Clinical features, diagnostic evaluation and responses to treatment in Paget's disease of bone in a center specialized in bone metabolism / Características clínicas, evaluación diagnóstica y respuestas al tratamiento de la enfermedad de Paget ósea en un centro especializado en metabolismo óseo

Abstract The epidemiology of Paget's disease of bone (PDB) has changed in the last years but there is no update data on its clinical presentation, diagnosis and management in Latin America. Our aim was to describe its clinical features, diagnostic evaluation and responses to treatment in a group of PDB patients treated between June 2012 and December 2019 in an institution specialized in bone diseases, in Buenos Aires, Argentina. The frequency of PDB (180/10 714) was 1.68%. Median age was 67 (range 39-97) years and 59.5% were women. Most patients were asymptomatic (58.6%) and had monostotic disease (54.3%). Favorable responses were obtained in all patients who were treated with zoledronate (n = 36), in 10 out of 14 treated with pamidronate, in 9 out of 10 who received intravenous ibandronate and in 12 out of 13 who received oral bisphosphonates. The response rates were not significantly different when we compared monostotic vs. polyostotic disease. Among the biochemical parameters, mean values of bone specific and total alkaline phosphatase, and C-terminal cross-linked telopeptide of type I collagen decreased significantly after treatment with bisphosphonates. It seems that our results reflect the change in PDB epidemiology towards a more indolent disease. In the future, this would probably allow physicians to use lower doses of bisphosphonates than the ones historically recommended for these patients.

Resumen La epidemiología de la en fermedad de Paget ósea (EPO) ha cambiado en los últimos años. Son necesarios datos actualizados sobre su forma de presentación clínica, diagnóstico y tratamiento en nuestra región. Nuestro objetivo fue describir las características clínicas, evaluación diagnóstica y respuestas al tratamiento de un grupo de pacientes con EPO en un centro especializado en salud ósea de Buenos Aires, Argentina. Se evaluaron todos los pacientes que fueron atendidos en nuestra institución por enfermedades óseas entre junio de 2012 y diciembre de 2019. La frecuencia de EPO (180/10 714) fue de 1.68%. La mediana de edad fue de 67 (rango 39-97) años. El 59.5% eran mujeres. La mayoría se encontraba asintomático (58.6%) y tenían enfermedad monostótica (54.3%). Se objetivaron respuestas favorables en todos los que recibieron zoledronato (n = 36), en 10 de 14 pacientes que recibieron pamidronato, en 9 de 10 que utilizaron ibandronato endovenoso y en 12 de 13 con bifosfonatos orales. Los porcentajes de respuesta no variaron significativamente entre pacientes con formas monostóticas y poliostóticas. Entre los parámetros bioquímicos, los valores de fosfatasa alcalina total y ósea y de β cross-laps disminuyeron significativamente luego del tratamiento con bifosfonatos. Nuestros resultados reflejarían un cambio en la epidemiología de la EPO hacia una forma de presentación más indolente. Esto permitiría probablemente el uso de dosis más bajas de bifosfonatos que las históricamente recomendadas para estos pacientes.

Dynamic risk allows us to adequately select patients with differentiated thyroid cancer who do not require radioiodine treatment

ABSTRACT Objective: The treatment of patients with differentiated thyroid cancer (DTC) was modified in the last decade towards a more individualized approach according to the risk of recurrence (RR). We compared the outcomes of patients with low and intermediate RR (LRR and IRR) who received or did not receive radioiodine remnant ablation (RRA) after assessing the dynamic risk. Materials and methods: We included 307 DTC patients with LRR and IRR submitted to total thyroidectomy. All patients were reclassified according to the dynamic risk stratification (low or high). Patients with high dynamic risk received RRA (141 patients). Results: LRR patients who received RRA presented a frequency of structural incomplete response (SIR) of 5% at the end of the follow-up, compared to 2% in those who did not receive it (p=0.353). IRR patients treated with RRA had a frequency of SIR of 22%, compared to 5% in patients without RRA (p=0.008). Conclusions: This study demonstrates the usefulness of dynamic risk assessment to decide RRA in a cohort with a long-term follow-up. The lower prevalence of SIR at the end of the follow-up in patients who did not receive RRA highlights the adequate selection of those who would not benefit from RRA, even with an intermediate risk of recurrence.

Detección ecográfica de remanentes del conducto tirogloso luego de tiroidectomía por cáncer de tiroides / Thyroglossal duct remnants detected by ultrasonography after total thyroidectomy for thyroid carcinoma

Resumen Existen numerosas comunicaciones de hallazgo incidental de remanentes del conducto tirogloso (CTG) posteriores a una tiroidectomía total, pero se desconoce su implicancia en pacientes con cáncer diferenciado de tiroides (CDT). Nuestro objetivo fue determinar frecuencia de detección ecográfica de remanentes del CTG posterior a la tiroidectomía total en pacientes con CDT y evaluar el impacto del hallazgo en la respuesta al tratamiento. Se incluyeron 377 pacientes con CDT tratados con tiroidectomía total entre enero 1994 y enero 2017, con seguimiento de al menos un año posterior a la cirugía. Se detectó la presencia de remanente del CTG en 16/377 (4.2%): 15 de bajo riesgo de recurrencia y uno de riesgo intermedio. Trece recibieron radioyodo. Todos tuvieron un estado sin evidencia de enfermedad al final del seguimiento, excepto uno con riesgo intermedio que presentó una respuesta inicial estructural incompleta e indeterminada posterior al vaciamiento ganglionar. La mediana del tiempo de diagnóstico del remanente del CTG luego de la tiroidectomía fue de 5 años (rango 1-16). Dos pacientes con remanentes del CTG fueron intervenidos quirúrgicamente, ambos presentaron tumoraciones de aparición súbita en región suprahioidea, 2.4 y 4 cm, detectados a los 9 y 16 años luego de la tiroidectomía, respectivamente. La prevalencia de esta condición parece ser poco frecuente. Sin embargo, la aparición de una masa quística en el seguimiento de un paciente con CDT puede ser confundido con enfermedad metastásica y generar ansiedad. El hallazgo de remanentes del CTG parecería no tener ningún impacto en la respuesta al tratamiento.

Abstract There are numerous reports of incidental findings of thyroglossal duct remnants (TGDR) after total thyroidectomy, but its implication on the outcome of patients with differentiated thyroid cancer (DTC) is unknown. The aim of this study was to determine the frequency of TGDR detected by ultrasonography after total thyroidectomy in patients with DTC and to evaluate the impact of this finding on the response to treatment. A total of 377 records of patients with DTC who received total thyroidectomy between January 1994 and January 2017 were reviewed. Patients with less than one year of follow-up after surgery were excluded. TGDR was diagnosed in 16 out of 377 (4.2%). Fifteen had a low risk of recurrence DTC and 13 of them were treated with radioactive iodine. All low risk patients had an excellent response to treatment. Only one with an intermediate risk of recurrence DTC had an initial structural incomplete response which changed to an indeterminate response after a modified central lymph node dissection. The median time of TGDR diagnosis after thyroidectomy was 5 years (1-16). Two patients underwent TGDR surgery due to the presence of a rapidly growing neck mass, 2.4 and 4 cm in size, detected 9 and 16 years after thyroidectomy, respectively. The prevalence of this condition seems to be rare. However, the appearance of a cystic mass during the follow-up of a patient with DTC cancer could be confused with metastatic disease. The diagnosis of TGDR seems not to have an impact on the response to treatment.

Rare complications of multikinase inhibitor treatment

ABSTRACT Objective: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. Subjects and methods: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. Results: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. Conclusions: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

Impact of historic histopathologic sample review on the risk of recurrence in patients with differentiated thyroid cancer

ABSTRACT Objective To compare the historic risk of recurrence (RR) and response to therapy to risk stratification estimated with historical pathology reports (HPRs) and contemporary re-review of the pathological slides in patients with differentiated thyroid cancer (DTC). Subjects and methods Out of 210 DTC patients with low and intermediate RR who underwent total thyroidectomy and remnant ablation in our hospital, 63 available historic pathologic samples (HPS) were reviewed. The RR and the response to therapy were evaluated considering historical histological features (histological type, tumor size, capsular invasion, number of lymph node metastases) and then, reassessed after observing additional histological features (vascular invasion, extrathyroidal extension, size of lymph node metastases, presence of extranodal extension, and/or status of the resection margins). Results A change in the RR category was observed in 16 of 63 cases (25.4%). Out of 46 patients initially classified as low RR, 2 patients were reclassified as intermediate RR, 4 as high RR, and 1 as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Out of 17 patients initially classified as intermediate RR, 3 were reassigned to the low RR group, 5 as high RR, and 1 as NIFTP. The percentages of structural incomplete response at final follow-up changed from 2.2 to 0% (p = 1) in patients with low RR and from 6.3 to 20% (p = 0.53) in patients with intermediate RR. Conclusion A detailed report of specific features in the HPR of patients with DTC might give a more accurate RR classification and a better estimation of the response to treatment.

Guía práctica para el manejo de efectos adversos por inhibidores multicinasas (sorafenib y vandetanib) en pacientes con cáncer de tiroides avanzado / Practice guidelines for the management of adverse effects due to multikinase inhibitors (sorafenib and vandetanib) in patients with advanced thyroid cancer

El advenimiento de la terapia con inhibidores multicinasas (IMK) representó un cambio radical en el tratamiento de pacientes con carcinoma avanzado de tiroides. Hasta la fecha, 2 fármacos se encuentran aprobados por la Asociación Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) en Argentina: sorafenib, para pacientes con carcinoma diferenciado de tiroides radiorresistente, y vandetanib, para aquellos con carcinoma medular de tiroides (enfermedad progresiva y/o sintomática). Los estudios de fase III han demostrado que estos fármacos aumentan significativamente la supervivencia libre de progresión en este grupo de pacientes. Si bien tienen una indicación precisa, su manejo requiere de un equipo multidisciplinario en contacto estrecho con un paciente involucrado en su tratamiento. Los efectos adversos de sorafenib y vandetanib son frecuentes, sin embargo, muchos de ellos disminuyen con el tiempo y la mayoría puede manejarse a menudo sin disminuir la dosis ni suspender el fármaco. El conocimiento del correcto manejo de los efectos adversos por parte del equipo tratante constituye una herramienta fundamental para poder educar al paciente y, consecuentemente, poder prevenirlos o minimizarlos, y de esta manera evitar complicaciones severas. El objetivo de esta publicación es brindar una guía para el diagnóstico y tratamiento de los efectos adversos de estos IMK y, por otro lado, presentar la iniciativa del Hospital de Clínicas de la Universidad de Buenos Aires en cuanto a la implementación de la misma.

The advent of multikinase inhibitors therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The ANMAT (the Argentinian regulatory health agency) has currently approved sorafenib for patients with radioiodine resistant differentiated thyroid carcinoma, and vandetanib for patients with medullary thyroid carcinoma (progressive and/or symptomatic disease). It has been demonstrated by phase III clinical trials that these drugs improve progression free survival in this group of patients. Although they have a precise indication, an interdisciplinary team in close contact with a committed patient, are required for their effective management. The adverse events of these drugs are common, but many of them may ameliorate over time, and most of them are manageable, even without the need for dose reduction or drug withdrawal. Knowledge of the correct management of the adverse events is a fundamental tool for the medical team and for the patient to prevent or minimise them, to avoid serious complications and to obtain better patient compliance. The primary objective of this article is to provide a guideline for the diagnosis and treatment of the adverse events produced by the multikinase inhibitors, and to present the initiative of the Hospital de Clinicas in order to implement these guidelines.

Partial response to sorafenib treatment associated with transient grade 3 thrombocytopenia in a patient with locally advanced thyroid cancer

Advanced radioactive refractory and progressive or symptomatic differentiated thyroid carcinoma (DTC) is a rare condition. Sorafenib was recently approved for the treatment of these patients. We present the case of a 67 year old woman diagnosed with DTC who underwent a total thyroidectomy with central, lateral-compartment neck dissection and shaving of the trachea and esophagus due to tumor infiltration. A local recurrence was detected 14 months later requiring, additionally, two tracheal rings resection. The patient received a cumulative 131I dose of 650 mCi and developed dysphagia and dyspnea 63 months after initial surgery. A 18FGD-PET/CT showed progression of the local mass associated to hypermetabolic pulmonary nodules. Sorafenib 800 mg/day was then prescribed. A dose reduction to 400 mg/day was necessary due to grade 3 thrombocytopenia that appeared four months after drug prescription. Platelet count went to normal after this dose reduction. Five months after initiation of sorafenib, a partial response of the local mass with significant intra-tumoral necrosis was observed. We conclude that sorafenib is a valid option for locally advanced DTC and that the platelet count should be evaluated regularly because it seems that thrombocytopenia might be more frequently observed in DTC than in other types of tumors.

Osteomalacia oncogénica: Presentación de dos casos

La osteomalacia oncogénica es una enfermedad rara. Existen descriptos alrededor de 337 casos. Es ocasionada por un tumor productor del factor de crecimiento fibroblástico 23 (FGF-23), hormona que disminuye la reabsorción tubular de fosfatos y altera la hidroxilación renal de la vitamina D, con hipofosfatemia, hiperfosfaturia y niveles bajos de calcitriol. Se presentan dos pacientes de 44 y 70 años, que consultaron por dolores óseos generalizados de aproximadamente un año de evolución en los que se hallaron alteraciones bioquímicas compatibles con osteomalacia hipofosfatémica. En el primer caso se realizó la resección de una tumoración en tejido celular subcutáneo del pie derecho, un año después del diagnóstico clínico. Luego de la exéresis, se disminuyó el aporte de fosfatos que recibía el paciente, pero reaparecieron los dolores al intentar suspenderlos. Ocho años más tarde, hubo recidiva local de la tumoración por lo que se efectuó resección completa. Después de la misma, se logró suspender el aporte de fosfatos. En el segundo caso, el paciente se estudió con tomografía por emisión de positrones con 18F-fluorodesoxiglucosa, hallando formación nodular hipermetabólica en partes blandas de antepie derecho, de 2.26 cm de diámetro. Luego de su escisión se pudo suspender el aporte de fosfatos. Ambos pacientes se encuentran asintomáticos con indicadores de metabolismo fosfocálcico normales. El diagnóstico anatomopatológico en ambos fue un tumor mesenquimático fosfatúrico, variante mixta del tejido conectivo, la entidad más frecuentemente asociada a la osteomalacia oncogénica.

Oncogenic osteomalacia is a rare disease. It is caused by a tumor that produces fibroblast growth factor 23, a hormone that decreases the tubular phosphate reabsorption and impairs renal hydroxylation of vitamin D. This leads to hyperphosphaturia with hypophosphatemia and low calcitriol levels. About 337 cases have been reported and we studied two cases; 44 and 70 year-old men who sought medical attention complaining of suffering diffuse bone pain over a period of approximately one year. In both cases, a laboratory test showed biochemical alterations compatible with a hypophosphatemic osteomalacia. In the first case, a soft tissue tumor of the right foot was removed, one year after the diagnosis. The patient was allowed to diminish the phosphate intake, but symptoms reappeared at this time. Eight years later, a local recurrence of the tumor was noted. A complete excision was now performed. The patient was able to finally interrupt the phosphate intake. In the second case, an F-18 fluorodeoxyglucose positron emission tomography, with computed tomography revealed a 2.26 cm diameter hypermetabolic nodule in the soft tissue of the right forefoot. After its removal, the patient discontinued the phosphate intake. Both patients are asymptomatic and show a regular phosphocalcic laboratory evaluation. The histopathological diagnosis was, in both cases, a phosphaturic mesenchymal tumor, a mixed connective tissue variant. This is the prototypical variant of these tumors.

Uso de plasmaféresis en pancreatitis hipertrigliceridémica / Use of plasmapheresis in hypertriglyceridemic pancreatitis

La hipertrigliceridemia es causa de 1-4% de las pancreatitis agudas. Presentamos el caso de una mujer de 42 años con antecedentes de obesidad, diabetes mellitus tipo 2, hipertrigliceridemia e hipercolesterolemia (9365 mg/dl y 1822 mg/dl, respectivamente, 1 mes previo a la consulta). Concurrió a nuestro hospital por cuadro de dolor abdominal de 5 días de evolución de tipo cólico con progresión continua en las últimas 48 horas. Se realizó tomografía de abdomen que informó imágenes compatibles con pancreatitis. A las 36 horas de su ingreso se inició la primera sesión de plasmaféresis con una reducción de triglicéridos y colesterol del 25 y 30% respectivamente y una segunda sesión al día siguiente con descenso de triglicéridos a 996 mg/dl y colesterol a 238 mg/dl. Durante su internación presentó bacteriemia por Klebsiella pneumoniae, sin colección ni necrosis pancreática detectables por tomografía de abdomen, y luego neumonía intrahospitalaria, ambas infecciones con buena respuesta a antibioticoterapia. Al alta, los triglicéridos habían descendido a 652 mg/dl, el colesterol a 167 mg/dl, el dolor abdominal había cedido y la paciente presentaba buena tolerancia por vía oral. Observamos una reducción del 90% de triglicéridos y 87% de colesterol luego de dos sesiones de plasmaféresis, comparado con 70% de reducción en promedio en la mayoría de los estudios consultados. En los mismos, no hemos encontrado la presencia de bacteriemia ni neumonía hospitalaria como complicaciones.

Hypertriglyceridemia is reported as cause of 1 to 4% of the episodes of acute pancreatitis. We report the case of a 42-year-old woman with a history of obesity, type 2 diabetes mellitus, hypertriglyceridemia and hypercholesterolemia, with triglycerides of 9365 mg/dl, total cholesterol of 1822 mg/dl, one month prior to the consultation. She presented at the emergency unit with a 5 day history of abdominal pain, which progressed in intensity in the last 48 hours. Abdominal computed tomography revealed pancreatic and peripancreatic inflammation. Thirty-six hours after admission, a first session of plasmapheresis was conducted with a plasma triglyceride and cholesterol reduction of 25 and 30%, respectively. A second session was performed the next day, with a further reduction of triglycerides to 996 mg/dl and cholesterol to 238 mg/dl. During hospitalization the patient presented fever and Klebsiella pneumoniae bacteremia with no pancreatic collection or necrosis in tomography and, later on, nosocomial pneumonia, both infections with adequate response to antibiotic therapy. At the time of discharge, triglycerides and cholesterol levels were 652 mg/dl and 167 mg/dl respectively, no abdominal pain was present and the patient resumed oral nutrition. We observed a 90% reduction of triglycerides and 87% of cholesterol after 2 sessions of plasmapheresis, compared to 70% in average of reduction in most of the studies reviewed. We did not find the presence of bacteremia or nosocomial pneumonia as complications in the reported cases.