Machine learning classification of breeding protocol descriptions from Canadian Holsteins.

Dairy farmers are motivated to ensure cows become pregnant in an optimal and timely manner. Although timed artificial insemination (TAI) is a successful management tool in dairy cattle, it masks an animal's innate fertility performance, likely reducing the accuracy of genetic evaluations for fertility traits. Therefore, separating fertility traits based on the recorded management technique involved in the breeding process or adding the breeding protocol as an effect to the model can be viable approaches to address the potential bias caused by such management decisions. Nevertheless, there is a lack of specificity and uniformity in the recording of breeding protocol descriptions by dairy farmers. Therefore, this study investigated the use of 8 supervised machine learning algorithms to classify 1,835 unique breeding protocol descriptions from 981 herds into the following 2 classes: TAI or other than TAI. Our results showed that models that used a stacking classifier algorithm had the highest Matthews correlation coefficient (0.94 ± 0.04, mean ± SD) and maximized precision and recall (F1-score = 0.96 ± 0.03) on test data. Nonetheless, their F1-scores on test data were not different from 5 out of the other 7 algorithms considered. Altogether, results presented herein suggest machine learning algorithms can be used to produce robust models that correctly identify TAI protocols from dairy cattle breeding records, thus opening the opportunity for unbiased genetic evaluation of animals based on their natural fertility.

Estimated genetic parameters for all genetically evaluated traits in Canadian Holsteins.

Genetic improvement is a crucial tool to deal with the increasing demand for high quality, sustainably produced dairy. Breeding programs are based on genetic parameters, such as heritability and genetic correlations, for economically important traits in a population. In this study, we estimated population genetic parameters and genetic trends for 67 traits evaluated on heifers and first-lactation Canadian Holstein cows. The data consisted of approximately 500,000 records with pedigree information collected from 1980 to 2019. Genetic parameters were estimated using bivariate linear animal models under a Bayesian approach. Analyses for the 67 traits resulted in 2,211 bivariate combinations, from which the estimated genetic parameters are reported here. The most highly heritable traits were fat percent (0.66) and protein percent (0.69), followed by stature (0.47). Lowest heritabilities (0.01) were observed for disease-related traits, such as lameness and toe ulcer, and calf survival. The genetic correlations between gestation length, calf size, and calving ease measured on both heifer and cows were close to unity. On the other hand, traits such as body condition score and pin width, cystic ovaries and sole ulcer, rear teat placement, and toe ulcer were genetically unrelated. This study reports genetic parameters that have not been previously published for Canadian Holstein cows, and provides updates of those previously estimated. These estimates are useful for building new indexes, updating existing selection indexes, and for predicting correlated responses due to inclusion of novel traits in the breeding programs.

Robotic transanal minimally invasive surgery - technical, oncological and patient outcomes from a single institution.

AIM: Robotic transanal minimally invasive surgery (R-TAMIS) is gaining traction around the globe as an alternative to laparoscopic conventional TAMIS for local excision of benign and early malignant rectal lesions. The aim was to analyse patient and oncological outcomes of R-TAMIS for consecutive cases in a single centre. METHODS: A prospective analysis of consecutive R-TAMIS procedures over a 12-month period was performed. Data were collated from hospital databases and theatre registers. RESULTS: Eleven patients (six men, five women), mean age 69.81 years (51-92 years), underwent R-TAMIS over 12 months utilizing a da Vinci Xi platform. The mean lesion size was 36 mm (20-60 mm) with a mean distance from the anal verge of 7.5 cm (3-14 cm). Five lesions were posterior in anatomical location, four anterior, one right lateral and one left lateral. All procedures were performed in the lithotomy position using a GelPOINT Path Platform. Mean operative time was 64 min (40-100 min). Complete resection was achieved in 10/11 patients with two patients being upgraded to a diagnosis of adenocarcinoma. Nine patients were diagnosed with dysplastic lesions. Four patients had a false positive diagnosis of an invasive tumour on MRI. Six patients required suturing for full-thickness resections. One patient had a postoperative bleed requiring repeat endoscopy and clipping. One patient (full-thickness resection of T3 tumour) proceeded to a formal resection without difficulty with no residual disease (T0N0, 0/22). One patient with a fully resected T2 tumour is undergoing a surveillance protocol. The mean length of stay was 1 day with two patients having a length of stay of 2 days and one patient of 4 days. CONCLUSION: R-TAMIS could potentially represent a safe novel approach for local resection of rectal lesions.

Projecting the fiscal impact of South Africa's contraceptive needs: Scaling up family planning post 2020.

BACKGROUND: Evidence-informed priority setting is vital to improved investment in public health interventions. This is particularly important as South Africa (SA) makes the shift to universal health coverage and institution of National Health Insurance. OBJECTIVES: To measure the financial impact of increasing the demand for modern contraceptive methods in the SA public health sector. We estimated the total cost of providing contraceptives, and specifically the budgetary impact of premature removals of long-acting reversible contraceptives. METHODS: We created a deterministic model in Microsoft Excel to estimate the costs of contraception provision over a 5-year time horizon (2018 - 2023) from a healthcare provider perspective. Only direct costs of service provision were considered, including drugs, supplies and personnel time. Costs were not discounted owing to the short time horizon. Scenario analyses were conducted to test uncertainty. RESULTS: The base-case cost of current contraceptive use in 2018 was estimated to be ZAR1.64 billion (ZAR29 per capita). Injectable contraceptives accounted for ~47% of total costs. To meet the total demand for family planning, SA would have to spend ~30% more than the estimate for current contraceptive use. In the year 2023, the 'current use' of modern contraceptives would increase to ZAR2.2 billion, and fulfilling the total demand for family planning would require ZAR2.9 billion. The base-case cost of implantable contraceptives was estimated at ZAR54 million. Assuming a normal removal rate, the use of implants is projected to increase by 20% during the 5-year period between 2019 and 2023, with an estimated 46% increase in costs. The cost of early removal of Implanon NXT is estimated at ZAR75 million, with total contraception costs estimated at ZAR102 million in 2019, compared with ZAR56 million when a normal removal rate is applied. CONCLUSIONS: The costs of scaling up modern contraceptives in SA are substantial. Early and premature removals of implantable contraceptives are costly to the nation and must be minimised. The government should consider conducting appropriate health technology assessments to inform the introduction of new public health interventions as SA makes the shift to universal health coverage by means of National Health Insurance.

An Audit of Neural Tube Defects in the Republic Of Ireland for 2012-2015.

Neural tube defects (NTD) are potentially preventable in two-thirds of cases by periconceptional maternal Folic Acid (FA) supplementation. A national audit for the years 2009-11 showed no decline in NTD rates over twenty years. The aim of this national audit was to determine trends/rates and inform revision of national FA supplementation and food fortification strategies. Of 274,732 live and stillbirths there were 121(42.0%) cases of anencephaly, 136(47.2%) cases of spina bifida and 31(10.8%) cases of encephalocoele giving a total of 288 and overall rate of 1.05/1000 compared with 1.04/1000 in 2009-11(NS). In the 184 women where the information was available, only 29.9%(n=55) reported starting FA before pregnancy. The number of cases diagnosed antenatally was 91%(n=262) and 53%(n=154) were live-born. This audit confirms that over a generation, healthcare interventions have not succeeded in decreasing the number of pregnancies in Ireland complicated by NTD, and that revised strategies need to be developed and implemented.

Spatial constraints govern competition of mutant clones in human epidermis.

Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. This has been applied to human epidermis, where sun exposure leads to the accumulation of mutations and an increased risk of skin cancer. However, previous studies have yielded conflicting conclusions about the relative importance of positive selection and neutral drift in clonal evolution. Here, we sequenced larger areas of skin than previously, focusing on cancer-prone skin spanning five decades of life. The mutant clones identified were too large to be accounted for solely by neutral drift. Rather, using mathematical modelling and computational lattice-based simulations, we show that observed clone size distributions can be explained by a combination of neutral drift and stochastic nucleation of mutations at the boundary of expanding mutant clones that have a competitive advantage. These findings demonstrate that spatial context and cell competition cooperate to determine the fate of a mutant stem cell.

A radio counterpart to a neutron star merger.

Gravitational waves have been detected from a binary neutron star merger event, GW170817. The detection of electromagnetic radiation from the same source has shown that the merger occurred in the outskirts of the galaxy NGC 4993, at a distance of 40 megaparsecs from Earth. We report the detection of a counterpart radio source that appears 16 days after the event, allowing us to diagnose the energetics and environment of the merger. The observed radio emission can be explained by either a collimated ultrarelativistic jet, viewed off-axis, or a cocoon of mildly relativistic ejecta. Within 100 days of the merger, the radio light curves will enable observers to distinguish between these models, and the angular velocity and geometry of the debris will be directly measurable by very long baseline interferometry.

Agreement between fragility fracture risk assessment algorithms as applied to adults with chronic spinal cord injury.

STUDY DESIGN: Cross-sectional. OBJECTIVES: The objective of the study was to determine and report agreement in fracture risk stratification of adults with spinal cord injury (SCI) using (1) Canadian Association of Radiologists and Osteoporosis Canada (CAROC) and Canadian Fracture Risk Assessment (FRAX) tools with and without areal bone mineral density (aBMD) and (2) SCI-specific fracture thresholds. SETTING: Tertiary rehabilitation center, Ontario, Canada. METHODS: Community-dwelling adults with chronic SCI (n=90, C2-T12, AIS A-D) consented to participation. Femoral neck aBMD values determined 10-year fracture risk (CAROC and FRAX). Knee-region aBMD and distal tibia volumetric BMD values were compared to SCI-specific fracture thresholds. Agreements between CAROC and FRAX risk stratifications, and between fracture threshold risk stratification, were assessed using prevalence- and bias-adjusted Kappa statistics (PABAK). RESULTS: CAROC and FRAX assessment tools showed moderate agreement for post-menopausal women (PABAK=0.56, 95% confidence interval (CI): 0.27, 0.84) and men aged ⩾50 years (PABAK=0.51, 95% CI: 0.34, 0.67), with poor agreement for young men and pre-menopausal women (PABAK⩽0). Excellent agreement was evident between FRAX with and without aBMD in young adults and in those with motor incomplete injury (PABAK=0.86-0.92). In other subgroups, agreement ranged from moderate to substantial (PABAK=0.41-0.73). SCI-specific fracture thresholds (Eser versus Garland) showed poor agreement (PABAK⩽0). CONCLUSION: Fracture risk estimates among individuals with SCI vary substantially with the risk assessment tool. Use of SCI-specific risk factors to identify patients with high fracture risk is recommended until a validated SCI-specific tool for predicting fracture risk is developed.

Risk of Thyroid Cancer Among Solid Organ Transplant Recipients.

Solid organ transplant recipients have an elevated incidence of thyroid cancer. We evaluated a wide range of potential risk factors in a cohort of 229 300 U.S. solid organ transplant recipients linked with 15 stage/regional cancer registries (1987-2012). Incidence rate ratios (IRRs) were adjusted for age, sex, race/ethnicity, transplanted organ, year of transplantation, and time since transplantation. Hazard ratios (HRs) for death and/or graft failure were adjusted for age, sex, race/ethnicity, transplanted organ, and year of transplantation. After transplantation, 356 thyroid cancers were diagnosed. Thyroid cancer incidence was 2.50-fold higher in transplant recipients than the general population (95% confidence interval [CI] 2.25-2.77). Among recipients of different organs, kidney recipients had the highest incidence of thyroid cancer (IRR = 1.26, 95% CI 1.03-1.53). Elevated thyroid cancer incidence was associated with cholestatic liver disease/cirrhosis as an indication for liver transplantation (IRR = 1.69, 95% CI 1.09-2.63), hypertensive nephrosclerosis as an indication for kidney transplantation (IRR = 1.41, 95% CI 1.03-1.94), and longer prior dialysis among kidney recipients (5+ vs. <1 year, IRR = 1.92, 95% CI 1.32-2.80; p-trend <0.01). Posttransplantation diagnosis of thyroid cancer was associated with modestly increased risk of death (HR = 1.33, 95% CI 1.02-1.73). Overall, our results suggest that end-stage organ disease and longer duration of dialysis may contribute to higher thyroid cancer incidence in transplant recipients.

Matrix metalloproteinase processing of PTHrP yields a selective regulator of osteogenesis, PTHrP1-17.

Parathyroid hormone-related protein (PTHrP) is a critical regulator of bone resorption and augments osteolysis in skeletal malignancies. Here we report that the mature PTHrP1-36 hormone is processed by matrix metalloproteinases to yield a stable product, PTHrP1-17. PTHrP1-17 retains the ability to signal through PTH1R to induce calcium flux and ERK phosphorylation but not cyclic AMP production or CREB phosphorylation. Notably, PTHrP1-17 promotes osteoblast migration and mineralization in vitro, and systemic administration of PTHrP1-17 augments ectopic bone formation in vivo. Further, in contrast to PTHrP1-36, PTHrP1-17 does not affect osteoclast formation/function in vitro or in vivo. Finally, immunoprecipitation-mass spectrometry analyses using PTHrP1-17-specific antibodies establish that PTHrP1-17 is indeed generated by cancer cells. Thus, matrix metalloproteinase-directed processing of PTHrP disables the osteolytic functions of the mature hormone to promote osteogenesis, indicating important roles for this circuit in bone remodelling in normal and disease contexts.

A loss of host-derived MMP-7 promotes myeloma growth and osteolytic bone disease in vivo.

Matrix metalloproteinases (MMPs) play a critical role in cancer pathogenesis, including tumor growth and osteolysis within the bone marrow microenvironment. However, the anti-tumor effects of MMPs are poorly understood, yet have significant implications for the therapeutic potential of targeting MMPs. Host derived MMP-7 has previously been shown to support the growth of bone metastatic breast and prostate cancer. In contrast and underscoring the complexity of MMP biology, here we identified a tumor-suppressive role for host MMP-7 in the progression of multiple myeloma in vivo. An increase in tumor burden and osteolytic bone disease was observed in myeloma-bearing MMP-7 deficient mice, as compared to wild-type controls. We observed that systemic MMP-7 activity was reduced in tumor-bearing mice and, in patients with multiple myeloma this reduced activity was concomitant with increased levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Our studies have identified an unexpected tumour-suppressive role for host-derived MMP-7 in myeloma bone disease in vivo, and highlight the importance of elucidating the effect of individual MMPs in a disease-specific context.

Early life programming and the risk of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, type 2 diabetes and cardiovascular disease and can be considered the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of disease, from the relatively benign simple steatosis to the more serious non-alcoholic steatohepatitis, which can progress to liver cirrhosis, hepatocellular carcinoma and end-stage liver failure, necessitating liver transplantation. Although the increasing prevalence of NAFLD in developed countries has substantial implications for public health, many of the precise mechanisms accounting for the development and progression of NAFLD are unclear. The environment in early life is an important determinant of cardiovascular disease risk in later life and studies suggest this also extends to NAFLD. Here we review data from animal models and human studies which suggest that fetal and early life exposure to maternal under- and overnutrition, excess glucocorticoids and environmental pollutants may confer an increased susceptibility to NAFLD development and progression in offspring and that such effects may be sex-specific. We also consider studies aimed at identifying potential dietary and pharmacological interventions aimed at reducing this risk. We suggest that further human epidemiological studies are needed to ensure that data from animal models are relevant to human health.

Re-calculating! Navigating through the osteosarcoma treatment roadblock.

The survival rates for patients with osteosarcoma have remained almost static for the past three decades. Current standard of care therapy includes chemotherapies such as doxorubicin, cisplatin, and methotrexate along with complete surgical resection and surgery with or without ifosfamide and etoposide for relapse, though outcomes are hoped to be improved through clinical trials. Additionally, increased understanding of the genetics, signaling pathways and microenvironmental factors driving the disease have led to the identification of promising agents and potential paths towards translation of an exciting array of novel targeted therapies. Here, we review the mechanism of action of these emerging therapies and how, with clinical translation, they can potentially improve the survival rates for osteosarcoma patients in the near future.

Risk of Renal Cell Carcinoma Among Kidney Transplant Recipients in the United States.

Renal cell carcinoma (RCC) is a common malignancy following kidney transplantation. We describe RCC risk and examine RCC risk factors among US kidney recipients (1987-2010). The Transplant Cancer Match Study links the US transplant registry with 15 cancer registries. Standardized incidence ratios (SIRs) were used to compare RCC risk (overall and for clear cell [ccRCC] and papillary subtypes) to the general population. Associations with risk factors were assessed using Cox models. We identified 683 RCCs among 116 208 kidney recipients. RCC risk was substantially elevated compared with the general population (SIR 5.68, 95% confidence interval 5.27-6.13), especially for papillary RCC (SIR 13.3 versus 3.98 for ccRCC). Among kidney recipients, RCC risk was significantly elevated for blacks compared to whites (hazard ratio [HR] 1.50) and lower in females than males (HR 0.56). RCC risk increased with prolonged dialysis preceding transplantation (p-trend < 0.0001). Risk was variably associated for RCC subtypes with some medical conditions that were indications for transplantation: ccRCC risk was reduced with polycystic kidney disease (HR 0.54), and papillary RCC was increased with hypertensive nephrosclerosis (HR 2.02) and vascular diseases (HR 1.86). In conclusion, kidney recipients experience substantially elevated risk of RCC, especially for papillary RCC, and multiple factors contribute to these cancers.

Comparison of Cancer Diagnoses Between the US Solid Organ Transplant Registry and Linked Central Cancer Registries.

US transplant centers are required to report cancers in transplant recipients to the transplant network. The accuracy and completeness of these data, collected in the Scientific Registry of Transplant Recipients (SRTR), are unknown. We compared diagnoses in the SRTR and 15 linked cancer registries for colorectal, liver, lung, breast, prostate and kidney cancers; melanoma; and non-Hodgkin lymphoma (NHL). Among 187 384 transplants, 9323 cancers were documented in the SRTR or cancer registries. Only 36.8% of cancers were in both, with 47.5% and 15.7% of cases additionally documented solely in cancer registries or the SRTR, respectively. Agreement between the SRTR and cancer registries varied (kappa = 0.28 for liver cancer and kappa = 0.52-0.66 for lung, prostate, kidney, colorectum, and breast cancers). Upon evaluation, some NHLs documented only in cancer registries were identified in the SRTR as another type of posttransplant lymphoproliferative disorder. Some SRTR-only cases were explained by miscoding (colorectal cancer instead of anal cancer, metastases as lung or liver cancers) or missed matches with cancer registries, partly due to recipients' outmigration from catchment areas. Estimated sensitivity for identifying cancer was 52.5% for the SRTR and 84.3% for cancer registries. In conclusion, SRTR cancer data are substantially incomplete, limiting their usefulness for surveillance and research.

Risk of Colorectal Cancer After Solid Organ Transplantation in the United States.

Solid organ transplant recipients have increased colorectal cancer (CRC) risk. We assessed CRC risk among transplant recipients and identified factors contributing to this association. The US transplant registry was linked to 15 population-based cancer registries (1987-2010). We compared CRC risk in recipients to the general population by using standardized incidence ratios (SIRs) and identified CRC risk factors by using Poisson regression. Based on 790 cases of CRC among 224 098 transplant recipients, the recipients had elevated CRC risk (SIR 1.12, 95% confidence interval [CI] 1.04 to 1.20). The increase was driven by an excess of proximal colon cancer (SIR 1.69, 95% CI 1.53 to 1.87), while distal colon cancer was not increased (SIR 0.93, 95% CI 0.80 to 1.07), and rectal cancer was reduced (SIR 0.64, 95% CI 0.54 to 0.76). In multivariate analyses, CRC was increased markedly in lung recipients with cystic fibrosis (incidence rate ratio [IRR] 12.3, 95% CI 6.94 to 21.9, vs. kidney recipients). Liver recipients with primary sclerosing cholangitis and inflammatory bowel disease also had elevated CRC risk (IRR 5.32, 95% CI 3.73 to 7.58). Maintenance therapy with cyclosporine and azathioprine was associated with proximal colon cancer (IRR 1.53, 95% CI 1.05 to 2.23). Incidence was not elevated in a subgroup of kidney recipients treated with tacrolimus and mycophenolate mofetil, pointing to the relevance of the identified risk factors. Transplant recipients have increased proximal colon cancer risk, likely related to underlying medical conditions (cystic fibrosis and primary sclerosing cholangitis) and specific immunosuppressive regimens.

Dissecting the multiple myeloma-bone microenvironment reveals new therapeutic opportunities.

Multiple myeloma is a plasma cell skeletal malignancy. While therapeutic agents such as bortezomib and lenalidomide have significantly improved overall survival, the disease is currently incurable with the emergence of drug resistance limiting the efficacy of chemotherapeutic strategies. Failure to cure the disease is in part due to the underlying genetic heterogeneity of the cancer. Myeloma progression is critically dependent on the surrounding microenvironment. Defining the interactions between myeloma cells and the more genetically stable hematopoietic and mesenchymal components of the bone microenvironment is critical for the development of new therapeutic targets. In this review, we discuss recent advances in our understanding of how microenvironmental elements contribute to myeloma progression and, therapeutically, how those elements can or are currently being targeted in a bid to eradicate the disease.

Isolation & identification of bacteria for the treatment of brown crab (Cancer pagurus) waste to produce chitinous material.

AIMS: To isolate bacteria from soil for microbial pretreatment of brown crab (Cancer pagurus) shell waste and the production of chitin. METHODS AND RESULTS: Isolates were screened for protease enzymes and acid production in order to facilitate the removal of protein and calcium carbonate fractions from brown crab shell to yield a chitinous material. Selected isolates were applied in various combinations in successive, two-step fermentations with brown crab shell waste. These isolates were identified as: Exiguobacterium spp. (GenBank accession number: KP050496), Bacillus cereus (GenBank accession number: KP050499), B. subtilis (GenBank accession number: KP050498), Bacillus licheniformis (GenBank accession number: KP050497), Pseudomonas migulae (GenBank accession number: KP050501), Pseudomonas spp. (GenBank accession number: KP050500), Pseudomonas spp. (GenBank accession number: KP050502), Arthrobacter luteolus (GenBank accession number: KP050503), Lactobacillus spp. (GenBank accession number: KP072000) and Enterococcus spp. (GenBank accession number: KP071999). CONCLUSIONS: Successive two-step fermentations with isolates in certain combinations resulted in a demineralization of >94% and the extraction of a crude chitin fraction from brown crab processing waste. The highest demineralization, 98·9% was achieved when isolates identified as B. cereus and Pseudomonas spp. were used in combination. The transfer of fermentations to a larger scale requires further research for optimization. SIGNIFICANCE AND IMPACT OF THE STUDY: The successful application of these isolates in successive two-step fermentation of brown crab shell waste to extract chitin means with further research into optimization and scale up, this chitin extraction process may be applied on an industrial scale and provide further commercial value from brown crab shell waste.

Increased stomach cancer risk following radiotherapy for testicular cancer.

BACKGROUND: Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose-response relationship are sparse. METHODS: In a cohort of 22,269 5-year TC survivors diagnosed during 1959-1987, doses to stomach subsites were estimated for 92 patients who developed stomach cancer and 180 matched controls. Chemotherapy details were recorded. Odds ratios (ORs) were estimated using logistic regression. RESULTS: Cumulative incidence of second primary stomach cancer was 1.45% at 30 years after TC diagnosis. The TC survivors who received radiotherapy (87 (95%) cases, 151 (84%) controls) had a 5.9-fold (95% confidence interval (CI) 1.7-20.7) increased risk of stomach cancer. Risk increased with increasing stomach dose (P-trend<0.001), with an OR of 20.5 (3.7-114.3) for ⩾50.0 Gy compared with <10 Gy. Radiation-related risks remained elevated ⩾20 years after exposure (P<0.001). Risk after any chemotherapy was not elevated (OR=1.1; 95% CI 0.5-2.5; 14 cases and 23 controls). CONCLUSIONS: Radiotherapy for TC involving parts of the stomach increased gastric cancer risk for several decades, with the highest risks after stomach doses of ⩾30 Gy. Clinicians should be aware of these excesses when previously irradiated TC survivors present with gastrointestinal symptoms and when any radiotherapy is considered in newly diagnosed TC patients.

Pancreatic cancer risk after treatment of Hodgkin lymphoma.

BACKGROUND: Although elevated risks of pancreatic cancer have been observed in long-term survivors of Hodgkin lymphoma (HL), no prior study has assessed the risk of second pancreatic cancer in relation to radiation dose and specific chemotherapeutic agents. PATIENTS AND METHODS: We conducted an international case-control study within a cohort of 19 882 HL survivors diagnosed from 1953 to 2003 including 36 cases and 70 matched controls. RESULTS: Median ages at HL and pancreatic cancer diagnoses were 47 and 60.5 years, respectively; median time to pancreatic cancer was 19 years. Pancreatic cancer risk increased with increasing radiation dose to the pancreatic tumor location (Ptrend = 0.005) and increasing number of alkylating agent (AA)-containing cycles of chemotherapy (Ptrend = 0.008). The odds ratio (OR) for patients treated with both subdiaphragmatic radiation (≥10 Gy) and ≥6 AA-containing chemotherapy cycles (13 cases, 6 controls) compared with patients with neither treatment was 17.9 (95% confidence interval 3.5-158). The joint effect of these two treatments was significantly greater than additive (P = 0.041) and nonsignificantly greater than multiplicative (P = 0.29). Especially high risks were observed among patients receiving ≥8400 mg/m(2) of procarbazine with nitrogen mustard or ≥3900 mg/m(2) of cyclophosphamide. CONCLUSION: Our study demonstrates for the first time that both radiotherapy and chemotherapy substantially increase pancreatic cancer risks among HL survivors treated in the past. These findings extend the range of nonhematologic cancers associated with chemotherapy and add to the evidence that the combination of radiotherapy and chemotherapy can lead to especially large risks.