The Future of Breast Cancer Research in the Survivorship Field.

Prevalence of survivors of breast cancer has been steadily increasing in the last 20 years. Currently, more than 90% of women diagnosed with early-stage breast cancer are expected to be alive at 5 years from diagnosis thanks to early detection and breakthrough innovations in multimodal treatment strategies. Alongside this advancement in clinical outcomes, survivors of breast cancer might experience several specific challenges and present with unique needs. Survivorship trajectories after diagnosis and treatment of breast cancer can be significantly impacted by long-lasting and severe treatment-related side effects, including physical problems, psychological distress, fertility issues in young women, and impaired social and work reintegration, which add up to patients' individual risk of cancer recurrence and second primary malignancies. Alongside cancer-specific sequelae, survivors still present with general health needs, including management of chronic preexisting or ensuing conditions. Survivorship care should implement high-quality, evidence-based strategies to promptly screen, identify, and address survivors' needs in a comprehensive way and minimize the impact of severe treatment sequelae, preexisting comorbidities, unhealthy lifestyles, and risk of recurrence on quality of life. This narrative review focuses on core areas of survivorship care and discuss the state of the art and future research perspectives in key domains including selected long-term side effects, surveillance for recurrences and second cancers, well-being promotion, and specific survivors' needs.

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.

Chyloperitoneum: Diagnostic and Therapeutic Options.

Chyloperitoneum is not rare and is often associated with other chylous disorders particularly in more complex clinical conditions. An accurate diagnostic study is indispensable to plan the correct therapeutic approach, and we examined the long-term outcomes of our experience in the management of primary and secondary chyloperitoneum in fifty-eight patients (50 adults and 8 children; 34 primary and 24 secondary forms). Diagnostic assessment consisted of aracentesis, whole body lymphoscintigraphy, lymphangio-MR, and lymphangio-CT (LAG-CT). The management of chyloperitoneum consisted initially of non-operative procedures (MCT diet, TPN, octreotide). Surgical treatment was performed in patients not responsive to conservative methods and involved different options using surgical and microsurgical approaches. Microsurgical techniques included chylousvenous shunts connecting chyliferous vessels and mesenteric veins. Fibrin glue or platelet gel injection at the site of the chylous leakage was also used to treat one case of refractory secondary chyloperitoneum. Patients were followed clinically and instrumentally (echography and labs tests) for 6 months to over 5 years. We found that LAG-CT was the primary diagnostic modality to provide precise topographic information concerning the site, cause, and extension of chylous pathology, all of which allowed proper planning of therapeutic procedures. Thirty-four patients did not have a relapse of the chyloperitoneum and 22 patients had a persistence of a small quanitity of ascites with no protein imbalance. We observed early relapse of chylous ascites in 2 cases that required a peritoneal-jugular shunt leading to good outcomes. An accurate diagnostic study (above all LAG-CT) and a microsurgical approach proved to represent an effective management of chyloperitoneum refractory to non-operative treatment.

Chylopericardium: a case report demonstrating utility of lymphography combined with 3D computed tomography for corrective surgical treatment using VATS.

We present a case of a 58 year-old woman with primary chylopericardium associated with chylothorax. Chylopericardium is a condition in which chylous fluid containing a high concentration of triglycerides accumulates in the pericardial cavity, and it can form for many different reasons. 3D computed tomography with lymphography precisely depicted the specific location of the lymphatic leak in this patient, which was successfully repaired using targeted video assisted thoracic surgery (VATS).

Surgical prevention and treatment of lymphedema after lymph node dissection in patients with cutaneous melanoma.

Despite the development of minimal access dissection techniques, use of superficial groin dissection alone, and other recommendations to reduce morbidity in melanoma treatment, the incidence of lymphedema is still significant. The purpose of the current study was to assess the efficacy of microsurgical methods to limit the morbidity of inguinal lymphadenectomy. We conducted a retrospective review of patients who underwent groin dissection for melanoma treatment from February 2006 to April 2009. A total of 59 melanoma patients with positive groin lymph nodes comprised 18 patients (T-group) with melanoma in the trunk and 41 patients (E-group) who had melanoma in an extremity and currently have lymphedema. The T-group patients underwent primary prevention of lymphedema with microsurgical lymphatic-venous anastomoses (LVA) performed simultaneously with groin dissection. The E-group patients underwent LVA to treat the secondary lymphedema after an accurate oncological and lymphological assessment. Limb volume measurements and lymphoscintigraphy were performed pre- and postoperatively to assess short and long term outcome. No lymphedema occurred after microsurgical primary preventive approach in the T- group. Significant (average 80% reduction of pre-op excess volume) reduction of lymphedema resulted after microsurgical treatment for secondary leg lymphedema. Post-operative lymphoscintigraphy in 35 patients demonstrated patency of microsurgical anastomoses in all cases with an average follow-up of 42 months. Study results demonstrate that microsurgical LVA primary prevention prevented lymphedema after inguinal lymphadenectomy in the T-group patients. In addition, lymphatic-venous multiple anastomoses proved to be a successful treatment for clinical lymphedema with particular success if treated at the early stages.

Immunodeficiency due to chylous dysplasia: diagnostic and therapeutic considerations.

Among primary immunodeficiencies, common variable immunodeficiency (CVID) is defined by an impaired production of immunoglobulins characterized by low levels of plasma immunoglobulins and an altered antibody response. The case reported here was initially interpreted as a CVID. A 20 year old male suffered from diarrhea, weight loss, and malnutrition. Accurate diagnostic assessment uncovered a protein-losing enteropathy. Conventional oil contrast lymphangiography accurately documented the underlying problem and established the appropriate therapeutic approach. The operation consisted of multiple antigravitational ligatures of dilated and incompetent chylous vessels and chylous vessel-mesenteric vein microanastomoses. Serum albumin and leukocyte counts normalized by 1 week after operation and remained stable with time. There were no more episodes of diarrhea, and the patient regained weight. Accurate diagnostic assessment and particularly lymphangiography may be necessary to properly define difficult cases of immunodeficiency due to intestinal protein loss and to plan a corrective therapeutic functional approach.

Accuracy of sentinel lymph node biopsy after neo-adjuvant chemotherapy in patients with locally advanced breast cancer and clinically positive axillary nodes.

BACKGROUND: Feasibility and accuracy of sentinel node biopsy (SLNB) after the delivery of neo-adjuvant chemotherapy (NAC) is controversial. We here report our experience in NAC-treated patients with locally advanced breast cancer and clinically positive axillary nodes, and compare it with the results from our previous randomized trial assessing SLNB in early-stage breast cancer patients. PATIENTS AND METHODS: Sixty-four consecutive patients with large infiltrating tumor and clinically positive axillary nodes received NAC and subsequent lymphatic mapping, SLNB and complete axillary lymph node dissection (ALND). The status of the sentinel lymph node (SLN) was compared to that of the axilla. RESULTS: At least one SLN was identified in 60 of the 64 patients (93.8%). Among those 60 patients, 37 (61.7%) had one or more positive SLN(s) and 23 (38.3%) did not. Two of the patients with negative SLN(s) presented metastases in other non-sentinel nodes. SLNB thus had a false-negative rate, a negative predictive value and an overall accuracy of 5.1%, 91.3% and 96.7%, respectively. All these values were similar to those we reported for SLNB in the settings of early-stage breast cancer. CONCLUSION: SLNB after NAC is safe and feasible in patients with locally advanced breast cancer and clinically positive nodes, and accurately predicts the status of the axilla.

The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis.

There is considerable exigency to take all necessary steps to cure tuberculosis cases and prevent further emergence of drug-resistant tuberculosis. The most important of these steps is to ensure that the treatment, particularly of sputum smear-positive cases, is adequate and that patients adhere to their treatment by supervised, direct observation of drug-taking according to the standardized regimens. Use of fixed-dose combinations (FDCs) of tablets against tuberculosis is now being recommended by WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) as an additional step to ensuring proper treatment. FDCs simplify the prescription of drugs and the management of drug supply, and may also limit the risk of drug-resistant tuberculosis arising as a result of inappropriate drug selection and monotherapy. Only FDCs of proven quality and proven rifampicin bioavailability should be purchased and used. In most situations, blood levels of the drugs are inadequate because of poor drug quality rather than poor absorption. This is true irrespective of the human immunodeficiency virus (HIV) infection status of the tuberculosis patients (other than those with overt acquired immunodeficiency syndrome, with CD4 counts < 200 cells/mm3). Currently, WHO, IUATLD and their partners are developing strategies for ensuring that only quality FDCs are used in tuberculosis programmes. A simplified and effective protocol for assessment of rifampicin bioavailability has been developed, and laboratories are being recruited to form a supranational network for quality assurance of FDCs. Standardization of FDC drug formulations has been proposed, which limits rifampicin-containing preparations to nine (including a four-drug FDC and three paediatric FDCs).

Estimate of the global market for rifampicin-containing fixed-dose combination tablets.

SETTING: Despite WHO and IUATLD recommendations to use fixed-dose combination (FDC) tablets for treatment of tuberculosis, more than 75% of all rifampicin used in the public sector globally is administered as single drug tablets. OBJECTIVE: To estimate the potential global market for rifampicin-containing FDCs in the public and private sectors. DESIGN: The public sector market for FDCs was calculated from the number of tuberculosis cases notified to WHO for 1996 and from information on treatment regimens currently used in each country. The private sector market was calculated from the estimated number of treated tuberculosis cases and the treatment regimens presumed to be used in the private sector. RESULTS: The potential global market for the four-drug FDC tablet (rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg and ethambutol 275 mg) is 305 (90%CI 145-505) million tablets per year, 105 (90%CI 50-160) and 200 (90%CI 95-345) million of which would be distributed in the public and private sectors, respectively. The uncertainty of the estimate remains considerable, as shown by the 90% confidence intervals. CONCLUSION: The study demonstrated a large potential global market for FDCs that should encourage pharmaceutical manufacturers to produce WHO-recommended dosages of FDCs at affordable prices.

Structures required, roles and responsibilities in maintaining laboratories for quality assurance of anti-tuberculosis fixed-dose combinations in accordance with the IUATLD/WHO statement.

Combining rifampicin in the same tablet with isoniazid, with or without pyrazinamide, is known to affect the bioavailability of the drug. It is also known that many fixed-dose combination (FDC) preparations exist in the market which are of inferior quality, but are unknowingly used extensively in tuberculosis treatment programmes in low-income countries with high tuberculosis caseloads. This has led to joint statements by the International Union Against Tuberculosis and Lung Disease and the World Health Organization (WHO) pointing out that anti-tuberculosis FDCs should only be used in National Tuberculosis Programmes if the bioavailability of at least the rifampicin component has been demonstrated. Through the FDC Quality Assurance Project launched by the WHO in 1997, a strategy was proposed which aimed to provide specific guidance to ensure the improved quality of such preparations, and in particular the bioavailability of the rifampicin component. A crucial component of drug quality assurance is to ensure that the infrastructure and logistics required to carry out the operational aspects of quality assurance are adequate and sustainable. This paper describes the structures and management responsibilities required to meet this objective, based on general WHO guidelines for the quality assurance of pharmaceuticals.

Availability of quality fixed-dose combinations for the treatment of tuberculosis: what can we learn from studying the World Health Organization's vaccine model?

SETTING: In efforts to promote the use of fixed-dose combinations (FDCs) for the treatment of tuberculosis (TB), the World Health Organization (WHO) and partners address the issue of quality assurance. OBJECTIVE: To provide guidance for the development of strategies for quality assurance of FDCs. DESIGN: This review examines the WHO strategies for and experience with quality assurance and supply of vaccines. RESULTS: Several elements in the strategies for quality assurance and supply of vaccines may be applicable for FDCs. At national level, the important strategies are to strengthen National Regulatory Authorities (NRA) and procurement systems and develop planning activities. Stressing quality assurance of FDCs in training activities for regulatory personnel and recommending that aid agencies require adherence to quality assurance policies as conditions for support would promote the implementation of quality assurance of FDCs at country level. At the global level, pre-qualification of manufacturers of FDCs should be explored as a mechanism to assure quality. The pre-qualification process should include evaluation of product files, initial testing for compliance and consistency of specifications, and site visits to producers and NRAs. The vaccine model defines criteria for reassessment that can be used for FDCs.

DOTS (Directly Observed Treatment Strategy) project in Mongolia, 1995.

OBJECTIVE: To establish a tuberculosis (TB) control programme consistent with recommendations made by the WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) in a country where, as in control programmes of the former USSR, TB management previously relied on active case-finding with radiology and long-term monitoring and treatment of patients. DESIGN AND METHODS: A pilot DOTS strategy (directly observed treatment, short course) project was implemented in Dornod Aimak, Eastern Mongolia During a 6-week period, individuals with chronic cough of > or =3 weeks were screened with sputum smear microscopy. Smear-positive patients received a supervised 6-month regimen (2SRHZ/4RH). Outcome was assessed with smear examination 2, 5, and 6 months after the initiation of treatment. RESULTS: Screening of 1241 symptomatic individuals identified 169 smear-positive TB cases (14%). Most of them (92%) were cured as demonstrated by documented sputum conversion. Five patients completed treatment, but were not available for follow-up smear examination, four patients died and four defaulted. CONCLUSION: The DOTS strategy was successfully introduced in a former socialist model country, paving the way to national DOTS implementation in Mongolia. It may serve as an example for countries with a health care tradition similar to that of the Commonwealth of Independent States.

National tuberculosis programme review: experience over the period 1990-95.

Since 1990 the WHO Global Tuberculosis Programme (GTB) has promoted the revision of national tuberculosis programmes to strengthen the focus on directly observed treatment, short-course (DOTS) and close monitoring of treatment outcomes. GTB has encouraged in-depth evaluation of activities through a comprehensive programme review. Over the period 1990-95, WHO supported 12 such programme reviews. The criteria for selection were as follows: large population (Bangladesh, Brazil, China, Ethiopia, India, Indonesia, Mexico, and Thailand); good prospects of developing a model programme for a region (Nepal, Zimbabwe); or at advanced stage of implementation of a model programme for a region (Guinea, Peru). The estimated combined incidence of smear-positive pulmonary tuberculosis was 82 per 100,000 population, about 43% of the global incidence. The prevalence of infection with human immunodeficiency virus (HIV) was variable, being very high in Ethiopia and Zimbabwe, but negligible in Bangladesh, China, Nepal and Peru. The programme reviews were conducted by teams of 15-35 experts representing a wide range of national and external institutions. After a 2-3-month preparatory period, the conduct of the review usually lasted 2-3 weeks, including a first phase of meetings with authorities and review of documents, a second phase for field visits, and a third phase of discussion of findings and recommendations. The main lessons learned from the programme reviews were as follows: programme review is a useful tool to secure government commitment, reorient the tuberculosis control policies and replan the activities on solid grounds; the involvement of public health and academic institutions, cooperating agencies, and nongovernmental organizations secured a broad support to the new policies; programme success is linked to a centralized direction which supports a decentralized implementation through the primary health care services; monitoring and evaluation of case management functions well if it is based on the right classification of cases and quarterly reports on cohorts of patients; a comprehensive programme review should include teaching about tuberculosis in medical, nursing, and laboratory workers' schools; good quality diagnosis and treatment are the essential requirements for expanding a programme beyond the pilot testing; and control targets cannot be achieved if private and social security patients are left outside the programme scope. The methodology of comprehensive programme review should be recommended to all countries which require programme reorientation; it is also appropriate for carrying out evaluations at 4-5-year intervals in countries that are implementing the correct tuberculosis control policies.

PIP: Over the period 1990-95, the World Health Organization (WHO) conducted 12 reviews of national tuberculosis programs, with emphasis on passive case finding; directly observed treatment, short-course (DOTS); drug supply; and treatment outcome monitoring. Criteria for program selection were: large population (Bangladesh, Brazil, Chile, Ethiopia, India, Indonesia, Mexico, and Thailand); good potential for developing a model regional program (Nepal, Zimbabwe); or advanced stage of implementation of a model program (Guinea, Peru). The 2-3-week review process included interviews with authorities, document reviews, field visits, and discussions of findings. The estimated combined incidence of smear-positive pulmonary tuberculosis was 82/100,000 population--about 43% of the global incidence. These reviews suggested the following observations: 1) program review is a useful tool to secure government commitment, reorient tuberculosis control policies, and replan activities on a more solid basis; 2) the involvement of academic and public health institutions, cooperating agencies, and nongovernmental organizations secures broad support for new policies; 3) program success is linked to a centralized direction that supports a decentralized implementation through the primary health care system; 4) monitoring and evaluation of case management function well if based on the correct classification of cases and quarterly reports on cohorts of patients; 5) a comprehensive program review should include teaching about tuberculosis in medical, nursing, and laboratory workers' schools; 6) good quality diagnosis and treatment are essential requirements for expanding a program beyond pilot testing; and 7) tuberculosis control targets cannot be achieved if private and social security patients are excluded from program coverage.

Secular trends of tuberculosis in western Europe.

Deaths due to tuberculosis have decreased uniformly in all countries in Western Europe, and most have occurred among those aged > or = 65 years. In recent years, tuberculosis case notifications have continued to decline in Belgium, Finland, France, Germany, and Spain, and have levelled off in Sweden and the United Kingdom; increases have, however, been recorded in Austria, Denmark, Ireland, Italy, Netherlands, Norway, and Switzerland. In Denmark, Netherlands, Norway, Sweden, and Switzerland an increasing number of cases of tuberculosis among foreign-born residents has resulted in a change from the expected downward trend. Human immunodeficiency virus (HIV) infection appears to contribute only marginally to the overall tuberculosis morbidity; however, it appears to be important in Paris and its surrounding areas, and tuberculosis is very common among HIV-infected persons in Italy and Spain. Despite these recent changes in the incidence of tuberculosis, there is currently no evidence of its increased transmission among the youngest age groups of the indigenous populations. Properly designed disease surveillance systems are critical for monitoring the tuberculosis trends so that each country can identify its own high-risk groups and target interventions to prevent, diagnose, and treat the disease. Tuberculosis remains a global disease and because of increasing human migrations, its elimination in Western Europe cannot be envisaged without concomitant improvements in its control in high-incidence, resource-poor countries.