Influence of mRNA Covid-19 vaccine dosing interval on the risk of myocarditis.

Myocarditis is the most salient serious adverse event following messenger RNA-based Covid-19 vaccines. The highest risk is observed after the second dose compared to the first, whereas the level of risk associated with more distant booster doses seems to lie in between. We aimed to assess the relation between dosing interval and the risk of myocarditis, for both the two-dose primary series and the third dose (first booster). This matched case-control study included 7911 cases of myocarditis aged 12 or more in a period where approximately 130 million vaccine doses were administered. Here we show that longer intervals between each consecutive dose, including booster, may decrease the occurrence of vaccine-associated myocarditis by up to a factor of 4, especially under age 50. These results suggest that a minimum 6-month interval might be required when scheduling additional booster vaccination.

Risk of heavy menstrual bleeding following COVID-19 vaccination: A nationwide case-control study.

BACKGROUND: COVID-19 vaccination has been inconsistently associated with an increased risk of heavy menstrual bleeding in previous studies. This study aimed to assess the risk of heavy menstrual bleeding requiring hospital care following COVID-19 vaccination according to the number of doses received and the time elapsed since vaccination. METHODS: Using comprehensive data of the French National Health Data System, we carried out a case-control study. Non-pregnant 15-50 years old women who had a hospital discharge diagnosis of heavy menstrual bleeding between May 12, 2021, and August 31, 2022 (cases) were randomly matched to up to 30 controls of same age, place of residence, social deprivation index, and contraceptive use profile at the date of case hospital admission (index date). Conditional logistic regression models were used to estimate the risk of hospital care for heavy menstrual bleeding associated with primary or booster doses and delay since last COVID-19 vaccination at index date, adjusting for socio-demographic characteristics, comorbidities, healthcare use indicators, and recent SARS-CoV-2 infection. RESULTS: A total of 4610 cases and 89,375 matched controls were included (median age, 42 years). Compared to unvaccinated women, the risk of hospital care for heavy menstrual bleeding was increased in those having received a last dose of primary vaccination in the preceding 1-3 months (Odds Ratio, 1.20 [95% confidence interval, 1.07-1.35]). This association was marked among women residing in the most deprived municipalities (1.28 [1.07-1.52]) and those who were not using hormonal contraception (1.28 [1.11-1.48]). Assuming a causal relationship, a total of 103 cases [54-196] were estimated to be attributable to primary vaccination in France. CONCLUSION: These findings provide evidence of an increased risk of heavy menstrual bleeding during the three-month period following primary COVID-19 mRNA vaccination. No increased risk was found beyond 3 months after primary vaccination nor following booster doses.

Long-Term Prognosis of Patients With Myocarditis Attributed to COVID-19 mRNA Vaccination, SARS-CoV-2 Infection, or Conventional Etiologies.

Importance: Although patients with myocarditis after COVID-19 mRNA vaccination appear to have a good prognosis near hospital discharge, their longer-term prognosis and management remain unknown. Objective: To study the cardiovascular complications of post-COVID-19 mRNA vaccination myocarditis and other types of myocarditis during an 18-month follow-up, as well as disease management based on a study of the frequency of medical procedures and drug prescriptions. Design, Setting, and Participants: In this cohort study based on the French National Health Data System, all individuals aged 12 to 49 years hospitalized for myocarditis in France between December 27, 2020, and June 30, 2022, were identified. Exposure: Individuals were categorized as having postvaccine myocarditis (within 7 days after COVID-19 mRNA vaccine), post-COVID-19 myocarditis (within 30 days of SARS-CoV-2 infection), or conventional myocarditis. Main Outcomes and Measures: The occurrence of clinical outcomes (hospital readmission for myopericarditis, other cardiovascular events, all-cause death, and a composite outcome of these events) over the 18 months following hospital admission were analyzed using weighted Cox models to standardize the comparisons with the conventional myocarditis group. Also, medical management after hospital discharge was longitudinally assessed using generalized estimated equation models. Results: In total, 4635 individuals were hospitalized for myocarditis: 558 with postvaccine myocarditis, 298 with post-COVID-19 myocarditis, and 3779 with conventional myocarditis. Patients with postvaccine myocarditis were younger than those with post-COVID-19 and conventional myocarditis (mean [SD] age of 25.9 [8.6], 31.0 [10.9], and 28.3 [9.4] years, respectively) and were more frequently men (84%, 67%, and 79%). Patients with postvaccine myocarditis had a lower standardized incidence of the composite clinical outcome than those with conventional myocarditis (32/558 vs 497/3779 events; weighted hazard ratio, 0.55 [95% CI, 0.36-0.86]), whereas individuals with post-COVID-19 myocarditis had similar results (36/298 events; weighted hazard ratio, 1.04 [95% CI, 0.70-1.52]). The standardized frequency of medical procedures and drugs prescribed in patients with postvaccine myocarditis or post-COVID-19 myocarditis followed a similar trend in the 18 months following hospital discharge to that of patients with conventional myocarditis. Conclusions and Relevance: Patients with post-COVID-19 mRNA vaccination myocarditis, contrary to those with post-COVID-19 myocarditis, show a lower frequency of cardiovascular complications than those with conventional myocarditis at 18 months. However, affected patients, mainly healthy young men, may require medical management up to several months after hospital discharge.

Risk factors for COVID-19 hospitalisation after booster vaccination during the Omicron period: A French nationwide cohort study.

BACKGROUND: In spite of major effectiveness, a residual risk after COVID-19 primary vaccination was identified, in particular, for vulnerable individuals of advanced age or with comorbidities. Less is known about the Omicron period in people protected by a booster dose. We aimed to identify the characteristics associated with severe COVID-19 during the Omicron period in a population that had received a booster dose in France and to compare differences with the previous periods of the pandemic. METHODS: This study was carried out using the French national COVID-19 vaccination database (VAC-SI) coupled with the National Health Data System (SNDS). Individuals aged 12 years or over who received at least one booster dose were identified. Associations between socio-demographic and clinical characteristics and the risk of COVID-19 hospitalisation occurring at least 14 days after receiving a third dose of vaccine during the period of Omicron predominance, i.e., from 1 January 2022 to 10 November 2022, were assessed using Cox proportional hazard models adjusted for age, sex, time since booster dose and vaccination schedule. Analyses were performed overall and by sub-period of circulation of the strains BA.1, BA.2, and BA.4/BA.5, defined as periods where the main sub-variant accounted for more than 80 % of genotyped samples. FINDINGS: In total, 35,640,387 individuals received a booster dose (mean follow-up of 291 days) and 73,989 were hospitalised for COVID-19 during the total period. Older age (aHR 20.5 95 % CI [19.6-21.5] for 90 years of age or older versus 45-54 years of age), being male (aHR 1.52 [1.50-1.55]), and social deprivation (aHR 1.33 [1.30-1.37] for the most deprived areas versus the least deprived) were associated with an increased risk of hospitalisation for COVID-19. Most of the chronic diseases considered were also positively associated with a residual risk, in particular, cystic fibrosis (aHR 9.83 [7.68-12.56]), active lung cancer (aHR 3.26 [3.06-3.47]), chronic dialysis (aHR 3.79 [3.49-4.11]), psychological and neurodegenerative diseases (more markedly than during the periods of circulation of the alpha and delta variants), and organ transplantation. The use of immunosuppressants was also associated with an increased risk (aHR 2.24 [2.14-2.35], including oral corticosteroids aHR (2.58 [2.50-2.67]). CONCLUSION: Despite an effective booster and a generally less virulent circulating variant, a residual risk of severe COVID-19 still exists in vulnerable populations, especially those with neurological disorders.

Risk of Guillain-Barré Syndrome Following COVID-19 Vaccines: A Nationwide Self-Controlled Case Series Study.

BACKGROUND AND OBJECTIVES: Guillain-Barré syndrome (GBS) has been inconsistently associated with some coronavirus disease 2019 (COVID-19) vaccines. We aimed to quantify the risk of GBS according to the type of COVID-19 vaccine in a large population. METHODS: Using the French National Health Data System linked to the COVID-19 vaccine database, we analyzed all individuals aged 12 years or older admitted for GBS from December 27, 2020, to May 20, 2022. We estimated the relative incidence (RI) of GBS within 1-42 days after vaccination up to the first booster dose compared with baseline periods using a self-controlled case series design. We then derived the number of cases attributable to the vaccination. Analyses were adjusted for the period and stratified by age group, sex, and for the presence of severe acute respiratory syndrome coronavirus 2 or common acute infections. RESULTS: Of 58,530,770 people aged 12 years or older, 88.8% received at least 1 COVID-19 vaccine dose and 2,229 were hospitalized for GBS during the study period. Patients had a median age of 57 years, and 60% were male patients. The RI of GBS between 1-42 days was 2.5 (95% CI 1.8-3.6) for the first dose of ChAdOx1-S and 2.4 (95% CI 1.2-5.0) for the unique dose of Ad26.COV2.S vaccine. We estimated 6.5 attributable GBS cases per million persons having received a first dose of ChAdOx1-S and 5.7 cases per million for the Ad26.COV2.S vaccine. Except for the age group of 12-49 years after the second dose of the messenger RNA (mRNA)-1273 vaccine (RI 2.6, 95% CI 1.2-5.5), none of the RI estimates were found significantly increased for the mRNA vaccines. DISCUSSION: In summary, we found increased risks of GBS after the first administration of ChAdOx1-S and Ad26.COV2.S vaccines. In this comprehensive assessment at the French population level, there was no statistically significant increase in the risk of GBS after the administration of mRNA vaccines. This is reassuring in the context of the ongoing and future use of mRNA-based booster vaccination.

Protection of COVID-19 Vaccination Against Hospitalization During the Era of Omicron BA.4 and BA.5 Predominance: A Nationwide Case-Control Study Based on the French National Health Data System.

Background: Knowing the duration of effectiveness of coronavirus disease 2019 (COVID-19) booster doses is essential to providing decision-makers with scientific arguments about the frequency of subsequent injections. We estimated the level of protection against COVID-19-related hospitalizations (Omicron BA.4-BA.5) over time after vaccination, accounting for breakthrough infections. Methods: In this nationwide case-control study, all cases of hospitalizations for COVID-19 identified in the comprehensive French National Health Data System between June 1, 2022, and October 15, 2022, were matched with up to 10 controls by year of birth, sex, department, and an individual COVID-19 hospitalization risk score. Conditional logistic regressions were used to estimate the level of protection against COVID-19-related hospitalizations conferred by primary and booster vaccination, accounting for history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Results: A total of 38 839 cases were matched to 377 653 controls; 19.2% and 9.9% were unvaccinated, respectively, while 68.2% and 77.7% had received ≥1 booster dose. Protection provided by primary vaccination reached 45% (95% CI, 42%-47%). The incremental effectiveness of booster doses ranged from 69% (95% CI, 67%-71%; ≤2 months) to 22% (95% CI, 19%-25%; ≥6 months). Specifically, the second booster provided an additional protection compared with the first ranging from 61% (95% CI, 59%-64%; ≤2 months) to 7% (95% CI, 2%-13%; ≥4 months). Previous SARS-CoV-2 infection conferred a strong, long-lasting protection (51% ≥20 months). There was no incremental effectiveness of a second booster among individuals infected since the first booster. Conclusions: In the era of Omicron BA.4 and BA.5 predominance, primary vaccination still conferred protection against COVID-19 hospitalization, while booster doses provided an additional time-limited protection. The second booster had no additional protection in case of infection since the first booster.

Risk for Myocardial Infarction, Stroke, and Pulmonary Embolism Following COVID-19 Vaccines in Adults Younger Than 75 Years in France.

BACKGROUND: The BNT162b2 (Pfizer-BioNTech) vaccine has been shown to be safe with regard to risk for severe cardiovascular events (such as myocardial infarction [MI], pulmonary embolism [PE], and stroke) in persons aged 75 years or older. Less is known about the safety of other COVID-19 vaccines or outcomes in younger populations. OBJECTIVE: To assess short-term risk for severe cardiovascular events (excluding myocarditis and pericarditis) after COVID-19 vaccination in France's 46.5 million adults younger than 75 years. DESIGN: Self-controlled case series method adapted to event-dependent exposure and high event-related mortality. SETTING: France, 27 December 2020 to 20 July 2021. PATIENTS: All adults younger than 75 years hospitalized for PE, acute MI, hemorrhagic stroke, or ischemic stroke (n = 73 325 total events). MEASUREMENTS: Linkage between the French National Health Data System and COVID-19 vaccine databases enabled identification of hospitalizations for cardiovascular events (MI, PE, or stroke) and receipt of a first or second dose of the Pfizer-BioNTech, mRNA-1273 (Moderna), Ad26.COV2.S (Janssen), or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccine. The relative incidence (RI) of each cardiovascular event was estimated in the 3 weeks after vaccination compared with other periods, with adjustment for temporality (7-day periods). RESULTS: No association was found between the Pfizer-BioNTech or Moderna vaccine and severe cardiovascular events. The first dose of the Oxford-AstraZeneca vaccine was associated with acute MI and PE in the second week after vaccination (RI, 1.29 [95% CI, 1.11 to 1.51] and 1.41 [CI, 1.13 to 1.75], respectively). An association with MI in the second week after a single dose of the Janssen vaccine could not be ruled out (RI, 1.75 [CI, 1.16 to 2.62]). LIMITATIONS: It was not possible to ascertain the relative timing of injection and cardiovascular events on the day of vaccination. Outpatient deaths related to cardiovascular events were not included. CONCLUSION: In persons aged 18 to 74 years, adenoviral-based vaccines may be associated with increased incidence of MI and PE. No association between mRNA-based vaccines and the cardiovascular events studied was observed. PRIMARY FUNDING SOURCE: None.

Characteristics associated with the residual risk of severe COVID-19 after a complete vaccination schedule: A cohort study of 28 million people in France.

Background: Prior to the availability of vaccines, the risk factors for developing severe forms of COVID-19 were mostly older age and various comorbidities such as diabetes, cardiovascular diseases, mental disorders, transplantations, and kidney disease. Although vaccines have been shown to be highly effective in preventing severe forms of COVID-19, a residual risk may persist, despite vaccination, for certain population groups. Methods: The study was based on data from the national COVID-19 vaccination database (VAC-SI) coupled with the National Health Data System (SNDS), which contains comprehensive reimbursement and hospitalisation data for all of France. All people fully vaccinated by July 31, 2021, with a double-injection vaccine, i.e., the mRNA BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 vaccines, or a single dose for people with a previous confirmed SARS-CoV-2 infection were included and followed until August 31, 2021. Cox proportional hazard models were performed to estimate adjusted hazard ratios (aHR) for COVID-19-related hospitalisation or in-hospital death associated with age, gender, deprivation index, comorbidities, and immunosuppressive or oral corticosteroid therapy from day 14 after full-vaccination. Findings: In a population of 28,031,641 fully vaccinated individuals with an average follow-up of 80 days, 5,345 (87 hospitalisations per 100,000 person-years) were hospitalised for COVID-19 and 996 (16 in-hospital death per 100,000 person-years) died in hospital. In multivariable analysis, a higher risk was observed with increasing age, male gender, and social deprivation. Most of the 47 chronic conditions considered were positively associated with an increased risk of COVID-19-related hospitalisation and a slight excess risk of death. The risk of hospitalisation and in-hospital death for COVID-19 also increased with the use of immunosuppressants (aHR 3.3 [2.8-3.8] and 2.4 [1.7-3.5], respectively) and oral corticosteroids (aHR 2.8 [2.5-3.1] and 4.1 [3.3-5.1]).Less than 10% (519/5,345) of hospitalised cases and 2% (24/996) of those who died in hospital had no identified comorbidities. There was a strong association between an increasing number of comorbidities and the risk of hospitalisation and in-hospital death (e.g., 5+ versus none, aHR 10.1 95%CI 9.0-11.5 and 17.8 95%CI 11.5-27.4, respectively). Interpretation: Although vaccination has dramatically reduced the occurrence of severe forms of COVID-19, a residual risk remains for the elderly, immunocompromised, and polypathological populations and warrants complementary preventive measures. Funding: None.

Age and sex-specific risks of myocarditis and pericarditis following Covid-19 messenger RNA vaccines.

Cases of myocarditis and pericarditis have been reported following the receipt of Covid-19 mRNA vaccines. As vaccination campaigns are still to be extended, we aimed to provide a comprehensive assessment of the association, by vaccine and across sex and age groups. Using nationwide hospital discharge and vaccine data, we analysed all 1612 cases of myocarditis and 1613 cases of pericarditis that occurred in France in the period from May 12, 2021 to October 31, 2021. We perform matched case-control studies and find increased risks of myocarditis and pericarditis during the first week following vaccination, and particularly after the second dose, with adjusted odds ratios of myocarditis of 8.1 (95% confidence interval [CI], 6.7 to 9.9) for the BNT162b2 and 30 (95% CI, 21 to 43) for the mRNA-1273 vaccine. The largest associations are observed for myocarditis following mRNA-1273 vaccination in persons aged 18 to 24 years. Estimates of excess cases attributable to vaccination also reveal a substantial burden of both myocarditis and pericarditis across other age groups and in both males and females.

A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.

We propose a modified self-controlled case series (SCCS) method to handle both event-dependent exposures and high event-related mortality. This development is motivated by an epidemiological study undertaken in France to quantify potential risks of cardiovascular events associated with COVID-19 vaccines. Event-dependence of vaccinations, and high event-related mortality, are likely to arise in other SCCS studies of COVID-19 vaccine safety. Using this case study and simulations to broaden its scope, we explore these features and the biases they may generate, implement the modified SCCS model, illustrate some of the properties of this model, and develop a new test for presence of a dose effect. The model we propose has wider application, notably when the event of interest is death.

Reduced risk of severe COVID-19 in more than 1.4 million elderly people aged 75 years and older vaccinated with mRNA-based vaccines.

Randomized clinical trials have shown mRNA-based vaccines to be 92-95% effective to prevent COVID-19 in adults. We aimed to estimate the impact of vaccination on the risk of severe COVID-19 (requiring hospitalization) in elderly people. Each 1,422,461 vaccinated subject aged 75 or older was matched to two unvaccinated subjects of same age, sex, administrative region, and type of residence. They were followed from date of first injection between 27 December 2020 and 24 February 2021 to 20 March 2021 for COVID-19 hospitalization. Mean age was 82.4 years (SD, 5.7) and median follow-up was 38 days [IQR, 17-54]. Adjusted Hazard Ratio for COVID-19 hospitalization from day 7 after the second dose was estimated at 0.14 (95% confidence interval, 0.11-0.17), i.e. an estimated 86% risk reduction in people aged 75 and older, highlighting the major impact of mRNA vaccination on reducing the risk of COVID-19 among elderly people.

Effectiveness of BNT162b2, mRNA-1273, and ChAdOx1-S vaccines against severe covid-19 outcomes in a nationwide mass vaccination setting: cohort study.

Objective: To estimate the effectiveness of the three covid-19 vaccines by Pfizer-BioNTech (BNT162b2), Moderna (mRNA-1273), and Oxford-AstraZeneca (ChAdOx1-S) in people after receiving two doses. Design: Cohort study. Setting: Nationwide, population based data in France, from the French National Health Data System (Système National des Données de Santé), between 27 December 2020 and 30 April 2021. Participants: Adults aged ≥50 years receiving a first dose of BNT162b2, mRNA-1273, or ChAdOx1-S were randomly selected (1:1) and matched on the date of vaccination with one unvaccinated control. Individuals were matched on year of birth, sex, region of residence, and residence in a nursing home (for individuals aged ≥75 years). All individuals were followed up until 20 August 2021. Main outcome measures: Primary outcome measure was vaccine effectiveness estimated at least 14 days after the second dose against covid-19 related hospital admission using Cox proportional hazards models adjusted for baseline characteristics and comorbidities. Vaccine effectiveness against covid-19 related death in hospital was also investigated. Results: 11 256 832 vaccinated individuals were included in the study (63.6% (n=7 161 658) with the BNT162b2 vaccine, 7.6% (n=856 599) with the mRNA-1273 vaccine, and 28.8% (n=3 238 575) with the ChAdOx1-S vaccine), along with 11 256 832 matched unvaccinated controls. During follow-up (up to 20 August 2021), 43 158 covid-19 related hospital admissions and 7957 covid-19 related deaths in hospital were registered. Compared with unvaccinated controls, vaccine effectiveness of two doses against covid-19 related hospital admission was 91% (95% confidence interval 91% to 92%), 95% (93% to 96%), and 91% (89% to 94%) for the BNT162b2, mRNA-1273, and ChAdOx1-S vaccines, respectively. Similar results were observed for vaccine effectiveness of two doses against covid-19 related deaths in hospital (BNT162b2, 91% (90% to 93%); mRNA-1273, 96% (92% to 98%); and ChAdOx1 nCoV-19, 88% (68% to 95%)). At 5-6 months after receiving the second dose of vaccine, effectiveness remained high at 94% (92% to 95%) for the BNT162b2 vaccine and 98% (93% to 100%) for the mRNA-1273 vaccine. Vaccine effectiveness of ChAdOx1-S estimated at 3-4 months was 90% (63% to 97%). All three vaccines remained effective at the time of circulation of the delta variant of SARS-CoV-2 between 1 July and 20 August 2021 (effectiveness between 89% and 95%). Conclusions: These findings provide evidence indicating that two doses of ChAdOx1-S is as effective as two doses of mRNA vaccines in France against the alpha and delta variants of SARS-CoV-2. The effectiveness of ChAdOx1-S should be further examined with a longer follow-up and in the light of the circulation of new SARS-CoV-2 variants of concern.

Risk of secondary hematologic malignancies associated with breast cancer chemotherapy and G-CSF support: A nationwide population-based cohort.

Our study aimed to analyze the risk of hematologic malignancies (HM) associated with the use of G-CSF with chemotherapy for BC. Using the French National Health Data System, we examined the HM risks in patients diagnosed with an incident breast cancer between 2007 and 2015, who received chemotherapy for BC. Main outcomes were acute myeloid leukemia (AML), Myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), multiple myeloma (MM), Hodgkin lymphoma or non-Hodgkin lymphoma (HL/NHL) and acute lymphoblastic leukemia or lymphocytic lymphoma (ALL/LL). Among a total of 122 373 BC survivors, 38.9% received chemotherapy only and 61.1% received chemotherapy + G-CSF. Overall, 781 cases of hematologic malignancies occurred. We observed a nonsignificant increase in the risk of AML (aHR, 1.3; 95% CI, 1.0-1.7), of MDS (aHR, 1.3; 95% CI, 0.9-1.8) and of ALL/LL (aHR, 2.0; 95% CI, 1.0-4.4) among patients treated by chemotherapy + G-CSF compared to chemotherapy only. In analyses by dose, we observed a slight increase in the risk of AML (1-3 doses: aHR, 1.2; 95% CI, 0.8-1.7/4+ doses: aHR, 1.3; 95% CI, 1.0-1.8) and of MDS (1-3 doses: aHR, 1.1; 95% CI, 0.7-1.7/4+ doses: aHR, 1.4; 95% CI, 1.0-1.9), a significant increase in risk of ALL (1-3 doses: aHR, 1.5; 95% CI, 0.5-3.9 / 4+ doses: aHR, 2.3; 95% CI, 1.0-5.1) with increasing cycles of G-CSF. Our population-based study showed that the ALL/LL was the only HM at increased risk with the use of growth factors with a possible dose-effect relationship. Our data regarding the risk of all the other HM are reassuring.

Risk of Hematologic Malignant Neoplasms after Postoperative Treatment of Breast Cancer.

An indirect consequence of the improved long-term survival seen in patients with breast cancer (BC) is the increased risk of hematologic malignant neoplasms (HM). This study aimed to analyze the role of postoperative treatment for BC in the development of subsequent HM. Using the French National Health Data System, we examined the HM risks in patients diagnosed with an incident primary breast cancer between 2007 and 2015, who underwent surgery as first-line treatment for BC. Main outcomes were acute myeloid leukemia (AML), Myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), multiple myeloma (MM), Hodgkin's lymphoma or non-Hodgkin's lymphoma (HL/NHL), and acute lymphoblastic leukemia or lymphocytic lymphoma (ALL/LL). Analyses were censored at HM occurrence, death, loss to follow up, or December 2017. The risk of each type of HM was compared according to the initial postoperative treatment of breast cancer. Of a total of 324,056 BC survivors, 15.5% underwent surgery only, 46.7% received radiotherapy after surgery, 4.3% received chemotherapy after surgery, and 33.5% received all three modalities. Overall, 2236 cases of hematologic malignancies occurred. Compared to the surgery alone group, AML was significantly increased after surgery plus radiation (aHR, 1.5; 95% CI, 1.0-2.1), surgery plus chemotherapy (aHR, 2.1; 95% CI, 1.2-3.6) and all modalities (aHR, 3.3; 95% CI, 2.3-4.7). MDS was significantly increased after surgery plus chemotherapy (aHR, 1.7; 95% CI, 1.1-2.5) or after all modalities (aHR, 1.4; 95% CI, 1.1-1.8). HL/NHL were significantly increased only in the radiotherapy and surgery group (aHR, 1.3; 95% CI, 1.0-1.6). A nonsignificant increase of ALL/LL (aHR, 1.8; 95% CI, 0.6-3.5) was noted after chemotherapy and with all three modalities (aHR, 1.4; 95% CI, 0.7-2.8). Our population based study revealed increased risks of various HM associated with postoperative BC treatment. The added benefit of chemotherapy and radiation therapy should take into consideration these long-term complications.

Vitamin K antagonism impairs the bone marrow microenvironment and hematopoiesis.

Vitamin K antagonists (VKAs) have been used in 1% of the world's population for prophylaxis or treatment of thromboembolic events for 64 years. Impairment of osteoblast function and osteoporosis has been described in patients receiving VKAs. Given the involvement of cells of the bone marrow microenvironment (BMM), such as mesenchymal stem cells (MSCs) and macrophages, as well as other factors such as the extracellular matrix for the maintenance of normal hematopoietic stem cells (HSCs), we investigated a possible effect of VKAs on hematopoiesis via the BMM. Using various transplantation and in vitro assays, we show here that VKAs alter parameters of bone physiology and reduce functional HSCs 8-fold. We implicate impairment of the functional, secreted, vitamin K-dependent, γ-carboxylated form of periostin by macrophages and, to a lesser extent, MSCs of the BMM and integrin ß3-AKT signaling in HSCs as at least partly causative of this effect, with VKAs not being directly toxic to HSCs. In patients, VKA use associates with modestly reduced leukocyte and monocyte counts, albeit within the normal reference range. VKAs decrease human HSC engraftment in immunosuppressed mice. Following published examples that alteration of the BMM can lead to hematological malignancies in mice, we describe, without providing a causal link, that the odds of VKA use are higher in patients with vs without a diagnosis of myelodysplastic syndrome (MDS). These results demonstrate that VKA treatment impairs HSC function via impairment of the BMM and the periostin/integrin ß3 axis, possibly associating with increased MDS risk.

Evaluation of the Incidence of Hematologic Malignant Neoplasms Among Breast Cancer Survivors in France.

Importance: Breast cancer survivors are at an increased risk of developing certain types of hematologic malignant neoplasm after diagnosis. Objective: To estimate the incidence of various types of hematologic malignant neoplasm in breast cancer survivors, both in absolute terms and in association with the general population. Design, Setting, and Participants: This nationwide cohort study conducted in France used data from the French National Health Data System, a database that contains all of French residents' health-related expenses. All French women aged 20 to 85 years with an incident breast cancer diagnosis between July 1, 2006, and December 31, 2015, were included (n = 439 704) and followed up until hematologic malignant neoplasm occurrence, death, loss of follow-up, or December 31, 2016, whichever came first. Comparisons were made with all French women in the general population who were registered in the French general health insurance program each year from January 1, 2007, and December 31, 2016. Data analysis was performed from January 23, 2018, to May 25, 2018. Main Outcomes and Measures: Main outcomes were incident hematologic malignant neoplasm cases occurring at least 6 months after breast cancer diagnosis. The various types of hematologic malignant neoplasm considered were acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), multiple myeloma (MM), Hodgkin lymphoma or non-Hodgkin lymphoma (HL/NHL), and acute lymphoblastic leukemia or lymphocytic lymphoma (ALL/LL). Incidence of these various types was estimated among breast cancer survivors and compared with the incidence in women in the general population. Results: The 439 704 women in the study had a median (interquartile range [IQR]) age of 59 (50-69) years and were followed up for a median (IQR) duration of 5 (2.8-7.5) years. Overall, 3046 cases of hematologic malignant neoplasm occurred: 509 cases (16.7%) of AML (crude incidence rate [CIR] per 100 000 person-years, 24.5; 95% CI, 22.4-26.8), 832 cases (27.3%) of MDS (CIR, 40.1; 95% CI, 37.4-42.9), and 267 cases (8.8%) of MPN (CIR, 12.8; 95% CI, 11.4-14.5). Lymphoid neoplasm cases included 420 cases (13.8%) of MM (CIR, 20.3; 95% CI, 18.4-22.3), 912 cases (29.9%) of HL/NHL (CIR, 44.4; 95% CI, 41.1-50.0), and 106 cases (3.5%) of ALL/LL (CIR, 5.1; 95% CI, 4.2-6.2). Compared with the general population, breast cancer survivors had statistically significantly higher incidence of AML (standardized incidence rate ratio [SIRR], 2.8; 95% CI, 2.5-3.2) and MDS (SIRR, 5.0; 95% CI, 4.4-5.7) and, to a lesser extent, MM (SIRR, 1.5; 95% CI, 1.3-1.7]) and ALL/LL (SIRR, 2.0; 95% CI, 1.3-3.0). Conclusions and Relevance: The finding that AML and MDS still occur among breast cancer survivors today, and that ALL/LL and MM may also be of concern, merits the continuous monitoring of hematologic malignant neoplasms and the thorough investigations into their underlying mechanisms.