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1. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Author

Pål Møller, Toni Seppälä, James G. Dowty, Saskia Haupt, Mev Dominguez-Valentin, Lone Sunde, Inge Bernstein, Christoph Engel, Stefan Aretz, Maartje Nielsen, Gabriel Capella, Dafydd Gareth Evans, John Burn, Elke Holinski-Feder, Lucio Bertario, Bernardo Bonanni, Annika Lindblom, Zohar Levi, Finlay Macrae, Ingrid Winship, John-Paul Plazzer, Rolf Sijmons, Luigi Laghi, Adriana Della Valle, Karl Heinimann, Elizabeth Half, Francisco Lopez-Koestner, Karin Alvarez-Valenzuela, Rodney J. Scott, Lior Katz, Ido Laish, Elez Vainer, Carlos Alberto Vaccaro, Dirce Maria Carraro, Nathan Gluck, Naim Abu-Freha, Aine Stakelum, Rory Kennelly, Des Winter, Benedito Mauro Rossi, Marc Greenblatt, Mabel Bohorquez, Harsh Sheth, Maria Grazia Tibiletti, Leonardo S. Lino-Silva, Karoline Horisberger, Carmen Portenkirchner, Ivana Nascimento, Norma Teresa Rossi, Leandro Apolinário da Silva, Huw Thomas, Attila Zaránd, Jukka-Pekka Mecklin, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Anna Lepisto, Päivi Peltomäki, Christina Therkildsen, Lars Joachim Lindberg, Ole Thorlacius-Ussing, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Claudia Perne, Robert Hüneburg, Aída Falcón de Vargas, Andrew Latchford, Anne-Marie Gerdes, Ann-Sofie Backman, Carmen Guillén-Ponce, Carrie Snyder, Charlotte K. Lautrup, David Amor, Edenir Palmero, Elena Stoffel, Floor Duijkers, Michael J. Hall, Heather Hampel, Heinric Williams, Henrik Okkels, Jan Lubiński, Jeanette Reece, Joanne Ngeow, Jose G. Guillem, Julie Arnold, Karin Wadt, Kevin Monahan, Leigha Senter, Lene J. Rasmussen, Liselotte P. van Hest, Luigi Ricciardiello, Maija R. J. Kohonen-Corish, Marjolijn J. L. Ligtenberg, Melissa Southey, Melyssa Aronson, Mohd N. Zahary, N. Jewel Samadder, Nicola Poplawski, Nicoline Hoogerbrugge, Patrick J. Morrison, Paul James, Grant Lee, Rakefet Chen-Shtoyerman, Ravindran Ankathil, Rish Pai, Robyn Ward, Susan Parry, Tadeusz Dębniak, Thomas John, Thomas van Overeem Hansen, Trinidad Caldés, Tatsuro Yamaguchi, Verónica Barca-Tierno, Pilar Garre, Giulia Martina Cavestro, Jürgen Weitz, Silke Redler, Reinhard Büttner, Vincent Heuveline, John L. Hopper, Aung Ko Win, Noralane Lindor, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, Jane Figueiredo, Daniel D. Buchanan, Stephen N. Thibodeau, Sanne W. ten Broeke, Eivind Hovig, Sigve Nakken, Marta Pineda, Nuria Dueñas, Joan Brunet, Kate Green, Fiona Lalloo, Katie Newton, Emma J. Crosbie, Miriam Mints, Douglas Tjandra, Florencia Neffa, Patricia Esperon, Revital Kariv, Guy Rosner, Walter Hernán Pavicic, Pablo Kalfayan, Giovana Tardin Torrezan, Thiago Bassaneze, Claudia Martin, Gabriela Moslein, Aysel Ahadova, Matthias Kloor, Julian R. Sampson, Mark A. Jenkins, and The European Hereditary Tumour Group (EHTG) and the International Mismatch Repair Consortium (IMRC)

Subjects
Lynch Syndrome, Epidemiology, Prevention, Penetrance, Colorectal cancer, Segregation analysis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Abstract

Abstract Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

Published
2022
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2. ALTERNATIVE FISTULA RISK SCORE AND FIRST POSTOPERATIVE DAY DRAIN FLUID AMYLASE AS PREDICTORS OF PANCREATIC FISTULA AFTER PANCREATICODUODENECTOMY

Author

Karina Scalabrin Longo, Thiago Bassaneze, Manuela Corrêa de Toledo Peres, Rogério Tadeu Palma, and Jaques Waisberg

Subjects
Pancreatic Fistula, Pancreaticoduodenectomy, Postoperative Complications, Prognosis, Surgery, RD1-811, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

ABSTRACT BACKGROUND: The high morbidity and mortality rates of pancreaticoduodenectomy are mainly associated with pancreaticojejunal anastomosis, the most fragile and susceptible to complications such as clinically relevant postoperative pancreatic fistula. AIMS: The alternative fistula risk score and the first postoperative day drain fluid amylase are predictors of the occurrence of clinically relevant postoperative pancreatic fistula. No consensus has been reached on which of the scores is a better predictor; moreover, their combined predictive power remains unclear. To the best of our knowledge, this association had not yet been studied. METHODS: This study assessed the predictive effect of alternative fistula risk score and/or drain fluid amylase on clinically relevant postoperative pancreatic fistula in a retrospective cohort of 58 patients following pancreaticoduodenectomy. The Shapiro-Wilk and Mann-Whitney tests were applied for assessing the distribution of the samples and for comparing the medians, respectively. The receiver operating characteristics curve and the confusion matrix were used to analyze the predictive models. RESULTS: The alternative fistula risk score values were not statistically different between patients in the clinically relevant postoperative pancreatic fistula and non- clinically relevant postoperative pancreatic fistula groups (Mann-Whitney U test 59.5, p=0.12). The drain fluid amylase values were statistically different between clinically relevant postoperative pancreatic fistula and non- clinically relevant postoperative pancreatic fistula groups (Mann-Whitney U test 27, p=0.004). The alternative fistula risk score and drain fluid amylase were independently less predictive for clinically relevant postoperative pancreatic fistula, compared to combined alternative fistula risk score + drain fluid amylase. CONCLUSION: The combined model involving alternative fistula risk score >20% + drain fluid amylase=5,000 U/L was the most effective predictor of clinically relevant postoperative pancreatic fistula occurrence following pancreaticoduodenectomy.

Published
2023
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3. Primary extensive perianal cutaneous tuberculosis: A challenging diagnosis. Case report and a review of the literature

Author

André Akira Ramos Takahashi, Thiago Bassaneze, Karina Scalabrin Longo, Juliana Giangiardi Batista, and Jaques Waisberg

Subjects
Tuberculosis, Perianal, Mycobacterium tuberculosis, Cutaneous, Infectious and parasitic diseases, RC109-216, Microbiology, QR1-502
Abstract

Rationale: Perianal tuberculosis is extremely rare without previous or active pulmonary infection. Ulcerative skin lesion is a rare presentation of extrapulmonary tuberculosis in the oral, perianal, or genital mucosa and the adjacent skin. Case report: A 71-year-old woman complained of pain during evacuation and fecal incontinence for two years. There was an ulcerated lesion in the perianal and intergluteal region and perianal fistulous tracts. A polymerase chain reaction test on blood and biopsies of perianal ulcers, perianal fistula, and the intergluteal area was positive for Mycobacterium tuberculosis. The pathological examination revealed a chronic epithelioid granulomatous inflammatory process with the presence of multinucleated giant cells. After the end of the tuberculosis drug regimen, there was marked improvement in the patient's clinical condition. Conclusion: Even in the absence of an identifiable primary focus, tuberculosis should be considered in the differential diagnosis of ulcerative and fistulous lesions of the perianal area.

Published
2023
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4. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment:a report from the prospective Lynch syndrome database

Author

Mev Dominguez-Valentin, Saskia Haupt, Toni T. Seppälä, Julian R. Sampson, Lone Sunde, Inge Bernstein, Mark A. Jenkins, Christoph Engel, Stefan Aretz, Maartje Nielsen, Gabriel Capella, Francesc Balaguer, Dafydd Gareth Evans, John Burn, Elke Holinski-Feder, Lucio Bertario, Bernardo Bonanni, Annika Lindblom, Zohar Levi, Finlay Macrae, Ingrid Winship, John-Paul Plazzer, Rolf Sijmons, Luigi Laghi, Adriana Della Valle, Karl Heinimann, Tadeusz Dębniak, Robert Fruscio, Francisco Lopez-Koestner, Karin Alvarez-Valenzuela, Lior H. Katz, Ido Laish, Elez Vainer, Carlos Vaccaro, Dirce Maria Carraro, Kevin Monahan, Elizabeth Half, Aine Stakelum, Des Winter, Rory Kennelly, Nathan Gluck, Harsh Sheth, Naim Abu-Freha, Marc Greenblatt, Benedito Mauro Rossi, Mabel Bohorquez, Giulia Martina Cavestro, Leonardo S. Lino-Silva, Karoline Horisberger, Maria Grazia Tibiletti, Ivana do Nascimento, Huw Thomas, Norma Teresa Rossi, Leandro Apolinário da Silva, Attila Zaránd, Juan Ruiz-Bañobre, Vincent Heuveline, Jukka-Pekka Mecklin, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Anna Lepistö, Päivi Peltomäki, Christina Therkildsen, Mia Gebauer Madsen, Stefan Kobbelgaard Burgdorf, John L. Hopper, Aung Ko Win, Robert W. Haile, Noralane Lindor, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, Jane Figueiredo, Daniel D. Buchanan, Stephen N. Thibodeau, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Evelin Schröck, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Claudia Perne, Robert Hüneburg, Silke Redler, Reinhard Büttner, Jürgen Weitz, Marta Pineda, Nuria Duenas, Joan Brunet Vidal, Leticia Moreira, Ariadna Sánchez, Eivind Hovig, Sigve Nakken, Kate Green, Fiona Lalloo, James Hill, Emma Crosbie, Miriam Mints, Yael Goldberg, Douglas Tjandra, Sanne W. ten Broeke, Revital Kariv, Guy Rosner, Suresh H. Advani, Lidiya Thomas, Pankaj Shah, Mithun Shah, Florencia Neffa, Patricia Esperon, Walter Pavicic, Giovana Tardin Torrezan, Thiago Bassaneze, Claudia Alejandra Martin, Gabriela Moslein, Pål Moller, Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schröck, E, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hüneburg, R, Redler, S, Büttner, R, Weitz, J, Pineda, M, Duenas, N, Vidal, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, and Goldberg, Y

Subjects
kuolleisuus, perinnölliset taudit, Survival, MLH1, riskitekijät, General Medicine, MSH6, sukupuoli, MSH2, Cancer risk, Lynch syndrome, PMS2, syöpägeenit, syöpätaudit, Lynchin oireyhtymä, Mortality, Prospective study, ilmaantuvuus, ikä, henkiinjääminen, kohorttitutkimus
Abstract

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

Published
2023

5. Alternative Fistula Risk Score and First Postoperative Day Drain Fluid Amylase as Predictors of Pancreatic Fistula After Pancreatoduodenectomy

Author

Karina Scalabrin Longo, Thiago Bassaneze, Rogério Tadeu Palma, and Jaques Waisberg

Abstract

Objectives: The alternative fistula risk score (aFRS) and the first postoperative day drain fluid amylase (DFA) are predictors of the occurrence of clinically relevant postoperative pancreatic fistula (CR-POPF). No consensus has been reached on which of the scores is a better predictor; moreover, their combined predictive power remains unclear. To our knowledge, this association had not yet been studied.Methods: This study assessed the predictive effect of aFRS and/or DFA on CR-POPF in a retrospective cohort of 58 patients following PD. The Shapiro-Wilk and the Mann-Whitney tests were applied for assessing the distribution of the samples and for comparing the medians, respectively. The receiver operating characteristics (ROC) curve and the confusion matrix were used to analyze the predictive models.Results: The aFRS values were not statistically different between patients in the CR-POPF and non-CR-POPF groups (Mann-Whitney U test: 59.5, p=0.12). The DFA values were statistically different between the CR-POPF and non-CR-POPF groups (Mann-Whitney U test: 27, p=0.004). The aFRS and DFA were independently less predictive for CR-POPF, compared to combined aFRS + DFA.Conclusions: The combined model involving aFRS>20% + DFA≥5,000 U/L was the most effective predictor of CR-POPF occurrence following PD.

Published
2021

6. Quantitative aspects of diffusion-weighted magnetic resonance imaging in rectal cancer response to neoadjuvant therapy

Author

Rogério Tadeu Palma, José Eduardo Gonçalves, Thiago Bassaneze, Juliano Faria, and Jaques Waisberg

Subjects
medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, R895-920, 030218 nuclear medicine & medical imaging, Medical physics. Medical radiology. Nuclear medicine, 03 medical and health sciences, 0302 clinical medicine, Rectal carcinoma, medicine, Effective diffusion coefficient, Cutoff, Radiology, Nuclear Medicine and imaging, neoadjuvant therapy, rectal cancer, Neoadjuvant therapy, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, medicine.disease, Diffusion-Weighted Magnetic Resonance Imaging, body regions, diffusion mri, Oncology, 030220 oncology & carcinogenesis, Radiology, business, Research Article, Diffusion MRI
Abstract

Background The aim of the study was to evaluate the added value of the apparent diffusion coefficient (ADC) of diffusion-weighted magnetic resonance imaging (DW-MRI) in patients with rectal cancer who received neoadjuvant chemoradiotherapy (CRT). The use of DW-MRI for response evaluation in rectal cancer still remains a widely investigated issue, as the accurate detection of pathologic complete response (pCR) is critical in making therapeutic decisions. Patients and methods Thirty-three patients with locally advanced rectal cancer were evaluated retrospectively by MRI in addition to diffusion-weighted images (DWI) and its ADC pre- and post-neoadjuvant CRT. These patients subsequently underwent curative-intent surgery. Tumor staging by MRI and ADC value were compared with histopathological findings of the surgical specimen. Results MRI in addition to DWI had a sensitivity of 96.1%, specificity of 71.4%, positive predictive value of 92.5%, and negative predictive value of 83.3% in the detection of pCR. The pre-CRT ADC alone could not reliably predict the pCR group. Post-CRT ADC cutoff value of 1.49 x 10−3 mm2/s had the highest accuracy and allowed a 16.7% increase in negative predictive value and 3.9% increase in sensitivity. Patients with pCR to neoadjuvant treatment differed from the other groups in their absolute values of post-CRT ADC (p < 0.01). Conclusions The use of post-CRT ADC increased the diagnostic performance of MRI in addition to DWI in predicting the final pathologic staging of rectal carcinoma.

Published
2017

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