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.

A multi-context CNN ensemble for small lesion detection.

In this paper, we propose a novel method for the detection of small lesions in digital medical images. Our approach is based on a multi-context ensemble of convolutional neural networks (CNNs), aiming at learning different levels of image spatial context and improving detection performance. The main innovation behind the proposed method is the use of multiple-depth CNNs, individually trained on image patches of different dimensions and then combined together. In this way, the final ensemble is able to find and locate abnormalities on the images by exploiting both the local features and the surrounding context of a lesion. Experiments were focused on two well-known medical detection problems that have been recently faced with CNNs: microcalcification detection on full-field digital mammograms and microaneurysm detection on ocular fundus images. To this end, we used two publicly available datasets, INbreast and E-ophtha. Statistically significantly better detection performance were obtained by the proposed ensemble with respect to other approaches in the literature, demonstrating its effectiveness in the detection of small abnormalities.

Experience with early TEVAR treatment of uncomplicated type B aortic dissection.

The current paradigm for the treatment of chronic type B aortic dissection involves primarily medical treatment. The patients are then followed for sequelae like progressive dissection or aneurysmal degeneration, selecting this subgroup for further intervention. The European Collaborator Registry, the Talent Thoracic Retrospective Registry, and several meta-analysis showed that the uncomplicated type B dissection patients who underwent thoracic endovascular aortic repair (TEVAR) outperformed their counterpart in the complicated group. The INSTEAD trial, the first randomized trial to examine whether TEVAR is better than medical management in the chronic stable dissection patients, showed no benefit early on although mid-term data might show some benefit. Clearly more randomized controlled trials are necessary to create a paradigm shift. In the United States, the FDA approved TEVAR devices are for the descending thoracic aortic aneurysm and transection only. The use of these devices for dissection is off-label or for investigation only. As future study might broaden the use of TEVAR for the chronic dissection patients, the use of TEVAR in hybrid surgery and in the ascending aorta is also broadening the indication for this technology. With two decades of innovation behind, TEVAR will continue to evolve and innovate in the years ahead.

Influence of chronic coinfection with hepatitis B and C virus on liver histology.

BACKGROUND: Few data are available on histological features of chronic hepatitis B (HBV) and C (HCV) virus coinfection. PATIENTS AND METHODS: We enrolled 142 consecutive patients with viral chronic hepatitis on their first liver biopsy: 27 HBsAg and anti-HCV positive (case BC group), 57 HBsAg positive and anti-HCV negative (control B group) and 58 anti-HCV positive, HBsAg/anti-HBs/anti-HBc negative (control C group). RESULTS: Patients in the case BC group showed serum HBVDNA (37% vs 71.9%, p < 0.005) and ground-glass hepatocytes (37% vs 66.7%, p < 0.01) less frequently than those in the control B group. The case BC group showed a lower prevalence of patients with detectable HCV-RNA than the control C group (60% vs 92.3%, p < 0.001) and a significantly higher fibrosis score (2.1 +/- 1.2 vs 1.5 +/- 1.1, p < 0.05). Of the 27 patients in the case BC group, 10 lacked serum HCV-RNA and showed significantly higher histological activity index (HAI) and fibrosis scores than those found in the 17 HCV-RNA positive (8.5 +/- 4.4 vs 5.4 +/- 2.4 for HAI, p < 0.05; 3.0 +/- 1.3 vs 1.69 +/- 1.0, p < 0.05 for fibrosis). CONCLUSION: Liver histology seems to be more severe in chronic coinfection with HBV and HCV than in single infection, particularly when HCV replication is impaired.

Diagnosis of HCV related acute hepatitis by serial determination of IgM to HCV: a preliminary observation.

OBJECTIVE: To verify whether serial determination of titre of IgM to HCV core protein (HCV IgM) may be useful to distinguish acute hepatitis C (AHC) from reactivation of chronic hepatitis C (r-CHC), we studied 18 consecutive patients with AHC (identified by seroconversion to anti-HCV) and 15 consecutive patients who had been anti-HCV positive for at least one year at the time of reactivation. METHODS: Samples of serum were obtained from all patients on hospitalisation and every 5 days during the follow-up and stored at -80 degrees C: 54 samples of serum for the AHC group and 41 for the r-CHC group. Titres of HCV IgM were calculated as Index values by a commercially available enzyme immunoassay (HCV-IgM EIA 2.0, Abbott Laboratories, North Chicago, IL, USA). RESULTS: No difference was observed between the two groups of patients as regards age, sex, risk factors for the acquisition of HCV infection, clinical and biochemical data on presentation, prevalence of cases with detectable viremia or distribution of HCV genotypes. HCV IgM was detected with an Index value of 350 or more in only 1 (6.7%) in the r-CHC group and in 17 (94.4%) in the AHC group (p<0.01). Moreover, during the early phase of the illness we observed a wide variation in the HCV IgM Index values in AHC and consistent values in r-CHC. CONCLUSIONS: Our data indicate that AHC is characterised by high and variable titres of HCV IgM during the acute phase of the illness, which may be considered diagnostic, whereas in r-CHC the IgM titre remains stable and rarely reaches a high level.