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• W2743508051 abstract "Venous thromboembolism (VTE) can be the first manifestation of cancer. Although four prospective studies have suggested that limited occult cancer screening might be adequate after a first unprovoked VTE 1.Carrier M. Lazo‐Langner A. Shivakumar S. Tagalakis V. Zarychanski R. Solymoss S. Routhier N. Douketis J. Danovitch K. Lee A.Y. Le Gal G. Wells P.S. Corsi D.J. Ramsay T. Coyle D. Chagnon I. Kassam Z. Tao H. Rodger M.A. Screening for occult cancer in unprovoked venous thromboembolism.N Engl J Med. 2015; 373: 697-704Crossref PubMed Scopus (223) Google Scholar, 2.Robin P. Le Roux P.Y. Planquette B. Accassat S. Roy P.M. Couturaud F. Ghazzar N. Prevot‐Bitot N. Couturier O. Delluc A. Sanchez O. Tardy B. Le Gal G. Salaun P.Y. Limited screening with versus without (18)F‐fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: an open‐label randomised controlled trial.Lancet Oncol. 2016; 17: 193-9Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 3.Van Doormaal F.F. Terpstra W. Van Der Griend R. Prins M.H. Nijziel M.R. Van De Ree M.A. Buller H.R. Dutilh J.C. ten Cate‐Hoek A. Van Den Heiligenberg S.M. Van Der Meer J. Otten J.M. Is extensive screening for cancer in idiopathic venous thromboembolism warranted?.J Thromb Haemost. 2011; 9: 79-84Crossref PubMed Scopus (123) Google Scholar, 4.Prandoni P. Bernardi E. Valle F.D. Visona A. Tropeano P.F. Bova C. Bucherini E. Islam M.S. Piccioli A. Extensive computed tomography versus limited screening for detection of occult cancer in unprovoked venous thromboembolism: a multicenter, controlled, randomized clinical trial.Semin Thromb Hemost. 2016; 42: 884-90Crossref PubMed Scopus (45) Google Scholar, there is no evidence that it should be applied to all VTE patients (provoked events, unusual site VTE, etc.). Furthermore, other uncertainties, such as which tests should be performed or whether occult cancer screening should be performed after a recurrent VTE event, still remain. Our objective is to provide guidance on the different management options for clinicians facing these frequent challenges. The incidence of occult cancer detection in patients with unprovoked VTE can be as high as 10% within the first year following their thrombotic event. Although recent studies have reported a lower incidence of occult cancer detection of ≈ 5% in this patient population, it still represents a four‐fold to six‐fold increased risk as compared with the incidence reported in the general population of the same age 5.Gheshmy A. Carrier M. Venous thromboembolism and occult cancer: impact on clinical practice.Thromb Res. 2016; 140: S8-11Abstract Full Text PDF PubMed Scopus (11) Google Scholar. The risk of occult cancer detection seems to be highest during the first year following the unprovoked VTE diagnosis. However, a recent study suggested that it may remain elevated for up to 6 years for certain types of tumor, including colon or pancreatic cancers and multiple myeloma 6.Marks M.A. Engels E.A. Venous thromboembolism and cancer risk among elderly adults in the United States.Cancer Epidemiol Biomarkers Prev. 2014; 23: 774-83Crossref PubMed Scopus (28) Google Scholar. The frequency of occult cancer in patients with unprovoked VTE is clinically relevant and may warrant consideration of different types of screening strategy. Several studies have directly compared limited and extensive occult cancer screening strategies 1.Carrier M. Lazo‐Langner A. Shivakumar S. Tagalakis V. Zarychanski R. Solymoss S. Routhier N. Douketis J. Danovitch K. Lee A.Y. Le Gal G. Wells P.S. Corsi D.J. Ramsay T. Coyle D. Chagnon I. Kassam Z. Tao H. Rodger M.A. Screening for occult cancer in unprovoked venous thromboembolism.N Engl J Med. 2015; 373: 697-704Crossref PubMed Scopus (223) Google Scholar, 2.Robin P. Le Roux P.Y. Planquette B. Accassat S. Roy P.M. Couturaud F. Ghazzar N. Prevot‐Bitot N. Couturier O. Delluc A. Sanchez O. Tardy B. Le Gal G. Salaun P.Y. Limited screening with versus without (18)F‐fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: an open‐label randomised controlled trial.Lancet Oncol. 2016; 17: 193-9Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 3.Van Doormaal F.F. Terpstra W. Van Der Griend R. Prins M.H. Nijziel M.R. Van De Ree M.A. Buller H.R. Dutilh J.C. ten Cate‐Hoek A. Van Den Heiligenberg S.M. Van Der Meer J. Otten J.M. Is extensive screening for cancer in idiopathic venous thromboembolism warranted?.J Thromb Haemost. 2011; 9: 79-84Crossref PubMed Scopus (123) Google Scholar, 4.Prandoni P. Bernardi E. Valle F.D. Visona A. Tropeano P.F. Bova C. Bucherini E. Islam M.S. Piccioli A. Extensive computed tomography versus limited screening for detection of occult cancer in unprovoked venous thromboembolism: a multicenter, controlled, randomized clinical trial.Semin Thromb Hemost. 2016; 42: 884-90Crossref PubMed Scopus (45) Google Scholar, 7.Piccioli A. Lensing A.W. Prins M.H. Falanga A. Scannapieco G.L. Ieran M. Cigolini M. Ambrosio G.B. Monreal M. Girolami A. Prandoni P. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial.J Thromb Haemost. 2004; 2: 884-9Crossref PubMed Scopus (281) Google Scholar. In these studies, the limited screening strategy generally includes a thorough history and physical examination, blood work (complete blood count and differential blood count, electrolytes, creatinine, liver function tests, and lactate dehydrogenase), a chest X‐ray, and age‐specific and gender‐specific cancer screening, whereas an extensive screening strategy also includes one or more of computed tomography (CT) of the abdomen, pelvis, and thorax, ultrasound of the abdomen and pelvis, endoscopy, mammography and/or serum tumor markers, and, more recently, positron emission tomography–CT. Although all studies showed that a more extensive screening strategy did not detect more occult cancer than a more limited strategy, two studies suggested that an extensive screening strategy might detect earlier‐stage tumors and be associated with a lower number of newly diagnosed cancers (or fewer occult cancers being missed) during follow‐up 2.Robin P. Le Roux P.Y. Planquette B. Accassat S. Roy P.M. Couturaud F. Ghazzar N. Prevot‐Bitot N. Couturier O. Delluc A. Sanchez O. Tardy B. Le Gal G. Salaun P.Y. Limited screening with versus without (18)F‐fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: an open‐label randomised controlled trial.Lancet Oncol. 2016; 17: 193-9Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 7.Piccioli A. Lensing A.W. Prins M.H. Falanga A. Scannapieco G.L. Ieran M. Cigolini M. Ambrosio G.B. Monreal M. Girolami A. Prandoni P. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial.J Thromb Haemost. 2004; 2: 884-9Crossref PubMed Scopus (281) Google Scholar. Nonetheless, it remains unclear whether these findings translate into an improvement in patient‐important outcomes, including a decrease in morbidity or an increase in survival, in this patient population. Clinical practice guidelines and guidance documents have reported different opinions and polarized recommendations on this important topic. The UK National Institute for Health and Care Excellence (NICE) suggests, on the basis of data available up to 2012, screening of patients aged > 40 years with unprovoked VTE, and recommends that CT of the abdomen/pelvis and mammography for women be considered, as these interventions would probably provide more benefit than harm. Also, the NICE recommends lowering the threshold for occult cancer screening of those with bilateral deep vein thrombosis (DVT), very high D‐dimer levels, or an early recurrence of VTE 8.Langford N. Stansby G. Avital L. The management of venous thromboembolic diseases and the role of thrombophilia testing: summary of NICE Guideline CG144.Acute Med. 2012; 11: 138-42Crossref PubMed Google Scholar. More recently, the Anticoagulation Forum (USA) guidance document suggested that patients with unprovoked VTE only undergo a thorough medical history and physical examination, basic laboratory investigations, chest X‐ray, and age‐specific and gender‐specific cancer screening (i.e. cervical, breast, prostate and colon cancer) 9.Khorana A.A. Carrier M. Garcia D.A. Lee A.Y. Guidance for the prevention and treatment of cancer‐associated venous thromboembolism.J Thromb Thrombolysis. 2016; 41: 81-91Crossref PubMed Scopus (152) Google Scholar. Occult cancer screening potentially has a large economic cost, and may pose an important significant psychological burden. A cost–utility analysis performed alongside one of the previously described trials comparing an extensive with a limited screening strategy demonstrated that an extensive screening strategy, including CT of the abdomen and pelvis, was not cost‐effective 10.Coyle K. Carrier M. Lazo‐Langner A. Shivakumar S. Zarychanski R. Tagalakis V. Solymoss S. Routhier N. Douketis J. Coyle D. Cost effectiveness of the addition of a comprehensive CT scan to the abdomen and pelvis for the detection of cancer after unprovoked venous thromboembolism.Thromb Res. 2017; 151: 67-71Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar. Furthermore, aggressive cancer screening may lead to unnecessary early anticoagulation withdrawal, which can potentially lead to recurrent VTE. Clinical prediction rules aimed at stratifying patients with VTE according to their underlying risk of occult cancer have recently been derived 9.Khorana A.A. Carrier M. Garcia D.A. Lee A.Y. Guidance for the prevention and treatment of cancer‐associated venous thromboembolism.J Thromb Thrombolysis. 2016; 41: 81-91Crossref PubMed Scopus (152) Google Scholar, 11.Jara‐Palomares L. Otero R. Jimenez D. Carrier M. Tzoran I. Brenner B. Margeli M. Praena‐Fernandez J.M. Grandone E. Monreal M. Development of a risk prediction score for occult cancer in patients with venous thromboembolism.Chest. 2017; 151: 564-71Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar. Age, previous VTE and chronic lung disease/smoking status seemed to be important risk factors. However, none of them have yet been validated, and they should not currently be used to make decisions about screening. Therefore, further clinical trials are required to assess the risks and benefits of an extensive occult cancer screening program in high‐risk patients with unprovoked VTE 6.Marks M.A. Engels E.A. Venous thromboembolism and cancer risk among elderly adults in the United States.Cancer Epidemiol Biomarkers Prev. 2014; 23: 774-83Crossref PubMed Scopus (28) Google Scholar, 9.Khorana A.A. Carrier M. Garcia D.A. Lee A.Y. Guidance for the prevention and treatment of cancer‐associated venous thromboembolism.J Thromb Thrombolysis. 2016; 41: 81-91Crossref PubMed Scopus (152) Google Scholar, 11.Jara‐Palomares L. Otero R. Jimenez D. Carrier M. Tzoran I. Brenner B. Margeli M. Praena‐Fernandez J.M. Grandone E. Monreal M. Development of a risk prediction score for occult cancer in patients with venous thromboembolism.Chest. 2017; 151: 564-71Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 12.Lecumberri R. Alfonso A. Cancer screening after unprovoked venous thrombosis.Lancet Oncol. 2016; 17: 128-9Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar. 1.Patients with unprovoked VTE should undergo limited cancer screening, including a thorough medical history and physical examination, laboratory investigations (complete blood count, calcium, urinalysis, and liver function tests), and chest X‐ray.2.Age‐specific and gender‐specific cancer screening (colon, breast, cervix, and prostate) should also be performed according to national recommendations. Few studies have evaluated the incidence of occult cancer detection in patients with recurrent unprovoked VTE. As mentioned above, previous unprovoked VTE seems to be an important risk factor for occult cancer detection in this population 11.Jara‐Palomares L. Otero R. Jimenez D. Carrier M. Tzoran I. Brenner B. Margeli M. Praena‐Fernandez J.M. Grandone E. Monreal M. Development of a risk prediction score for occult cancer in patients with venous thromboembolism.Chest. 2017; 151: 564-71Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar. A cohort study previously reported that 17% of patients with recurrent VTE also had a newly diagnosed cancer within 2 years of follow‐up, as compared with only 4.5% of patients with no VTE recurrence (odds ratio 4.3; 95% confidence interval [CI] 1.2–15.3, P = 0.024) 13.Prandoni P. Lensing A.W. Büller H.R. Cogo A. Prins M.H. Cattelan A.M. Cuppini S. Noventa F. ten Cate J.W. Deep‐vein thrombosis and the incidence of subsequent symptomatic cancer.N Engl J Med. 1992; 327: 1128-33Crossref PubMed Scopus (659) Google Scholar. Therefore, occult cancer screening might be more appealing to clinicians for patients with recurrent unprovoked VTE, especially when recurrence occurs or the patient is undergoing full therapeutic anticoagulation. However, no formal evaluation of occult cancer screening strategies has been made in this patient population. Nonetheless, it might be reasonable for clinicians to maintain a lower threshold for cancer detection and to consider more extensive screening procedures than those used for a patient with a first unprovoked VTE. 1.Patients with recurrent unprovoked VTE should undergo limited cancer screening (see above for details).2.Age‐specific and gender‐specific cancer screening should also be performed according to national recommendations.3.A lower threshold for cancer detection may be reasonable. Upper‐extremity (UE) DVT represents 5–10% of all VTE events 14.Grant J.D. Stevens S.M. Woller S.C. Lee E.W. Kee S.T. Liu D.M. Lohan D.G. Elliott C.G. Diagnosis and management of upper extremity deep‐vein thrombosis in adults.Thromb Haemost. 2012; 108: 1097-108Crossref PubMed Scopus (92) Google Scholar. A large majority of the cases are related to underlying risk factors, including known active cancer or an indwelling central venous catheter, or both 14.Grant J.D. Stevens S.M. Woller S.C. Lee E.W. Kee S.T. Liu D.M. Lohan D.G. Elliott C.G. Diagnosis and management of upper extremity deep‐vein thrombosis in adults.Thromb Haemost. 2012; 108: 1097-108Crossref PubMed Scopus (92) Google Scholar. Data on the incidence of an occult cancer following a diagnosis of unprovoked UE DVT are scarce. However, given the importance of additional local risk factors (e.g. extrinsic compression) for the risk of development of UE DVT, it appears that almost all occult cancers are simultaneously diagnosed with the same diagnostic modality used to confirm the UE DVT 15.Girolami A. Prandoni P. Zanon E. Bagatella P. Girolami B. Venous thromboses of upper limbs are more frequently associated with occult cancer as compared with those of lower limbs.Blood Coagul Fibrinolysis. 1999; 10: 455-7Crossref PubMed Scopus (71) Google Scholar. Therefore, additional occult cancer screening does not seem to be necessary. Similarly, local or regional risk factors are strongly associated with the development of splanchnic vein thrombosis 16.De Stefano V. Martinelli I. Splanchnic vein thrombosis: clinical presentation, risk factors and treatment.Intern Emerg Med. 2010; 5: 487-94Crossref PubMed Scopus (98) Google Scholar. Abdominal cancer, mainly in the gastrointestinal tract, pancreatic system, or hepatobiliary system, can be present in up to 30% of patients with splanchnic vein thrombosis 17.Riva N. Donadini M.P. Dentali F. Squizzato A. Ageno W. Clinical approach to splanchnic vein thrombosis: risk factors and treatment.Thromb Res. 2012; 130: S1-3Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar. Given that CT of the abdomen and pelvis is generally used to diagnose splanchnic vein thrombosis, this imaging test is usually enough to provide a regional assessment for occult cancer. Splanchnic vein thrombosis may also be the first manifestation of myeloproliferative disorders, even in the absence of an abnormal complete blood count. In a meta‐analysis of four observational studies, the prevalence of the JAK2 V617F mutation in patients with splanchnic vein thrombosis was 32.7% (95% CI 25.5–35.9%). Approximately half of these patients developed an overt myeloproliferative disorder during the follow‐up period 18.Dentali F. Squizzato A. Brivio L. Appio L. Campiotti L. Crowther M. Grandi A.M. Ageno W. JAK2V617F mutation for the early diagnosis of Ph‐ myeloproliferative neoplasms in patients with venous thromboembolism: a meta‐analysis.Blood. 2009; 113: 5617-23Crossref PubMed Scopus (158) Google Scholar. Finally, in cases of unknown/unexplained aplasia or hemolytic anemia associated with splanchnic vein thrombosis, or in the presence of Budd–Chiari syndrome, screening for paroxysmal nocturnal hemoglobinuria (PNH) should be considered. It is estimated that 7.4% of cases of cerebral vein thrombosis are associated with cancer. The mechanisms underlying this association involve tumor compression and tumor invasion of cerebral sinuses, and chemotherapeutic or hormonal drugs 19.Saposnik G. Barinagarrementeria F. Brown Jr, R.D. Bushnell C.D. Cucchiara B. Cushman M. deVeber G. Ferro J.M. Tsai F.Y. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2011; 42: 1158-92Crossref PubMed Scopus (1215) Google Scholar. In the setting of cerebral vein thrombosis diagnosed in the absence of known cancer, contrast‐enhanced cerebral imaging performed at diagnosis is enough to rule out occult intracranial cancer. Furthermore, because myeloproliferative disorders can be found in up to 13% of patients with cerebral vein thrombosis, screening for the JAK2 V617F mutation might also be beneficial in this patient population. 1.Patients with unusual site VTE should undergo limited cancer screening (see above for details).2.Age‐specific and gender‐specific cancer screening should also be performed according to national recommendations.3.In patients with splanchnic vein thrombosis or cerebral vein thrombosis, we suggest testing for underlying myeloproliferative disorder by the use of JAK 2V617F testing.4.In patients with splanchnic vein thrombosis and aplasia or hemolytic anemia, and in patients with Budd–Chiari syndrome, we suggest testing for PNH. The criteria used to classify a VTE event as unprovoked (idiopathic) or provoked (secondary) vary across different studies. However, for this Guidance Statement, provoked and unprovoked VTE are defined according to the ISTH standardization of nomenclature and categorization 20.Kearon C. Ageno W. Cannegieter S.C. Cosmi B. Geersing G.J. Kyrle P.A. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH.J Thromb Haemost. 2016; 14: 1480-3Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar. Several prospective studies have shown that the incidence of occult cancer in patients with provoked VTE is significantly lower than in patients with unprovoked VTE. Patients with surgery‐related VTE appear to be at particularly low risk of occult cancer detection 11.Jara‐Palomares L. Otero R. Jimenez D. Carrier M. Tzoran I. Brenner B. Margeli M. Praena‐Fernandez J.M. Grandone E. Monreal M. Development of a risk prediction score for occult cancer in patients with venous thromboembolism.Chest. 2017; 151: 564-71Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 21.Monreal M. Lensing A.W. Prins M.H. Bonet M. Fernandez‐Llamazares J. Muchart J. Prandoni P. Jimenez J.A. Screening for occult cancer in patients with acute deep vein thrombosis or pulmonary embolism.J Thromb Haemost. 2004; 2: 876-81Crossref PubMed Scopus (142) Google Scholar. Overall, the absolute rate of cancer between diagnosis and up to 12–24 months of follow‐up in patients with provoked VTE seems to be < 2% 13.Prandoni P. Lensing A.W. Büller H.R. Cogo A. Prins M.H. Cattelan A.M. Cuppini S. Noventa F. ten Cate J.W. Deep‐vein thrombosis and the incidence of subsequent symptomatic cancer.N Engl J Med. 1992; 327: 1128-33Crossref PubMed Scopus (659) Google Scholar, 21.Monreal M. Lensing A.W. Prins M.H. Bonet M. Fernandez‐Llamazares J. Muchart J. Prandoni P. Jimenez J.A. Screening for occult cancer in patients with acute deep vein thrombosis or pulmonary embolism.J Thromb Haemost. 2004; 2: 876-81Crossref PubMed Scopus (142) Google Scholar. There are no randomized clinical trials assessing screening for occult cancer in patients with provoked VTE. Given the low burden of occult cancer detection and lack of apparent benefits in recent clinical trials assessing extensive occult cancer screening in patients with unprovoked VTE, it is unlikely that a new study will be performed in the near future in this specific population 1.Carrier M. Lazo‐Langner A. Shivakumar S. Tagalakis V. Zarychanski R. Solymoss S. Routhier N. Douketis J. Danovitch K. Lee A.Y. Le Gal G. Wells P.S. Corsi D.J. Ramsay T. Coyle D. Chagnon I. Kassam Z. Tao H. Rodger M.A. Screening for occult cancer in unprovoked venous thromboembolism.N Engl J Med. 2015; 373: 697-704Crossref PubMed Scopus (223) Google Scholar, 2.Robin P. Le Roux P.Y. Planquette B. Accassat S. Roy P.M. Couturaud F. Ghazzar N. Prevot‐Bitot N. Couturier O. Delluc A. Sanchez O. Tardy B. Le Gal G. Salaun P.Y. Limited screening with versus without (18)F‐fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: an open‐label randomised controlled trial.Lancet Oncol. 2016; 17: 193-9Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 3.Van Doormaal F.F. Terpstra W. Van Der Griend R. Prins M.H. Nijziel M.R. Van De Ree M.A. Buller H.R. Dutilh J.C. ten Cate‐Hoek A. Van Den Heiligenberg S.M. Van Der Meer J. Otten J.M. Is extensive screening for cancer in idiopathic venous thromboembolism warranted?.J Thromb Haemost. 2011; 9: 79-84Crossref PubMed Scopus (123) Google Scholar. 1.Routine cancer screening in patients with provoked VTE is not recommended. A. Delluc, D. Antic, R. Lecumberri, C. Ay, and M. Carrier performed the literature searches, study selection, and data extraction, and drafted the manuscript. G. Meyer critically revised the manuscript, and provided important intellectual content. G. Meyer reports receiving travel support from Leo Pharma, BMS‐Pfizer, Stago, and Bayer Healthcare, outside the submitted work. Leo PharmaBMS-PfizerStagoBayer Healthcare CorrigendumJournal of Thrombosis and HaemostasisVol. 15Issue 12PreviewDelluc A, Antic D, Lecumberri R, Ay C, Meyer G, Carrier M. Occult cancer screening in patients with venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2017 Aug 5. https://doi.org/10.1111/jth.13791 Full-Text PDF Open Archive" @default.
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• W2743508051 title "Occult cancer screening in patients with venous thromboembolism: guidance from the SSC of the ISTH" @default.
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