was lower (9.1% vs. 14.7%, p<0.001) compared to patients with hormone receptor-negative disease. The 8-years DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive vs. negative disease changed over time for DFS, BCSS, and OS (p<0.05 for interactions of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-years DFS: 60.8% in luminal A-like vs. 63.5% in triple-negative vs. 65.5% in HER2-positive and 69.7% in luminal B-like subtype). CONCLUSIONS: In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive vs. negative disease warrants consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.

Safety of fertility preservation techniques before and after anticancer treatments in young women with breast cancer: a systematic review and meta-analysis.

STUDY QUESTION: Is it safe to perform controlled ovarian stimulation (COS) for fertility preservation before starting anticancer therapies or ART after treatments in young breast cancer patients? SUMMARY ANSWER: Performing COS before, or ART following anticancer treatment in young women with breast cancer does not seem to be associated with detrimental prognostic effect in terms of breast cancer recurrence, mortality or event-free survival (EFS). WHAT IS KNOWN ALREADY: COS for oocyte/embryo cryopreservation before starting chemotherapy is standard of care for young women with breast cancer wishing to preserve fertility. However, some oncologists remain concerned on the safety of COS, particularly in patients with hormone-sensitive tumors, even when associated with aromatase inhibitors. Moreover, limited evidence exists on the safety of ART in breast cancer survivors for achieving pregnancy after the completion of anticancer treatments. STUDY DESIGN, SIZE, DURATION: The present systematic review and meta-analysis was carried out by three blinded investigators using the keywords 'breast cancer' and 'fertility preservation'; keywords were combined with Boolean operators. Eligible studies were identified by a systematic literature search of Medline, Web of Science, Embase and Cochrane library with no language or date restriction up to 30 June 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: To be included in this meta-analysis, eligible studies had to be case-control or cohort studies comparing survival outcomes of women who underwent COS or ART before or after breast cancer treatments compared to breast cancer patients not exposed to these strategies. Survival outcomes of interest were cancer recurrence rate, relapse rate, overall survival and number of deaths. Adjusted relative risk (RR) and hazard ratio (HR) with 95% CI were extracted. When the number of events for each group were available but the above measures were not reported, HRs were estimated using the Watkins and Bennett method. We excluded case reports or case series with <10 patients and studies without a control group of breast cancer patients who did not pursue COS or ART. Quality of data and risk of bias were assessed using the Newcastle-Ottawa Assessment Scale. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1835 records were retrieved. After excluding ineligible publications, 15 studies were finally included in the present meta-analysis (n = 4643). Among them, 11 reported the outcomes of breast cancer patients who underwent COS for fertility preservation before starting chemotherapy, and 4 the safety of ART following anticancer treatment completion. Compared to women who did not receive fertility preservation at diagnosis (n = 2386), those who underwent COS (n = 1594) had reduced risk of recurrence (RR 0.58, 95% CI 0.46-0.73) and mortality (RR 0.54, 95% CI 0.38-0.76). No detrimental effect of COS on EFS was observed (HR 0.76, 95% CI 0.55-1.06). A similar trend of better outcomes in terms of EFS was observed in women with hormone-receptor-positive disease who underwent COS (HR 0.36, 95% CI 0.20-0.65). A reduced risk of recurrence was also observed in patients undergoing COS before neoadjuvant chemotherapy (RR 0.22, 95% CI 0.06-0.80). Compared to women not exposed to ART following completion of anticancer treatments (n = 540), those exposed to ART (n = 123) showed a tendency for better outcomes in terms of recurrence ratio (RR 0.34, 95% CI 0.17-0.70) and EFS (HR 0.43, 95% CI 0.17-1.11). LIMITATIONS, REASONS FOR CAUTION: This meta-analysis is based on abstracted data and most of the studies included are retrospective cohort studies. Not all studies had matching criteria between the study population and the controls, and these criteria often differed between the studies. Moreover, rate of recurrence is reported as a punctual event and it is not possible to establish when recurrences occurred and whether follow-up, which was shorter than 5 years in some of the included studies, is adequate to capture late recurrences. WIDER IMPLICATIONS OF THE FINDINGS: Our results demonstrate that performing COS at diagnosis or ART following treatment completion does not seem to be associated with detrimental prognostic effect in young women with breast cancer, including among patients with hormone receptor-positive disease and those receiving neoadjuvant chemotherapy. STUDY FUNDING/COMPETING INTEREST(S): Partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC; grant number MFAG 2020 ID 24698) and the Italian Ministry of Health-5 × 1000 funds 2017 (no grant number). M.L. acted as consultant for Roche, Pfizer, Novartis, Lilly, AstraZeneca, MSD, Exact Sciences, Gilead, Seagen and received speaker honoraria from Roche, Pfizer, Novartis, Lilly, Ipsen, Takeda, Libbs, Knight, Sandoz outside the submitted work. F.S. acted as consultant for Novartis, MSD, Sun Pharma, Philogen and Pierre Fabre and received speaker honoraria from Roche, Novartis, BMS, MSD, Merck, Sun Pharma, Sanofi and Pierre Fabre outside the submitted work. I.D. has acted as a consultant for Roche, has received research grants from Roche and Ferring, has received reagents for academic clinical trial from Roche diagnostics, speaker's fees from Novartis, and support for congresses from Theramex and Ferring outside the submitted work. L.D.M. reported honoraria from Roche, Novartis, Eli Lilly, MSD, Pfizer, Ipsen, Novartis and had an advisory role for Roche, Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, Seagen, AstraZeneca, Eisai outside the submitted work. The other authors declare no conflict of interest. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication. REGISTRATION NUMBER: N/A.

Periprosthetic osteolysis: a narrative review.

Periprosthetic osteolysis is still one of the major limitations of prosthetic joints longevity. The process of this "silent" iatrogenic disease involves both mechanical and biological factors that initiate a local immune response in the periprosthetic tissue that eventually lead to implant loosening and failure. There are many causes of the primary aseptic loosening inside the periprosthetic microenvironment, but the most important elements are the wear debris and the cell-particle interactions. Together with implant position, micromotion, bearings, joint fluid pressure, and increased load on the joints drive the pathogenesis of the disease. This narrative review aims to summarise recent studies describing the biological and mechanical factors in the pathogenesis of osteolysis and some of the current pharmacological attempts to "rescue" a failing implant.

Surgical treatment of a colon neoplasm of the splenic flexure: a multicentric study of short-term outcomes.

AIM: The optimal surgical treatment of splenic flexure neoplasm is still not well defined. Extended right hemicolectomy (ERH) and left colic resection (LCR) have been proposed but conclusive evidence concerning postoperative morbidity and oncological results is lacking. The aim of this study was to analyse the short-term outcomes after surgery for splenic flexure cancer with regard to surgical procedure and surgeon's specialty. METHODS: This was a multicentre study on patients who underwent surgery for primary colon cancer of the splenic flexure. RESULTS: From 2004 to 2015, 324 patients fulfilled the criteria for inclusion into the study; 270 (83.4%) had elective surgery while 54 (16.6%) had emergency resection: 158 (48.8%) underwent ERH and 166 (51.2%) LCR; 176 (54.3%) procedures were performed by colorectal surgeons, 148 (46.7%) by general surgeons. In the ERH group a significantly higher rate of emergency operations was carried out (P = 0.005). After elective surgery, no significant differences between ERH and LCR concerning 30-day mortality (3.3% vs 2.0%) and the need for reoperation (10.6% vs 7.4%) were found. Nodal harvesting was significantly higher in the ERH and colorectal surgeon groups in any clinical scenario. At multivariate analysis, age and smoking habit were predictive of the need for reoperation and major morbidity while the general surgeon group showed a higher risk of anastomotic failure (OR = 1.92; P = 0.168). CONCLUSION: We analysed the largest series in literature of curative resections for splenic flexure tumours. The optimal procedure still remains debatable as ERH and LCR appear to achieve comparable short-term outcomes. Surgeon's specialty seems to positively affect patient's outcomes.

Hospital admission for complicated diverticulitis is increasing in Italy, especially in younger patients: a national database study.

BACKGROUND: Epidemiological studies show an increasing trend of hospitalization for acute diverticulitis (AD), but data regarding the trend in hospitalization for complicated AD in Italy are scarce. The aim of this study was to analyze the Italian trend in hospitalization for complicated AD, from 2008 to 2015. METHODS: Using the Italian Hospital Information System, we identified all patients with complicated colonic AD as a discharge diagnosis. Age- and sex-specific rates for AD as well as type of hospital admission (emergency/elective), type of complication (peritonitis, obstruction, bleeding, abscess, fistula, perforation, sepsis) and type of treatment (medical/surgical), were analyzed. RESULTS: A total of 41,622 patients with a discharge diagnosis of complicated AD were identified. Over the study period the admission rate grew from 8.8 to 11.8 per 100,000 inhabitants. The hospitalization rate was highest for patients ≥ 70 years, but the increase in the admission rate was higher among patients aged ≤ 60 years. There were more males in the group < 60 years and more females in the group ≥ 60 years old. The rate of emergency admissions associated with surgery showed a significant mean annual increase (+ 3.9% per year) in the rate of emergency admissions associated with surgery, whereas elective admissions for surgery remained stable. Peritonitis was the most frequent complication (35.5%). The rate of surgery increased in AD complicated by peritonitis (+ 5.1% per year), abscess (+ 5.8% per year) and decreased for obstruction (- 1.8% per year). CONCLUSIONS: From 2008 to 2015, we documented an increasing rate of hospitalization for complicated AD, especially for younger patients, with an increase in surgery for peritonitis and abscess. Further studies are needed to clearly assess the risk factors for complications and risk of surgery.

Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis.

Background: The role of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients is highly controversial and it is not endorsed by current guidelines. Our meta-analysis aimed to better elucidate its activity, efficacy and safety. Material and methods: A systematic search of Medline, Web of Science and conferences proceedings up to 30 October 2017 was carried out to identify randomized controlled trials (RCTs) investigating platinum-based versus platinum-free neoadjuvant chemotherapy in TNBC patients. Using the fixed and random effects models, pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CI) were calculated for pathological complete response (pCR, defined as ypT0/is pN0), event-free survival (EFS), overall survival (OS) and grade 3 and 4 adverse events (AEs: neutropenia, anemia, thrombocytopenia and neuropathy). Results: Nine RCTs (N = 2109) were included. Overall, platinum-based neoadjuvant chemotherapy significantly increased pCR rate from 37.0% to 52.1% (OR 1.96, 95% CI 1.46-2.62, P < 0.001). Platinum-based neoadjuvant chemotherapy remained significantly associated with increased pCR rate also after restricting the analysis to the three RCTs (N = 611) that used the same standard regimen in both groups of weekly paclitaxel (with or without carboplatin) followed by anthracycline and cyclophosphamide (OR 2.53, 95% CI 1.37-4.66, P = 0.003). Conversely, among the 96 BRCA-mutated patients included in two RCTs, the addition of carboplatin was not associated with significantly increased pCR rate (OR 1.17, 95% CI 0.51-2.67, P = 0.711). Two RCTs (N = 748) reported survival outcomes: no significant difference in EFS (HR 0.72, 95% CI 0.49-1.06, P = 0.094) and OS (HR 0.86, 95% CI 0.46-1.63, P = 0.651) was observed. A significant higher risk of grade 3 and 4 hematological AEs, with no increased risk of grade 3 and 4 neuropathy was observed with platinum-based neoadjuvant chemotherapy. Conclusion: In TNBC patients, platinum-based neoadjuvant chemotherapy is associated with significantly increased pCR rates at the cost of worse hematological toxicities. Platinum-based neoadjuvant chemotherapy may be considered an option in TNBC patients. PROSPERO registration number: CRD42018080042.

Trends in hospital admission for acute diverticulitis in Italy from 2008 to 2015.

BACKGROUND: Epidemiological studies in Western countries have documented an increase of hospitalizations for acute diverticulitis (AD) but Italian evidence is scarce. The aim of the present study was to analyse the trend in hospitalization for AD, including in-hospital mortality, in Italy from 2008 to 2015. METHODS: Through the Italian Hospital Information System of the National Health System, we identified diverticulitis of the colon as a discharge diagnosis. Age- and gender-specific rates of hospitalization for AD were assessed. RESULTS: 174,436 hospitalizations were identified with an increasing rate in 2008-2015 from 39 to 48 per 100,000 inhabitants (p < 0.001). The rate of hospitalization was higher for women, but the increasing trend over time was even more pronounced among men (mean increase per year 3.9% and 2.1% among men and women, respectively) (p < 0.001). The increased rate of hospitalization was accounted for by patients less than 70 years old, especially those under 60. In contrast, the hospitalization rate for older patients (age ≥ 70 years) was higher but remained unchanged during the study period. The number of patients with one hospital admissions was significantly higher than the number of patients with at least two hospitalizations (p < 0.001) and both groups showed a significant and comparable increase year by year. The overall in-hospital mortality rate increased from 1.2 to 1.5% (p = 0.017). More specifically, the increase was observed in patients at their first hospitalization [from 1 to 1.4% (mean increase per year of 3%, p = 0.003)]. An increase in mortality was most evident among women (from 1.4 to 1.8% p = 0.025) and in older patients [age 70-79 years from 1.2 to 1.7% (p = 0.034), ≥ 80 years from 2.9 to 4% (p = 0.001)]. CONCLUSIONS: In Italy, between 2008 and 2015, the rate of hospitalization for AD has been constantly increasing due to the hospitalization of younger individuals, especially men. There was a significant increase of in-hospital mortality especially among women, elderly and during the first hospitalization. These findings suggest the need for increased awareness and clinical skills in the management of this common condition.

Advanced MRI may complement histological diagnosis of lower grade gliomas and help in predicting survival.

MRI grading of grade II and III gliomas may have an important impact on treatment decisions. Occasionally,both conventional MRI (cMRI) and histology fail to clearly establish the tumour grade. Three cMRI features(no necrosis; no relevant oedema; absent or faint contrast enhancement) previously validated in 196 patients with supratentorial gliomas directed our selection of 68 suspected low-grade gliomas (LGG) that were also investigated by advanced MRI (aMRI), including perfusion weighted imaging (PWI), diffusion weighted imaging(DWI) and spectroscopy. All the gliomas had histopathological diagnoses. Sensitivity and specificity of cMRI preoperative diagnosis were 78.5 and 38.5 %, respectively, and 85.7 and 53.8 % when a MRI was included, respectively. ROC analysis showed that cut-off values of 1.29 for maximum rCBV, 1.69 for minimum rADC, 2.1 for rCho/Cr ratio could differentiate between LGG and HGG with a sensitivity of 61.5, 53.8, and 53.8 % and a specificity of 54.7, 43 and 64.3 %, respectively. A significantly longer OS was observed in patients with a maximum rCBV<1.46 and minimum rADC>1.69 (80 vs 55 months, p = 0.01; 80 vs 51 months, p = 0.002, respectively). This result was also confirmed when cases were stratified according to pathology (LGG vs HGG). The ability of a MRI to differentiate between LGG and HGG and to predict survival improved as the number of a MRI techniques considered increased. In a selected population of suspected LGG,classification by cMRI underestimated the actual fraction of HGG. aMRI slightly increased the diagnostic accuracy compared to histopathology. However, DWI and PWI were prognostic markers independent of histological grade.

Central olfactory processing in patients with disorders of consciousness.

BACKGROUND AND PURPOSE: Previous studies have demonstrated that individuals suffering from disorder of consciousness (DOC) maintain some minor neural processing of percepts mediated by senses that early in their pathway intersect the thalamus, a key dysfunctional area in DOC patients. Here the degree of sensory preservation within the olfactory system, a system that lacks an obligatory thalamic relay, and its relationship to the consciousness level in DOC patients of various etiologies was assessed. METHODS: Clinical Coma Recovery Scale - Revised (CRS-R) as well as cerebral responses to odors by means of functional magnetic resonance were obtained in a group of vegetative state/unresponsive wakefulness syndrome (n = 26) patients, minimally conscious state (n = 7) patients and healthy controls (n = 25). RESULTS: A majority of vegetative state/unresponsive wakefulness syndrome patients (58%) and 100% of minimally conscious state patients demonstrated a significant preservation of olfactory neural processing, manifested by activation within the piriform cortex, an area considered as a primary olfactory region. Degree of preservation of olfactory processing differed linearly in line with the patients' etiologies where groups demonstrating greater conscious awareness demonstrated more significant processing. Viewed over all DOC patients, there was a significant negative association between odor-related activity in the orbitofrontal cortex and CRS-R scores. CONCLUSIONS: It is demonstrated that DOC patients exhibit a significant preservation of olfactory neural processing with a clear relationship to etiopathologies and clinical measures even years after of chronification of DOC.

Tranexamic acid effects on cartilage and synovial tissue: an in vitro study for a possible safe intra-articular use.

The possible toxic effects of intra-articular tranexamic acid (TA) are still debated. The aim of this study was to evaluate TA effects on human cartilage fragments and synovial biopsies. Explant culture of minced articular cartilage underwent prolonged TA exposure. Histological analysis, immunofluorescence and colorimetric assay for quantification of s-GAG and DNA were performed at the end term. Synoviocytes were cultured for 48h in presence of TA. Light microscopy and flow cytometry analysis were performed at the end of the exposure to TA and one week after the treatment. TA exposure did not influence i) the chondrocyte outgrowth and migration, ii) the expression of chondrogenic and proliferative markers and iii) the s-GAG/DNA ratio. TA treatment did not affect synoviocytes' morphology and treated cells were phenotypically similar to control cells. This study demonstrated that TA does not negatively affect chondrocytes and synoviocytes cultured in vitro. Thus, our findings may be clinically relevant in order to validate the intra-articular TA administration during orthopedic procedures.

Serum allergen-specific IgE, allergic rhinitis severity, and age.

BACKGROUND: Allergic rhinitis (AR) is characterized by an IgE-mediated reaction. Aging usually induces a progressive decline of immune system function. There is common belief that both allergic symptoms severity and serum IgE production decline during aging. OBJECTIVE: This study aimed to evaluate the possible impact of age on: i) serum allergen-specific IgE levels in a large sample of subjects, and ii) AR symptom severity in a group of mono-allergic patients. METHODS: Serum allergen-specific IgE to birch, Bet v 1, Parietaria, and Dermatophagoides pteronyssinus were measured by immunofluorometric assay (IFMA) in a sample of 8098 subjects. AR symptom severity was assessed by visual analogue scale (VAS) in a sub-group of 531 mono-allergic patients. RESULTS: The analysis of variance showed that IgE to Bet v 1, birch, and Dermatophagoides pteronyssinus significantly decreased considering the age, whereas IgE to Parietaria did not significantly decline in respect of the age. Considering the global sample of mono-allergic patients, elderly subjects (over 65 years old) tended to have lower IgE levels, but had significantly lower VAS rating, and significantly less sensitizations than adult subjects (18-65 years old). In both adult and elderly patients VAS strongly correlated with IgE values. CONCLUSIONS: Allergen-specific IgE levels tend to reduce with aging, but with differences between types of allergy. The IgE decrease is usually associated with reduced AR symptom severity. Elderly AR patients seem to have a different phenotype/endotype in comparison with adult AR ones, characterized by milder symptoms, lower IgE production, and less sensitizations. However, a close positive relationship between IgE values and VAS scores is shared by both adult and elderly AR patients, confirming the close link between allergy and symptoms that persists also in the elderly.

Cumulative dose of hydroxychloroquine is associated with a decrease of resting heart rate in patients with systemic lupus erythematosus: a pilot study.

INTRODUCTION: The use of hydroxychloroquine (HCQ) in patients with systemic lupus erythematosus (SLE) offers a wide range of benefits. However, there are evidence in favour of cardiotoxicity, including heart conduction disturbances and congestive heart failure. OBJECTIVE: To determine the effects of HCQ in the resting heart rate (RHR) of SLE patients. PATIENTS AND METHODS: Included were patients with non active SLE, with a sedentary lifestyle and treated with HCQ. Excluded were patients on beta blocker treatment, trained patients, pacemaker's users and patients with clinical or analytical evidence of anemia, renal disease, obstructive pulmonary disease, obesity, uncontrolled thyroid disease, fever or current infection. Standard 12-lead electrocardiogram was performed in the resting condition (supine decubitus and orthostatic position). Comparison between groups was performed using Mann-Whitney U test. A multiple linear regression was performed. A p value <0.05 was considered statistically significant. RESULTS: 42 patients were included. Patients were divided in two groups based on the cumulative dose of HCQ (CD-HCQ), considering 365 g as cut-off. There were 24 patients with low-HCQ (<365 g) and 18 patients with high-HCQ (>365 g). Non significant differences were found in age, sex, prednisone dose or SLEDAI. The mean RHR was 73 ± 6 beats/min in the low-HCQ and 65 ± 7 beats/min in the high-HCQ, with a significant decrease of 11% (p = 0.003). In multiple linear regressions, there were non significant association between the decrease of RHR and prednisone dose, age, SLEDAI or TSH, but there was significant association between RHR and CD-HCQ (p = 0.024) and RHR and time of exposure to HCQ (p = 0.029). CONCLUSION: CD-HCQ higher than 365 g was associated with a significant decrease (11%) in RHR in non-active SLE patients, although a larger prospective study is required to allow more definitive conclusions.

Resting state fMRI in cluster headache: which role?

The pathophysiology of cluster headache (CH) is not well-known. For several years, the most widely accepted theory was that CH was triggered by hypothalamus with secondary activation of the trigeminal-autonomic reflex. However, it was recently suggested that the posterior hypothalamus might be an actor of the pain modulating network more involved in terminating rather than triggering attacks. To investigate this hypothesis, resting state fMRI could provide valuable information on functional connectivity between brainstem and hypothalamus, as well as other brain structures that could be involved in CH pathophysiology. In this framework, here we review recent studies investigating functional connectivity by means of resting state fMRI. Despite the important findings of these studies, we suggest that important steps in the comprehension of CH pathophysiology will be done when the scientific community will use the new methodological approaches recently suggested to study functional connectivity in the brainstem.

Indoor pollution and burning practices in wood stove management.

This study evaluates effects of good burning practice and correct installation and management of wood heaters on indoor air pollution in an Italian rural area. The same study attests the role of education in mitigating wood smoke pollution. In August 2007 and winters of 2007 and 2008, in a little mountain village of Liguria Apennines (Italy), indoor and outdoor benzene, toluene, ethylbenzene, and xylene (BTEX) concentrations were measured in nine wood-heated houses. During the first sampling, several mistakes in heating plant installations and management were found in all houses. Indoor BTEX concentrations increased during use of wood burning. Low toluene/benzene ratios were in agreement with wood smoke as main indoor and outdoor pollution source. Other BTEX sources were identified as the indoor use ofsolvents andpaints and incense burning. Results obtained during 2007 were presented and discussed with homeowners. Following this preventive intervention, in the second winter sampling all indoor BTEX concentrations decreased, in spite of the colder outdoor air temperatures. Information provided to families has induced the adoption of effective good practices in stoves and fire management. These results highlight the importance ofeducation, supported by reliable data on air pollution, as an effective method to reduce wood smoke exposures.

Efficacy of bosentan in the treatment of Raynaud's phenomenon in patients with systemic sclerosis never treated with prostanoids.

The objective of this study was to evaluate the efficacy of the endothelin receptor antagonist, bosentan, in patients with Raynaud's phenomenon secondary to systemic sclerosis never treated with prostanoids and without digital ulcers. The study design is a preliminary, prospective open label trial. The patients recruited took one 62.5 mg dose of bosentan twice daily for 4 weeks, followed by 125 mg twice daily for 24 weeks. Of the 10 patients recruited, all completed the study. The reduction in Raynaud's phenomenon attacks at week 24 from the baseline was statistically significant (Δ-1.3, P=0.0126). The Raynaud's condition score showed a statistically significant improvement (Δ-1.4, P=0.0279), as did the visual analog pain scale (Δ-1.5, P=0.0016) at the 24th week. Bosentan appears to be effective and may be a valid alternative for the treatment of severe secondary Raynaud's phenomenon for patients where prostanoids therapy is contraindicated or refused.

Human cartilage fragments in a composite scaffold for single-stage cartilage repair: an in vitro study of the chondrocyte migration and the influence of TGF-ß1 and G-CSF.

PURPOSE: Minced chondral fragments are becoming popular as a source of cells for cartilage repair, as a growing interest is developing towards one-stage procedures to treat cartilage lesions. The purpose of this study is to (A) compare cell outgrowth from cartilage fragments of adult and young donors using two different types of scaffolds and (B) evaluate the influence of transforming-growth-factor-ß1 (TGF-ß1) and granulocyte colony-stimulating factor (G-CSF) on chondrocyte behaviour. METHODS: In part (A) cartilage fragments from adult and young donors were either loaded onto an HA-derivative injectable paste scaffold or onto an HA-derivative membrane scaffold. Construct sections were then examined for cell counting after 1, 2 and 3 months. In part (B) only membrane scaffolds were prepared using cartilage fragments from young donors. Constructs were cultured either in standard growth medium or in the presence of specific growth factors, such as TGF-ß1 or G-CSF or TGF-ß1 + G-CSF. After 1 month, construct sections were examined for cell counting. Expression of chondrocyte markers (SOX9, CD151, CD49c) and proliferative markers (ß-catenin, PCNA) was assessed using immunofluorescence techniques, both in unstimulated construct sections and in cells from unstimulated and stimulated construct cultures. RESULTS: Part (A): histological analysis showed age-dependent and time-dependent chondrocyte migration. A significant difference (p < 0.05) was observed between young and older donors at the same time point. No difference was detected between the two types of scaffolds within the same group at the same time point. Part (B): after 1 month, the number of migrating cells/area significantly increased due to exposure to TGF-ß1 and/or G-CSF (p < 0.05). Immunofluorescence revealed that outgrowing cells from unstimulated scaffold sections were positive for SOX9, CD151, CD49c and G-CSF receptor. Immunofluorescence of cells from construct cultures showed an increase in ß-catenin in all stimulated groups and an increased PCNA expression in G-CSF-exposed cultures (p < 0.05). CONCLUSION: Outgrowing cells may represent a subset of chondrocytes undergoing a phenotypic shift towards a proliferative state. TGF-ß1, and to a greater extent G-CSF, may accelerate this outgrowth. The clinical relevance of this study may involve a potential future clinical application of scaffolds preloaded with growth factors as an additional coating for chondral fragments. Indeed, a controlled delivery of G-CSF, widely employed in various clinical settings, might improve the repair process driven by minced human cartilage fragments during one-stage cartilage repair.

Protective ileostomy after low anterior resection for extraperitoneal rectal cancer: does the reversal surgery timing affect closure failure?

Loop ileostomy is commonly performed after LAR with TME to temporarily protect the anastomosis. Usually, defunctioning stoma is closed after 1-6 months, although sometimes it becomes definitive de facto. The aim of this study is to investigate the long-term risk of no-reversal of protective ileostomy after LAR for middle-low rectal cancer and the predictive risk factors. A retrospective analysis of a consecutive cohort of patients who underwent curative LAR with covering ileostomy for extraperitoneal rectal cancer in two colorectal units was performed. A different policy for scheduling stoma closure was applied between centers. All the data were collected through an electronic database (Microsoft Excel®). Descriptive statistical analysis was performed using Fisher's exact and Student's t test. Multivariate logistic regression analysis was conducted. Two-hundred twenty-two patients were analysed: reversal procedure was carried out in 193 patients, in 29 cases stoma was never closed. The mean interval time from index surgery was 4.9 months (Center1: 3 vs. Center2: 7.8). At the univariate analysis, mean age and tumor stage were significantly higher in the "no-reversal" group. Unclosed ostomies were significantly lower in Center 1 than Center 2 (8% vs. 19.6%). At the multivariate analysis female gender, anastomotic leakage and Center 2 had significant higher risk of unclosed ileostomy. Currently, no clinical recommendations have been established and the policy of scheduling stoma reversal is variable. Our study suggests that an established protocol could avoid closure delay, decreasing permanent stomas. Consequently, ileostomy closure should be weighed as standardized step in cancer therapeutic pathway.

Prognostic value of HER2-low status in breast cancer: a systematic review and meta-analysis.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low expression in breast cancer has been recently identified as a new therapeutic target. However, it is unclear if HER2-low status has an independent impact on prognosis. MATERIALS AND METHODS: A systematic literature research was carried out to identify studies comparing survival outcomes of patients affected by HER2-low versus HER2-zero breast cancer. Using random-effects models, pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for progression-free survival (PFS) and overall survival (OS) in the metastatic setting as well as disease-free survival (DFS), OS and pathological complete response (pCR) in the early setting. Subgroup analyses by hormone receptor (HoR) status were carried out. The study protocol is registered on PROSPERO (n.CRD42023390777). RESULTS: Among 1916 identified records, 42 studies including 1 797 175 patients were eligible. In the early setting, HER2-low status was associated with significant improved DFS (HR 0.86, 95% CI 0.79-0.92, P < 0.001) and OS (HR 0.90, 95% CI 0.85-0.95, P < 0.001) when compared to HER2-zero status. Improved OS was observed for both HoR-positive and HoR-negative HER2-low populations, while DFS improvement was observed only in the HoR-positive subgroup. HER2-low status was significantly associated with a lower rate of pCR as compared to HER2-zero status both in the overall population (OR 0.74, 95% CI 0.62-0.88, P = 0.001) and in the HoR-positive subgroup (OR 0.77, 95% CI 0.65-0.90, P = 0.001). In the metastatic setting, patients with HER2-low breast cancers showed better OS when compared with those with HER2-zero tumours in the overall population (HR 0.94, 95% CI 0.89-0.98, P = 0.008), regardless of HoR status. No significant PFS differences were found. CONCLUSIONS: Compared with HER2-zero status, HER2-low status appears to be associated with a slightly increased OS both in the advanced and early settings, regardless of HoR expression. In the early setting, HER2-low tumours seem to be associated to lower pCR rates, especially if HoR-positive.

Safety of pregnancy after breast cancer in young women with hormone receptor-positive disease: a systematic review and meta-analysis.

BACKGROUND: Despite increasing evidence on the safety of pregnancy after anticancer treatments in breast cancer survivors, many physicians and patients remain concerned about a potential risk of pregnancy specifically in the case of hormone receptor-positive breast cancer. MATERIALS AND METHODS: A systematic literature search of Medline, Embase and Cochrane library with no language or date restriction up to 31 March 2023 was carried out. To be included, articles had to be retrospective and prospective case-control and cohort studies as well as clinical trials comparing survival outcomes of premenopausal women with or without a pregnancy after prior diagnosis of hormone receptor-positive breast cancer. Disease-free survival (DFS) and overall survival (OS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Study protocol is registered in PROSPERO (n. CRD42023394232). RESULTS: Out of 7796 screened studies, 8 were eligible to be included in the final analysis. A total of 3805 patients with hormone receptor-positive invasive early breast cancer were included in these studies, of whom 1285 had a pregnancy after breast cancer diagnosis. Median follow-up time ranged from 3.8 to 15.8 years and was similar in the pregnancy and non-pregnancy cohorts. In three studies (n = 987 patients) reporting on DFS, no difference was observed between patients with and those without a subsequent pregnancy (HR 0.96, 95% CI 0.75-1.24, P = 0.781). In the six studies (n = 3504 patients) reporting on OS, patients with a pregnancy after breast cancer had a statistically significant better OS than those without a pregnancy (HR 0.46, 95% CI 0.27-0.77, P < 0.05). CONCLUSIONS: This systematic review and meta-analysis of retrospective cohort studies provides updated evidence that having a pregnancy in patients with prior history of hormone receptor-positive invasive early breast cancer appears safe without detrimental effect on prognosis.