Excess Absolute Risk Research Articles

Second Primary Malignancy Risk Among HIV-Uninfected and HIV-Infected Survivors of Hodgkin Lymphoma: A 30-Year Follow-up Population-Based Study

Introduction Second primary malignancy (SPM) is one of the most devastating late complications following Hodgkin lymphoma (HL) treatment. Historically, the most common SPMs in patients treated for HL are solid tumors, which are largely related to radiation exposure during initial therapy. For the last three decades, efforts to address the risk of SPM after HL therapy have focused on reducing exposure to radiation, as well as refining the approach for patients where radiation is indicated. To date, few population-based studies in the United States have quantified the burden of SPMs and evaluated the potential effect of changes in therapeutic management over time. Additionally, to our knowledge, no study has compared SPM risk between human immunodeficiency virus (HIV)-infected and HIV-uninfected HL survivors. Methods We used data from the California Cancer Registry on 21,043 patients diagnosed with primary HL between 1988 and 2015 with follow-up through 2017. We calculated standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs) and absolute excess risks (AERs) to compare SPM incidence in our HL cohort with the expected number of first primary cancer incidence in the general California population, based on patient's age at diagnosis (5-year categories), sex, calendar year (3-year intervals), cancer site, and race/ethnicity. SIRs are presented by HIV status, SPM latency, treatment era, and cancer type. P-values for trends were used to examine whether SPM risk changed over time. Findings Among 20,303 HIV-uninfected patients (median follow-up of 14.1 years), overall SPM risk was increased 1.95-fold compared with the general population (SIR=1.95, 95% CI 1.86-2.04). In 740 HIV-infected patients (median follow-up of 11.7 years), overall risk was increased 2.68-fold compared with the general population (SIR=2.68, 95% CI 2.0-3.40), translating to an 37% higher incidence of SPM in HIV-infected vs. HIV-uninfected patients. The AER (per 10,000 person-years) of SPM was 43.1 in HIV-uninfected and 76.5 in HIV-infected patients, resulting in a 33.4 excess SPM per 10,000 person-years in HL survivors with HIV. Malignancies that contributed the most to overall AER were non-Hodgkin lymphoma (NHL), female breast and lung cancers in HIV-uninfected patients; and Kaposi sarcoma, NHL, anorectal and head & neck (HNC) cancers in HIV-infected patients. Notably, among HIV-uninfected patients, the highest overall risk of SPM occurred ≥20 years after diagnosis (SIR= 2.27, 95% CI 1.99-2.58) (Figure). In contrast, the highest overall risk in HIV-infected patients was observed <2 years after diagnosis (SIR=4.42, 95% CI 2.53-7.19). Radiation used decreased from 46.9% in 1988-1996 to 29.5% in 2007-2015. Among HIV-uninfected patients, there was a trend towards decreased risk over time of overall and selected solid SPMs (lung, female breast, and gastrointestinal cancers) (Table). In an analysis restricted to HIV-uninfected patients who received radiation irrespective of chemotherapy, findings also suggested a declined risk of overall and selected solid SPMs over time: any solid (SIR=2.15 in 1988-1996 and SIR=1.30 in 2007-2015, p<0.0001), lung (SIR=3.69 in 1988-1996 and SIR=1.81 in 2007-2015, p=0.0031), and female breast (SIR=2.95 in 1988-1996 and SIR=0.63 in 2007-2015, p<0.0001). Conclusion Compared with the general population, the risk of developing a SPM following HL treatment was significantly higher among both HIV-uninfected and HIV-infected patients, with the absolute excess risk greater for those with HIV infection. There were different temporal patterns and types of SPM between HIV-uninfected and HIV-infected patients. These findings prompt the question on whether earlier and/or more intensive cancer screening should be pursued for HIV-infected survivors. The trend towards decreased risk for selected solid SPMs among HIV-uninfected patients, especially lung and female breast cancers, suggest that strategies to reduce radiation in HL survivors may be working. Despite promising trends in this group, the observation that SPM risk was highest ≥20 years after initial therapy further highlights the need for long-term surveillance and survivorship care in this at-risk population. Disclosures Rosenberg: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Wun:Glycomimetics, Inc.: Consultancy.

Spectrum of Second Primary Malignancies in Pediatric and Adult Langerhans Cell Histiocytosis Cases

Introduction: Langerhans cell histiocytosis (LCH) is a rare MAPK-ERK pathway driven histiocytic neoplasm that occurs in pediatric as well as adult population. Despite improvement in clinical outcomes, there is some data to suggest an increased propensity to develop second primary malignancies (SPMs) in LCH patients. However, population-based studies analyzing the incidence and spectrum of SPMs in pediatric and adult LCH patients are lacking. In this study, we utilized the Surveillance, Epidemiology and End Results (SEER) database to examine the various SPMs occurring among pediatric and adult LCH cases. Methods: We used the November 2018 submission of the SEER 18 registry, which covers ~27.8% of the US population based on the 2010 census, as our database. We used the SEER*Stat version 8.3.6 statistical software to analyze data. We identified cases diagnosed with LCH as their first primary malignancy between 2000 and 2016 using International Classification of Diseases for Oncology edition 3 (ICD-O-3) codes, including LCH NOS (not otherwise specified) (9751/1), LCH (9751/3), LCH, unifocal (9752/1), LCH, multifocal (9753/3), LCH, disseminated, borderline (9754/1) and Disseminated LCH (9754/3). These cases were followed for 180+months, and the standardized incidence ratio (SIR) or relative risk and absolute excess risk (AER) were calculated. We examined the differences in occurrence of SPMs among the pediatric (Age <18 years) and adult population (Age ≥18 years). Additionally, we evaluated the concurrent and prior cancers in LCH patients as an exploratory objective. Results: The study included 1392 cases with LCH (Table 1), with median age at diagnosis 8 years (range newborn - 86 years). Out of these cases, 1205 (87%) were diagnosed as LCH and 186 (13%) as disseminated LCH. 936 cases (67%) were diagnosed at age <18 years (pediatric LCH), while 456 cases (33%) were diagnosed at age ≥18 years (adult LCH). The overall age-adjusted incidence rate for LCH was found to be 1 per 1,000,000. The incidence rate was 2.6 per 1,000,000 in pediatric LCH group and 0.4 per 1,000,000 in the adult LCH group. Out of the entire cohort, 20 (1.4%) cases developed a total of 21 SPMs [SIR 2.07; 95% Confidence Interval (CI): 1.28-3.16]. Median latency period to development of SPMs was 28 months. The pediatric LCH group had an overall higher risk of developing SPMs [SIR 6.42, 95%CI 2.08-14.97] than the general population, especially for hematologic malignancies [SIR 18.76, 95%CI 6.09-43.78], mainly, nodal Hodgkin lymphoma [SIR 60.93, 95%CI 7.38-220.12] and extranodal non-Hodgkin lymphoma [SIR 60.88, 95%CI 1.54-339.2]. No solid tumors were seen in this group. The adult LCH group did not have an overall increased risk of developing SPMs than the general population [SIR 1.71, 95%CI 0.98-2.77], except for Acute Lymphocytic Leukemia (ALL) [SIR 66.29, 95%CI 1.68-369.36] especially 60-119 months from diagnosis of LCH and miscellaneous cancers [SIR 11.43, 95%CI 2.36-33.39] especially 12-59 months after diagnosis of LCH. 62.5% of SPMs that developed in the adult LCH group were solid tumors, however, the overall risk for developing solid tumors was not higher than the general population [SIR 1.2, 95%CI 0.58-2.2], except for carcinoma in-situ of vulva [SIR 62.72, 95%CI 1.59-349.45] 2-11 months from diagnosis of LCH. Overall, tumors of the respiratory system (21%), female breast (13%) and prostate (9%) were the most common malignancies occurring prior to development of LCH whereas tumors of the respiratory system (28%), non-Hodgkin lymphoma (20%) and endocrine system (13%) occurred concurrent to LCH. Conclusion: To our knowledge, this is the first comprehensive population-based study assessing the incidence of SPMs in pediatric and adult LCH. Our study shows that the incidence of LCH is higher in the pediatric age group compared to adults. We found an increased risk for hematologic malignancies, specifically for Hodgkin and non-Hodgkin lymphoma in pediatric LCH compared to the general population. Among adult LCH, however, the risk was higher for development of ALL and carcinoma in-situ of vulva when compared to the general population. Our results may help guide survivorship and surveillance strategies among LCH patients. More studies are needed to understand the molecular underpinning leading to increased SPM formation in LCH patients. Disclosures No relevant conflicts of interest to declare.

Secondary malignancy risk for patients with localized prostate cancer after intensity-modulated radiotherapy with and without flattening filter.

Men treated for localized prostate cancer by radiotherapy have often a remaining life span of 10 yr or more. Therefore, the risk for secondary malignancies should be taken into account. Plans for ten patients were evaluated which had been performed on an Oncentra® treatment planning system for a treatment with an Elekta Synergy™ linac with Agility™ head. The investigated techniques involved IMRT and VMTA with and without flattening filter. Different dose response models were applied for secondary carcinoma and sarcoma risk in the treated region and also in the periphery. As organs at risk we regarded for carcinoma risk urinary bladder, rectum, colon, esophagus, thyroid, and for sarcoma risk bone and soft tissue. The excess absolute risk (EAR) was found very similar in the treated region for both techniques (IMRT and VMAT) and also for both with and without flattening filter. The secondary sarcoma risk resulted about one magnitude smaller than the secondary carcinoma risk. The EAR to the peripheral organs was statistically significant reduced by application of the flattening filter free mode concerning the flattening filter as main source of scattered dose. Application of flattening filter free mode can thus support to reduce second malignancy risk for patients with localized prostate cancer.

Risk of digestive cancers in a cohort of 69 460 five-year survivors of childhood cancer in Europe: the PanCareSurFup study

BackgroundSurvivors of childhood cancer are at risk of subsequent primary neoplasms (SPNs), but the risk of developing specific digestive SPNs beyond age 40 years remains uncertain. We investigated risks of...

Calculating and estimating second cancer risk from breast radiotherapy using Monte Carlo code with internal body scatter for each out-of-field organ.

Out‐of‐field organs are not commonly designated as dose calculation targets during radiation therapy treatment planning, but they might entail risks of second cancer. Risk components include specific internal body scatter, which is a dominant source of out‐of‐field doses, and head leakage, which can be reduced by external shielding. Our simulation study quantifies out‐of‐field organ doses and estimates second cancer risks attributable to internal body scatter in whole‐breast radiotherapy (WBRT) with or without additional regional nodal radiotherapy (RNRT), respectively, for right and left breast cancer using Monte Carlo code PHITS. Simulations were conducted using a complete whole‐body female model. Second cancer risk was estimated using the calculated doses with a concept of excess absolute risk. Simulation results revealed marked differences between WBRT alone and WBRT plus RNRT in out‐of‐field organ doses. The ratios of mean doses between them were as large as 3.5–8.0 for the head and neck region and about 1.5–6.6 for the lower abdominal region. Potentially, most out‐of‐field organs had excess absolute risks of less than 1 per 10,000 persons‐year. Our study surveyed the respective contributions of internal body scatter to out‐of‐field organ doses and second cancer risks in breast radiotherapy on this intact female model.

Incidence and Mortality of Second Primary Cancers in Danish Patients With Retinoblastoma, 1943-2013

In heritable retinoblastoma, there is a significantly increased risk of second primary cancers (SPCs). Improved knowledge about the incidence and influence of heritability and treatment is important during therapy for patients with retinoblastoma. To assess the incidence of SPC in patients diagnosed with retinoblastoma in Denmark from 1943 to 2013 with a focus on heritability and the association of external radiotherapy with mortality. In this retrospective cohort study, data were extracted from the Danish Ocular Oncology Group Database containing complete data on all patients diagnosed with retinoblastoma , and obtained from the Danish Cancer Registry, which includes information on all patients with cancer from 1943 to December 31, 2013. Data analysis was conducted from December 1, 2017, to October 1, 2019. Data on 323 patients were included. Heritability and retinoblastoma treatment. Standardized incidence rate, excess absolute risk, cumulative incidence of SPC, and mortality from SPC. Association of heritability and treatment with outcomes was estimated. Of the 323 patients included in the analysis, 181 were men (56%), 133 had heritable retinoblastoma (41%), and 190 had nonheritable retinoblastoma (59%). The median age at diagnosis of SPC was 32.4 (interquartile range, 15.4-43.9) years in patients with heritable retinoblastoma and 38.6 (interquartile range, 20.5-49.4) years in those with nonheritable retinoblastoma. Twenty-five SPCs were identified in patients with heritable retinoblastoma vs 14 in patients with nonheritable retinoblastoma. Standardized incidence rate (SIR) of SPC in patients with heritable retinoblastoma was 11.39 (95% CI, 7.37-16.81) with an excess absolute risk of 70 cases per 10 000 person-years; the highest SIRs were for sarcoma (181.13; 95% CI, 98.94-303.92) and malignant melanoma (26.78; 95% CI, 9.78-58.30). The SIR for SPC in patients with nonheritable retinoblastoma was 1.52 (95% CI, 0.81-2.60). The cumulative incidence of SPCs at age 60 years was significantly higher in patients with heritable retinoblastoma (51%) compared with those with nonheritable retinoblastoma (13%) (P < .001) (hazard ratio, 5.0; 95% CI, 2.5-10.3). No significant differences were identified in overall risk of SPC in patients with heritable retinoblastoma treated with 3 different modalities: external radiotherapy, plaque (but no external) radiotherapy, and enucleation only, but an increased proportion of sarcomas was noted in the irradiated field. Mortality due to SPC was also higher in survivors of heritable retinoblastoma compared with those with nonheritable retinoblastoma (cumulative mortality, 34% vs 12% at age 60 years; P = .03). The findings of this study suggest that the incidence and mortality associated with SPC were significantly higher in patients with heritable retinoblastoma vs patients with nonheritable retinoblastoma. The largest increases in risk were noted for sarcoma and malignant melanoma. External radiotherapy did not appear to increase the risk. These findings are relevant when treating patients with retinoblastoma to manage the risk for SPC.

Mammary Chain Irradiation in Left-Sided Breast Cancer: Can We Reduce the Risk of Secondary Cancer and Ischaemic Heart Disease with Modern Intensity-Modulated Radiotherapy Techniques?

Introduction: The aim of the present study was to estimate the impact of the addition of internal mammary chain (IMC) irradiation in node-positive left-sided breast cancer (BC) patients undergoing regional nodal irradiation (RNI) and comparatively evaluate excess relative and absolute risks of radiation-induced lung cancer/BC and ischaemic heart disease for intensity-modulated radiotherapy (IMRT) versus 3D conformal radiotherapy (3D-CRT). Methods: Four treatment plans were created (3D-CRT and IMRT –/+ IMC) for each of the 10 evaluated patients, and estimates of excess relative risk (ERR) and 10-year excess absolute risk (EAR) were calculated for radiation-induced lung cancer/BC and coronary events using linear, linear-exponential and plateau models. Results: The addition of IMC irradiation to RNI significantly increased the dose exposure of the heart, lung and contralateral breast using both techniques, increasing ERR for secondary lung cancer (58 vs. 44%, p = 0.002), contralateral BC (49 vs. 31%, p = 0.002) and ischaemic heart disease (41 vs. 27%, p = 0.002, IMRT plans). IMRT significantly reduced the mean cardiac dose and mean lung dose as compared to 3D-CRT, decreasing ERR for major coronary events (64% 3D-CRT vs. 41% IMRT, p = 0.002) and ERR for secondary lung cancer (75 vs. 58%, p = 0.004) in IMC irradiation, without a significant impact on secondary contralateral BC risks. Conclusion: Although IMC irradiation has been shown to increase survival rates in node-positive BC patients, it increased dose exposure of organs at risk in left-sided BC, resulting in significantly increased risks for secondary lung cancer/contralateral BC and ischaemic heart disease. In this setting, the adoption of IMRT seems advantageous when compared to 3D-CRT.

Proton pencil beam scanning reduces secondary cancer risk in breast cancer patients with internal mammary chain involvement compared to photon radiotherapy

PurposeProton pencil beam scanning (PBS) represents an interesting option for the treatment of breast cancer (BC) patients with nodal involvement. Here we compare tangential 3D-CRT and VMAT to PBS proton therapy (PT) in terms of secondary cancer risk (SCR) for the lungs and for contralateral breast.MethodsFive BC patients including supraclavicular (SVC) nodes in the target (Group 1) and five including SVC plus internal-mammary-nodes (IMNs, Group 2) were considered. The Group 1 patients were planned by PT versus tangential 3D-CRT in free-breathing (FB). The Group 2 patients were planned by PT versus VMAT considering both FB and deep-inspiration breath hold (DIBH) irradiation. The prescription dose to the target volume was 50 Gy (2 Gy/fraction). A constant RBE = 1.1 was assumed for PT. The SCR was evaluated with the excess absolute risk (EAR) formalism, considering also the age dependence. A cumulative EAR was finally computed.ResultsAccording to the linear, linear-exponential and linear-plateau dose response model, the cumulative EAR for Group 1 patients after PT was equal to 45 ± 10, 17 ± 3 and 15 ± 3, respectively. The corresponding relative increase for tangential 3D-CRT was equal to a factor 2.1 ± 0.5, 2.1 ± 0.4 and 2.3 ± 0.4. Group 2 patients showed a cumulative EAR after PT in FB equal to 65 ± 3, 21 ± 1 and 20 ± 1, according to the different models; the relative risk obtained with VMAT increased by a factor 3.5 ± 0.2, 5.2 ± 0.3 and 5.1 ± 0.3. Similar values emerge from DIBH plans. Contrary to photon radiotherapy, PT appears to be not sensitive to the age dependence due to the very low delivered dose.ConclusionsPBS PT is associated to significant SCR reduction in BC patients compared to photon radiotherapy. The benefits are maximized for young patients with both SVC and IMNs involvement. When combined with the improved sparing of the heart, this might contribute to the establishment of effective patient-selection criteria for proton BC treatments.

Relative and absolute cancer risks among Nordic kidney transplant recipients-a population-based study.

SummaryKidney transplant recipients (KTRs) have an increased cancer risk compared to the general population, but absolute risks that better reflect the clinical impact of cancer are seldom estimated. All KTRs in Sweden, Norway, Denmark, and Finland, with a first transplantation between 1995 and 2011, were identified through national registries. Post‐transplantation cancer occurrence was assessed through linkage with cancer registries. We estimated standardized incidence ratios (SIR), absolute excess risks (AER), and cumulative incidence of cancer in the presence of competing risks. Overall, 12 984 KTRs developed 2215 cancers. The incidence rate of cancer overall was threefold increased (SIR 3.3, 95% confidence interval [CI]: 3.2–3.4). The AER of any cancer was 1560 cases (95% CI: 1468–1656) per 100 000 person‐years. The highest AERs were observed for nonmelanoma skin cancer (838, 95% CI: 778–901), non‐Hodgkin lymphoma (145, 95% CI: 119–174), lung cancer (126, 95% CI: 98.2–149), and kidney cancer (122, 95% CI: 98.0–149). The five‐ and ten‐year cumulative incidence of any cancer was 8.1% (95% CI: 7.6–8.6%) and 16.8% (95% CI: 16.0–17.6%), respectively. Excess cancer risks were observed among Nordic KTRs for a wide range of cancers. Overall, 1 in 6 patients developed cancer within ten years, supporting extensive post‐transplantation cancer vigilance.

Second primary cancer after intensity-modulated radiotherapy for nasopharyngeal carcinoma: A territory-wide study by HKNPCSG.

Long-term risk of second primary cancer (SPC) after definitive intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) remains unclear. This study aims to evaluate the risk, predictive factors and survival impact of SPC in a large territory-wide cohort of NPC survivors in an endemic region. In this multicenter study, consecutive NPC patients (n = 3166) who underwent definitive IMRT in all six public oncology centers in Hong Kong between 2001 and 2010 were included. SPC risks were quantified by standardized incidence ratios (SIRs) and absolute excess risks (AERs) estimated from corresponding age-, sex-, and calendar year-specific population cancer incidence data from the Hong Kong Cancer Registry. Predictive factors and SPC-specific mortality were analyzed. Over a median follow-up period of 10.8 years, 290 cases of SPC were observed with a crude incidence of 9.2%. Cancer risk in NPC survivors was 90% higher than that in general population [SIR, 1.9; 95% confidence interval (CI), 1.7-2.2], with an AER of 52.1 (95% CI, 36.8-67.3) per 10,000 person-years at risk. Significant excess cancer risks were observed for oral cavity, sarcoma, oropharynx, paranasal sinus, salivary gland, thyroid, skin and lung. Advanced age, smoking, hepatitis B status, and re-irradiation were independent predictive factors. SPC accounted for 9.4% of all deaths among NPC survivors during the study period, and 10-year SPC-specific mortality was 3.4%. Second cancer risk after IMRT was substantial among NPC patients. SPC impairs long-term survival, and close surveillance is warranted as part of survivorship care.

Cause-Specific Mortality Following Initial Chemotherapy in a Population-Based Cohort of Patients With Classical Hodgkin Lymphoma, 2000-2016.

Mortality for patients with classical Hodgkin lymphoma (cHL) treated during an era characterized in the United States by widespread use of doxorubicin, bleomycin, vinblastine, and dacarbazine and diminishing use of radiotherapy is not well understood. We identified 20,007 individuals diagnosed with stage I/II (early) or III/IV (advanced) cHL between age 20 and 74 years treated with initial chemotherapy in US population-based cancer registries during 2000-2015 (follow-up through 2016). We used standardized mortality ratios (SMRs) to compare cause-specific relative mortality risk following cHL to that expected in the general population and estimated excess absolute risks (EARs; per 10,000 patient-years) to quantify disease-specific death burden. We identified 3,380 deaths in the cHL cohort, including 1,321 (39%) not attributed to lymphoma. Overall, noncancer SMRs were increased 2.4-fold (95% CI, 2.2 to 2.6; observed, 559; EAR, 61.6) and 1.6-fold (95% CI, 1.4 to 1.7; observed, 473; EAR, 18.2) for advanced- and early-stage cHL, respectively, compared with the general US population. SMRs and EARs differed substantially by cause of death and cHL stage. Among the highest EARs for noncancer causes of death were those for heart disease (EAR, 15.1; SMR, 2.1), infections (EAR, 10.6; SMR, 3.9), interstitial lung disease (ILD; EAR, 9.7; SMR, 22.1), and adverse events (AEs) related to medications/drugs (EAR, 7.4; SMR, 5.0) after advanced-stage cHL and heart disease (EAR, 6.6; SMR, 1.7), ILD (EAR, 3.7; SMR, 13.1), and infections (EAR, 3.1; SMR, 2.2) after early-stage cHL. Strikingly elevated SMRs for ILD, infections, and AEs were observed < 1 year after cHL. Individuals age 60-74 years with advanced-stage cHL experienced a disproportionate excess of deaths as a result of heart disease, ILD, infections, AEs, and solid tumors. Despite evolving cHL treatment approaches, patients continue to face increased nonlymphoma mortality risks from multiple, potentially preventable causes. Surveillance, early interventions, and cHL treatment refinements may favorably affect patient longevity, particularly among high-risk subgroups.

Cancer incidence risks above and below 1 Gy for radiation protection in space

The risk assessment quantities called lifetime attributable risk (LAR) and risk of exposure-induced cancer (REIC) are used to calculate the cumulative cancer incidence risks for astronauts, attributable to radiation exposure accumulated during long term lunar and Mars missions. These risk quantities are based on the most recently published epidemiological data on the Life Span Study (LSS) of Japanese A-bomb survivors, who were exposed to γ-rays and neutrons. In order to analyze the impact of a different neutron RBE on the risk quantities, a model for the neutron relative biological effectiveness (RBE) relative to gammas in the LSS is developed based on an older dataset with less follow-up time. Since both risk quantities are based on uncertain quantities, such as survival curves, and REIC includes deterministic radiation induced non-cancer mortality risks, modelled with data based on the general population, the risks for astronauts may not be optimally estimated. The suitability of these risk assessment measures for the use of cancer risk calculation for astronauts is discussed. The work presented here shows that the use of a higher neutron RBE than the value of 10, traditionally used in the LSS risk models, can reduce the risks up to almost 50%. Additionally, including an excess absolute risk (EAR) baseline scaling also increases the risks by between 0.4% and 8.1% for the space missions considered in this study. Using just an EAR model instead of an equally weighted EAR and excess relative risk (ERR) model can decrease the cumulative risks for the considered missions by between 0.4% and 4.1% if no EAR baseline scaling is applied. If EAR baseline scaling is included, the calculated risks with the EAR- and the mixed model, as well as the risks calculated with just the ERR model are almost identical and only small differences in the uncertainties are visible.

Excess mortality due to pandrug-resistant Acinetobacter baumannii infections in hospitalized patients

Pandrug-resistant Acinetobacter baumannii (PDRAB) is increasingly being reported as a nosocomial pathogen worldwide, but determining its clinical impact is challenging. To assess the spectrum of excess mortality attributable to PDRAB infection in acute care settings. This four-year cohort study was conducted in a tertiary-care referral hospital in Greece to estimate excess in-hospital mortality due to PDRAB infection by comparing patients infected to those colonized with PDRAB by means of competing risks survival analysis. The study cohort comprised 91 patients (median age: 67 years; 77% men). For most patients, PDRAB was first isolated in the intensive care unit (ICU) (N= 51; 57%) or following ICU discharge (N= 26; 29%). Overall in-hospital mortality was 68% (95% confidence interval (CI): 57.5-77.5%). PDRAB-infected patients (N= 62; 68%) and PDRAB-colonized patients (N= 29; 32%) had similar baseline characteristics, but the absolute excess risk of 30-day mortality in infected patients compared to colonized patients was 34% (95% CI: 14-54%). Multivariable competing risks regression showed that PDRAB infection significantly increased the daily hazard of 30-day in-hospital death (cause-specific hazard ratio (csHR): 3.10; 95% CI: 1.33-7.21) while simultaneously decreasing the daily rate of discharge (csHR: 0.24; 95% CI: 0.08-0.74), thereby leading to longer hospitalization. Stronger effects were observed for bloodstream infections. New effective antimicrobials would be expected to prevent mortality in one of every three patients treated for PDRAB infection and reduce their length of hospitalization. However, available therapeutic options remain extremely limited and emphasis on preventing healthcare-associated transmission of PDRAB is ever more important.

Disparities in the excess risk of mortality in the first wave of COVID-19: Cross sectional study of the English sentinel network

ObjectivesFew studies report contributors to the excess mortality in England during the first wave of coronavirus disease 2019 (COVID-19) infection. We report the absolute excess risk (AER) of mortality and excess mortality rate (EMR) from a nationally representative COVID-19 sentinel surveillance network including known COVID-19 risk factors in people aged 45 years and above. MethodsPseudonymised, coded clinical data were uploaded from contributing primary care providers (N = 1,970,314, ≥45years). We calculated the AER in mortality by comparing mortality for weeks 2 to 20 this year with mortality data from the Office for National Statistics (ONS) from 2018 for the same weeks. We conducted univariate and multivariate analysis including preselected variables. We report AER and EMR, with 95% confidence intervals (95% CI). ResultsThe AER of mortality was 197.8/10,000 person years (95%CI:194.30–201.40). The EMR for male gender, compared with female, was 1.4 (95%CI:1.35–1.44, p<0.00); for our oldest age band (≥75 years) 10.09 (95%CI:9.46–10.75, p<0.00) compared to 45–64 year olds; Black ethnicity's EMR was 1.17 (95%CI: 1.03–1.33, p<0.02), reference white; and for dwellings with ≥9 occupants 8.01 (95%CI: 9.46–10.75, p<0.00). Presence of all included comorbidities significantly increased EMR. Ranked from lowest to highest these were: hypertension, chronic kidney disease, chronic respiratory and heart disease, and cancer or immunocompromised. ConclusionsThe absolute excess mortality was approximately 2 deaths per 100 person years in the first wave of COVID-19. More personalised shielding advice for any second wave should include ethnicity, comorbidity and household size as predictors of risk.

Patients with APECED have increased early mortality due to endocrine causes, malignancies and infections

CONTEXT Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autoimmune endocrinopathy with severe and unpredictable course. The impact of APECED on mortality has not been determined. OBJECTIVE To assess overall and cause-specific mortality of patients with APECED. DESIGN AND SETTING A follow-up study of Finnish patients with APECED from 1971 to 2018. Causes and dates of death were collected from Finnish registries. PATIENTS Ninety-one patients with APECED. MAIN OUTCOME MEASURE Overall and cause-specific standardized mortality ratios (SMRs) determined by comparing the observed numbers of death and those expected on the basis of respective population death rates in Finland. RESULTS The overall disease mortality was significantly increased (29 deaths, SMR 11; 95% confidence interval [CI] 7.2-16; P < 0.001). The relative risk (SMR) was highest in the youngest age groups but the absolute excess risk was similar (about 10 per 10 000 person-years) in all age categories. The highest SMRs were seen for endocrine and metabolic diseases (SMR 570; 95% CI, 270-1000; P < 0.001) and for oral and esophageal malignancies (SMR 170; 95% CI, 68-360; P < 0.001). Mortality was also increased for infections, diseases of digestive system, alcohol-related deaths, and for accidents. Due to the small number of cases we were unable to evaluate whether mortality was affected by disease severity. CONCLUSIONS Patients with APECED have significantly increased mortality in all age groups. Highest SMRs are found for causes that are directly related to APECED but also for infections. Increased alcohol- and accident-related deaths may be influenced by psychosocial factors.

Population-based risk assessment of second primary cancers following a first head and neck cancer: patterns of association and difficulties of its analysis.

The diagnosis of a second primary cancer (SPC) is a major concern in the follow-up of survivors of a primary head and neck cancer (HNC), but the anatomic subsites in the head and neck area are close, making it difficult to distinguish a SPC of a recurrence and therefore register it correctly. We performed a retrospective cohort study using data from two population-based cancer registries in Catalonia, Spain: the Tarragona Cancer Registry and the Girona Cancer Registry. All patients diagnosed with HNC during the period 1994-2013 were registered and followed-up to collect cases of SPC. We analysed the standardized incidence ratio (SIR) and the excess absolute risk (EAR) to determine the risk of second malignancies following a prior HNC. 923 SPC were found in a cohort of 5646 patients diagnosed of a first head and neck cancer. Men had an increased risk of a SPC with a SIR of 2.22 and an EAR of 216.76. Women also had an increased risk with a SIR of 2.02 and an EAR of 95.70. We show the risk for different tumour sites and discuss the difficulties of the analysis. The risks of a SPC following a prior HNC in Tarragona and Girona are similar to those previously found in other similar cohorts. It would appear to be advisable to make a revision of the international rules of classification of multiple tumours, grouping the sites of head and neck area with new aetiological criteria to better determine and interpret the risks of SPC obtained in these studies.

Reducing the Risk of Secondary Lung Cancer in Treatment Planning of Accelerated Partial Breast Irradiation.

Purpose: Adjuvant accelerated partial breast irradiation (APBI) results in low local recurrence risks. However, the survival benefit of adjuvant radiotherapy APBI for low-risk breast cancer might partially be offset by the risk of radiation-induced lung cancer. Reducing the lung dose mitigates this risk, but this could result in higher doses to the ipsilateral breast. Different external beam APBI techniques are equally conformal and homogenous, but the intermediate to low dose distribution differs. Thus, the risk of toxicity is different. The purpose of this study is to quantify the trade-off between secondary lung cancer risk and breast dose in treatment planning and to compare an optimal coplanar and non-coplanar technique.Methods: A total of 440 APBI treatment plans were generated using automated treatment planning for a coplanar VMAT beam-setup and a non-coplanar robotic stereotactic radiotherapy beam-setup. This enabled an unbiased comparison of two times 11 Pareto-optimal plans for 20 patients, gradually shifting priority from maximum lung sparing to maximum ipsilateral breast sparing. The excess absolute risks of developing lung cancer and breast fibrosis were calculated using the Schneider model for lung cancer and the Avanzo model for breast fibrosis.Results: Prioritizing lung sparing reduced the mean lung dose from 2.2 Gy to as low as 0.3 Gy for the non-coplanar technique and from 1.9 Gy to 0.4 Gy for the coplanar technique, corresponding to a 7- and 4-fold median reduction of secondary lung cancer risk, respectively, compared to prioritizing breast sparing. The increase in breast dose resulted in a negligible 0.4% increase in fibrosis risk. The use of non-coplanar beams resulted in lower secondary cancer and fibrosis risks (p < 0.001). Lung sparing also reduced the mean heart dose for both techniques.Conclusions: The risk of secondary lung cancer of external beam APBI can be dramatically reduced by prioritizing lung sparing during treatment planning. The associated increase in breast dose did not lead to a relevant increase in fibrosis risk. The use of non-coplanar beams systematically resulted in the lowest risks of secondary lung cancer and fibrosis. Prioritizing lung sparing during treatment planning could increase the overall survival of early-stage breast cancer patients by reducing mortality due to secondary lung cancer and cardiovascular toxicity.

Risk of cerebrovascular disease among 13 457 five-year survivors of childhood cancer: A population-based cohort study.

Survivors of childhood cancer treated with cranial irradiation are at risk of cerebrovascular disease (CVD), but the risks beyond age 50 are unknown. In all, 13457 survivors of childhood cancer included in the population-based British Childhood Cancer Survivor Study cohort were linked to Hospital Episode Statistics data for England. Risk of CVD related hospitalisation was quantified by standardised hospitalisation ratios (SHRs), absolute excess risks and cumulative incidence. Overall, 315 (2.3%) survivors had been hospitalised at least once for CVD with a 4-fold risk compared to that expected (95% confidence interval [CI]: 3.7-4.3). Survivors of a central nervous system (CNS) tumour and leukaemia treated with cranial irradiation were at greatest risk of CVD (SHR = 15.6, 95% CI: 14.0-17.4; SHR = 5.4; 95% CI: 4.5-6.5, respectively). Beyond age 60, on average, 3.1% of CNS tumour survivors treated with cranial irradiation were hospitalised annually for CVD (0.4% general population). Cumulative incidence of CVD increased from 16.0% at age 50 to 26.0% at age 65 (general population: 1.4-4.2%). In conclusion, among CNS tumour survivors treated with cranial irradiation, the risk of CVD continues to increase substantially beyond age 50 up to at least age 65. Such survivors should be: counselled regarding this risk; regularly monitored for hypertension, dyslipidaemia and diabetes; advised on life-style risk behaviours. Future research should include the recall for counselling and brain MRI to identify subgroups that could benefit from pharmacological or surgical intervention and establishment of a case-control study to comprehensively determine risk-factors for CVD.

Risk of second primary malignancy in adults with pulmonary high-grade neuroendocrine carcinoma (HGNEC)

BackgroundPulmonary high-grade neuroendocrine carcinoma (HGNEC) has a rising incidence of developing second primary malignancies (SPMs). This study is the first population-based analysis to quantify the SPM risks among survivors of lung HGNEC.MethodsWe used the Surveillance, Epidemiology, and End Results (SEER) database to calculate standardized incidence ratio (SIR) and absolute excess risk (AER) between 2000 and 2016 for patients with pulmonary HGNEC. ResultsThe data of 1161 patients with SPMs were retrieved from the SEER database. The ratio of observed/expected number of SPMs in pulmonary HGNEC was 1.53. Solid tumours comprised 91% of all second malignancies in lung HGNEC patients, with the most common cancers reported in the oral cavity and pharynx, the urinary and respiratory systemsConclusionsOur study observed an increased risk of SPMs among patients with pulmongnancies.

Evidence for Increased Susceptibility to Breast Cancer From Exposure to Ionizing Radiation Due to a Familial History of Breast Cancer: Results From the Swedish Hemangioma Cohort.

Women with a history of breast cancer among family members are at increased risk for breast cancer. However, it is unknown whether a familial breast cancer history (FBCH) also increases individual susceptibility to breast cancer from radiation exposure. In this cohort study, 17,200 female Swedish hemangioma patients with 1,079 breast cancer cases diagnosed between 1958 and 2013, exposed to ionizing radiation in infancy, were linked to their first-degree relatives. The association between FBCH and radiation-induced breast cancer risk was assessed. Further, the relevance for breast cancer radiotherapy and mammography screening was evaluated. On average, the radiation-induced excess relative risk and excess absolute risk of breast cancer at age 50 years were 0.51 Gy−1 (95% confidence interval (CI): 0.33, 0.71) and 10.8 cases/10,000 person-years/Gy (95% CI: 7.0, 14.6), respectively. Radiation risk was higher by a factor of 2.7 (95% CI: 1.0, 4.8; P = 0.05) if 1 first-degree relative was affected by breast cancer. For whole-breast standard radiotherapy at age 40 years with a contralateral breast dose of 0.72 Gy, the 20-year radiation-related excess risk of contralateral breast cancer was estimated to increase from 0.6% for women without FBCH to 1.7% for women with FBCH. In a biennial mammography screening program at ages 40–74 years, radiation risk up to age 80 years would increase from 0.11% for women without FBCH to 0.29% for women with FBCH.