Clinicopathological features and prognostic factors of gastric intermediate-risk gastrointestinal stromal tumor after surgical resection: a retrospective study / 中华病理学杂志

Objective: To investigate the clinicopathological features, treatment and prognosis of gastric intermediate-risk gastrointestinal stromal tumor (GIST), so as to provide a reference for clinical management and further research. Methods: A retrospective observational study of patients with gastric intermediate-risk GIST, who underwent surgical resection between January 1996 and December 2019 at Zhongshan Hospital of Fudan University, was carried out. Results: Totally, 360 patients with a median age of 59 years were included. There were 190 males and 170 females with median tumor diameter of 5.9 cm. Routine genetic testing was performed in 247 cases (68.6%, 247/360), and 198 cases (80.2%) showed KIT mutation, 26 cases (10.5%) showed PDGFRA mutation, and 23 cases were wild-type GIST. According to "Zhongshan Method"(including 12 parameters), there were 121 malignant and 239 non-malignant cases. Complete follow-up data were available in 241 patients; 55 patients (22.8%) received imatinib therapy, 10 patients (4.1%) experienced tumor progression, and one patient (PDGFRA mutation, 0.4%) died. Disease-free survival (DFS) and overall survival rate at 5 years was 96.0% and 99.6%, respectively. Among the intermediate-risk GIST, there was no difference in DFS between the overall population, KIT mutation, PDGFRA mutation, wild-type, non-malignant and malignant subgroups (all P>0.05). However, the non-malignancy/malignancy analysis showed that there were significant differences in DFS among the overall population (P<0.01), imatinib treatment group (P=0.044) and no imatinib treatment group (P<0.01). Adjuvant imatinib resulted in potential survival benefit for KIT mutated malignant and intermediate-risk GIST in DFS (P=0.241). Conclusions: Gastric intermediate-risk GIST shows a heterogeneous biologic behavior spectrum from benign to highly malignant. It can be further classified into benign and malignant, mainly nonmalignant and low-grade malignant. The overall disease progression rate after surgical resection is low, and real-world data show that there is no significant benefit from imatinib treatment after surgery. However, adjuvant imatinib potentially improves DFS of intermediate-risk patients with tumors harboring KIT mutation in the malignant group. Therefore, a comprehensive analysis of gene mutations in benign/malignant GIST will facilitate improvements in therapeutic decision-making.

Study on the Relationship between Integrin 2A and Drug Resistance in Chronic Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To explore the expression pattern and clinical significance of Integral membrane protein 2A（ITM2A） in drug resistant patients with chronic myeloid leukemia (CML).@*METHODS@#The expression of ITM2A in CML was evaluated by qRT-PCR, Western blot and immunocytochemistry. In order to understand the possible biological effects of ITM2A, apoptosis, cell cycle and myeloid differentiation antigen expression of CML cells were detected by flow cytometry after over-expression of ITM2A. The nuderlying molecular mechanism of its biological effect was explored.@*RESULTS@#The expression of ITM2A in bone marrow of CML resistant patients was significantly lower than that of sensitive patients and healthy donors（P<0.05）. The CML resistant strain cell K562R was successfully constructed in vitro. The expression of ITM2A in the resistant strain was significantly lower than that in the sensitive strain(P<0.05). Overexpression of ITM2A in K562R cells increased the sensitivity of K562R cells to imatinib and blocked the cell cycle in G2 phase(P<0.05), but did not affect myeloid differentiation. Mechanistically, up-regulation of ITM2A reduced phosphorylation in ERK signaling (P<0.05).@*CONCLUSION@#The expression of ITM2A was low in patients with drug resistance of CML, and the low expression of ITM2A may be the key factor of imatinib resistance in CML.

Connexin 43-modified bone marrow stromal cells reverse the imatinib resistance of K562 cells via Ca 2+ -dependent gap junction intercellular communication / 中华医学杂志(英文版)

BACKGROUND@#Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic microenvironment (HM) protects minimal residual disease (MRD), but the mechanism remains unknown.@*METHODS@#Immunohistochemistry assays were employed to compare the expression of Cx43 and hypoxia-inducible factor 1α (HIF-1α) in bone marrow (BM) biopsies of CML patients and healthy donors. A coculture system of K562 cells and several Cx43-modified bone marrow stromal cells (BMSCs) was established under IM treatment. Proliferation, cell cycle, apoptosis, and other indicators of K562 cells in different groups were detected to investigate the function and possible mechanism of Cx43. We assessed the Ca 2+ -related pathway by Western blotting. Tumor-bearing models were also established to validate the causal role of Cx43 in reversing IM resistance.@*RESULTS@#Low levels of Cx43 in BMs were observed in CML patients, and Cx43 expression was negatively correlated with HIF-1α. We also observed that K562 cells cocultured with BMSCs transfected with adenovirus-short hairpin RNA of Cx43 (BMSCs-shCx43) had a lower apoptosis rate and that their cell cycle was blocked in G0/G1 phase, while the result was the opposite in the Cx43-overexpression setting. Cx43 mediates gap junction intercellular communication (GJIC) through direct contact, and Ca 2+ is the key factor mediating the downstream apoptotic pathway. In animal experiments, mice bearing K562, and BMSCs-Cx43 had the smallest tumor volume and spleen, which was consistent with the in vitro experiments.@*CONCLUSIONS@#Cx43 deficiency exists in CML patients, promoting the generation of MRD and inducing drug resistance. Enhancing Cx43 expression and GJIC function in the HM may be a novel strategy to reverse drug resistance and promote IM efficacy.

A scoring system to predict molecular responses in patients with chronic myeloid leukemia in the chronic phase receiving initial imatinib therapy / 中华血液学杂志

Objective: To develop a scoring system to predict molecular responses in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving initial imatinib therapy. Methods: Data from consecutive adults with newly diagnosed CML-CP treated by initial imatinib was interrogated and subjects were distributed randomly into training and validation cohort, in a ratio of 2∶1. Fine-gray models were applied in the training cohort to identify co-variates of predictive value for major molecular response (MMR) and MR4. A predictive system was built using significant co-variates. The predictive system was then tested in the validation cohort and the area under the receiver-operator characteristic curve (AUROC) was used to estimate accuracy of the predictive system. Results: 1 364 CML-CP subjects receiving initial imatinib were included in this study. Subjects were distributed randomly into training cohort (n=909) and validation cohort (n=455) . In the training cohort, the male gender, European Treatment and Outcome Study for CML (EUTOS) Long-Term Survival (ELTS) intermediate-risk, ELTS high-risk, high WBC (≥130×10(9)/L or 120×10(9)/L, MMR or MR4) and low HGB (<110 g/L) at diagnosis were significantly related with poor molecular responses and were given points based on their regression coefficients. For MMR, male gender, ELTS intermediate-risk and low HGB (<110 g/L) were given 1 point; ELTS high-risk and high WBC (≥130×10(9)/L) , 2 points. For MR4, male gender was given 1 point; ELTS intermediate-risk and low HGB (<110 g/L) were given 2 points; high WBC (≥120×10(9)/L) , 3 points; ELTS high-risk, 4 points. We divided all subjects into 3 risk subgroups according to the predictive system above. Cumulative incidence of achieving MMR and MR4 in 3 risk subgroups was significantly different in both training and validation cohort (all P values <0.001) . In the training and validation cohorts, the time-dependent AUROC ranges of MMR and MR4 predictive systems were 0.70-0.84 and 0.64-0.81, respectively. Conclusions: A scoring system combining gender, WBC, HGB level and ELTS risk was built to predict MMR and MR4 in CML-CP patients receiving initial imatinib therapy. This system had good discrimination and accuracy, which could help phsicians optimize the selsction of initial TKI-therapy.

Role and mechanism of platelet-derived growth factor BB in thrombocytosis in Kawasaki disease / 中国当代儿科杂志

OBJECTIVES@#To study the role and mechanism of platelet-derived growth factor BB (PDGF-BB) on platelet production in Kawasaki disease (KD) mice and human megakaryocytic Dami cells through in vitro and invivo experiments.@*METHODS@#ELISA was used to measure the expression of PDGF in the serum of 40 children with KD and 40 healthy children. C57BL/6 mice were used to establish a model of KD and were then randomly divided into a normal group, a KD group, and an imatinib group (30 mice in each group). Routine blood test was performed for each group, and the expression of PDGF-BB, megakaryocyte colony forming unit (CFU-MK), and the megakaryocyte marker CD41 were measured. CCK-8, flow cytometry, quantitative real-time PCR, and Western blot were used to analyze the role and mechanism of PDGF-BB in platelet production in Dami cells.@*RESULTS@#PDGF-BB was highly expressed in the serum of KD children (P<0.001). The KD group had a higher expression level of PDGF-BB in serum (P<0.05) and significant increases in the expression of CFU-MK and CD41 (P<0.001), and the imatinib group had significant reductions in the expression of CFU-MK and CD41 (P<0.001). In vitro experiments showed that PDGF-BB promoted Dami cell proliferation, platelet production, mRNA expression of PDGFR-β, and protein expression of p-Akt (P<0.05). Compared with the PDGF-BB group, the combination group (PDGF-BB 25 ng/mL + imatinib 20 μmol/L) had significantly lower levels of platelet production, mRNA expression of PDGFR-β, and protein expression of p-Akt (P<0.05).@*CONCLUSIONS@#PDGF-BB may promote megakaryocyte proliferation, differentiation, and platelet production by binding to PDGFR-β and activating the PI3K/Akt pathway, and the PDGFR-β inhibitor imatinib can reduce platelet production, which provides a new strategy for the treatment of thrombocytosis in KD.

Combination of socio-demographic and clinical co-variates for predicting treatment responses and outcomes in patients with chronic myeloid leukemia in the chronic phase / 中华血液学杂志

Objective: To explore the impacts of socio-demographic and clinical co-variates on treatment responses and outcomes in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitor (TKI) and identified the predictive models for them. Methods: Data of newly diagnosed adult patients with CML-CP receiving first-line TKI and having complete socio-demographic data and clinical information were reviewed. Cox model was used to identify the independent variables associated with complete cytogenetic response (CCyR) , major molecular response (MMR) , molecular response 4 (MR(4)) and molecular response 4.5 (MR(4.5)) , as well as failure-free survival (FFS) , progression-free survival (PFS) , overall survival (OS) and CML-related OS. Results: A total of 1414 CML-CP patients treated with first-line imatinib (n=1176) , nilotinib (n=170) or dasatinib (n=68) were reviewed. Median age was 40 (18-83) years and 873 patients (61.7% ) were males. Result of the multivariate analysis showed that lower educational level (P<0.001-0.070) and EUTOS long-term survival intermediate or high-risk (P<0.001-0.009) were significantly associated with lower cumulative incidences of CCyR, MMR, MR(4) and MR(4.5), as well as the inferior FFS, PFS, OS and CML-related OS. In addition, those who were males, from rural households, had white blood cells (WBC) ≥120×10(9)/L, hemoglobin (HGB) <115 g/L and treated with first-line imatinib had significantly lower cumulative incidences of cytogenetic and/or molecular responses. Being single, divorced or widowed, having, rural household registration, WBC≥120×10(9)/L, HGB<15 g/L, and comorbidity (ies) was significantly associated with inferior FFS, PFS, OS, and/or CML-related OS. Thereafter, the patients were classified into several subgroups using the socio-demographic characteristics and clinical variables by cytogenetic and molecular responses, treatment failure and disease progression, as well as overall survival and CML-related OS, respectively. There were significant differences in treatment responses and outcomes among the subgroups (P<0.001) . Conclusion: Except for clinical co-variates, socio-demographic co-variates significantly correlated with TKI treatment responses and outcomes in CML-CP patients. Models established by the combination of independent socio-demographic and clinical co-variates could effectively predict the responses and outcome.

Quimioterapia intensiva asociada a imatinib en leucemia linfoblástica aguda del adulto, Philadelphia positivo. Experiencia en un hospital público / Intensive chemotherapy with tyrosine kinase inhibitors in philadelphia-positive acute lymphoblastic leukemia

Background: Before the advent of tyrosine kinase inhibitors (TKIs), patients with Philadelphia-positive Acute Lymphoblastic Leukemia (Ph+ALL) had a poor prognosis. The association of TKIs to intensive chemotherapy (CT) improved outcome. Aim: To evaluate results of an intensive CT protocol including TKI in a public hospital in Santiago, Chile. Material and Methods: All patients with Ph+ALL diagnosed between January 2010 and February 2019, and who met inclusion criteria for intensive CT, received the Ph+ALL national protocol in association with imatinib and were included in this analysis. Results: Thirty-five patients aged 15 to 59 years received treatment. Complete response (CR) was obtained in 97%. Measurable residual disease (MRD) was negative in 61% (19/31 evaluable cases) during follow-up, and 55% (16/29) were MRD (-) before three months. Relapse was observed in 13 cases. Three patients underwent allogeneic hematopoietic stem cell transplant (HSCT), two in CR1. The overall survival (OS) and event-free survival (EFS) at three years were 52 and 34%, respectively. In patients who achieved MRD negativity before three months, no statistically significant differences in OS (64 and 42% respectively, p = 0.15) or EFS (35 and 32% respectively, p = 0.37) were observed. Conclusions: The prognosis of Ph+ALL improved with the association of imatinib to intensive CT. MRD-negative status before three months in this series was not significantly associated with better outcomes. Our series suggests that the Ph+ALL national protocol associated to TKI is a therapeutic alternative with high CR and aceptable MRD (-) rates.

Therapeutic Effect of Imatinib Made in Real World to Newly Diagnosed Chronic Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To evaluate the clinical efficacy and safety of domestic imatinib (made in China) in patients with newly diagnosed chronic myeloid leukemia chronic phase(CML-CP).@*METHODS@#Fifty-seven newly diagnosed CML-CP patients who did not receive any other anti-CML treatment were treated by domestic imatinib 400 mg once a day. The hematological, cytogenetic and molecular reactions and safety were observed and evaluated after 3, 6 and 12 months of treatment.@*RESULTS@#Fifty-six patients were treated for ≥3 and 6 months, among which 50 patients were treated for ≥12 months. After 3 months of treatment, 49 patients underwent hematological examination, 47 patients (95.9%) achieved complete hematological response (CHR), 49 patients underwent cytogenetic examination, 39 patients (79.6%) achieved major cytogenetic response (MCyR), and 12 patients (24.5%) achieved complete cytogenetic response (CCyR). 49 patients underwent the level of BCR-ABL test, including 41 patients (83.7%) with BCR-ABL@*CONCLUSION@#In the real world, Domestics imatinib mesylate is effective and safe in the treatment of newly diagnosed CML-CP patients, but long-term follow-up data are still necessary to verify its long-term efficacy.

Significance of circulating tumor cell monitoring in targeted therapy for gastrointestinal stromal tumors / 中华胃肠外科杂志

Objective: To explore the significance of circulating tumor cell (CTC) monitoring in evaluating the efficacy of targeted therapy for gastrointestinal stromal tumor (GIST). Methods: A prospective cohort study was performed. The data of patients with locally advanced GIST or liver metastasis who were admitted to The Affiliated Hospital of Nantong University from August 2013 to December 2018 were collected. Inclusion criteria: (1) patients aged older than 18 years; (2) patients who were diagnosed with GIST based on pathology; (3) patients without surgery, whose preoperative imaging evaluation of GIST found the violations of the surrounding organs or partial transfer of an estimated difficulty to achieve R0 resection, or the maximum diameter of the tumor > 10 cm, or the liver metastasis, or the expectation of higher risk of surgical complications; (4) patients who were treated with the imatinib 400 mg/d for the first time; (5) Eastern Cooperative Oncology Group (ECOG) score of 0-2. Exclusion criteria: (1) genetic testing revealed a D842V mutation in exon 18 of the PDGFRA gene; (2) alanine aminotransferase and/or aspartate aminotransferase > 2.5 times the normal upper limit; (3) serum total bilirubin >1.5 times of normal upper limit; (4) neutrophil count < 1.5×10(9)/L, or platelet count < 75×10(9)/L, or hemoglobin < 60 g/L; (5) creatinine > normal upper limit; (6) patients had serious cardiovascular and cerebrovascular diseases within 12 months before enrollment; (7) female patients were pregnant or lactating; (8) patients suffered from other serious acute and chronic physical or mental problems, and were not suitable for participating in this study judged by researchers. The patients who could not tolerate treatment regimen, or developed serious adverse reactions and did not follow the medication scheme after enrollment were excluded. Before imatinib treatment and 1-month and 2-month after treatment, quantitative PCR was used to detect the DOG-1 expression of monocytes in peripheral blood, and the ratio of DOG-1/β-actin > 3×10(-5) was used as the CTC positive threshold of GIST. The positive rate of CTC, the efficacy of imatinib treatment (complete response, partial response, stable disease, progressive disease, and occurrence of adverse reactions), and the relationship between CTC positive rate and clinicopathological characteristics of patients were analyzed. Furthermore, the ratio of DOG-1 decrease/baseline DOG-1 after 1-month of treatment was used as an indicator to evaluate whether targeted therapy was effective. The receiver operating characteristic (ROC) curve was rendered, and the area under the curve (AUC) was calculated. Results: A total of 68 GIST patients were enrolled in this study, including 39 cases of locally advanced GIST and 29 cases with liver metastases, 32 males and 36 females with the mean age of (51.2±11.8) (range 31 to 74) years. After 2-month of imatinib treatment, 43 cases were evaluated as partial response, 11 cases as stable disease, and 14 cases as progressive disease, with an effective rate of 79.4% (54/68). During the treatment of imatinib, the incidence of grade 3 or higher adverse reactions was 22.1% (15/68), including 12 cases of grade 3 neutropenia and 3 of grade 4 drug eruption, which were all relieved after conservative treatment. The positive rates of CTC in 68 patients before treatment, 1-month and 2-month after treatment were 66.2% (45/68), 41.2% (28/68) and 23.5% (16/68), respectively. The positive rate of CTC was associated with tumor size, liver metastasis, mitotic count and risk level (all P<0.05). By analyzing the effective group and the ineffective group of targeted therapy, it was found that the positive rate of CTC in the effective group showed a decreasing trend, while the positive rate of CTC in the ineffective group showed an increasing trend. The AUC of predicting the efficacy of targeted therapy for GIST was 0.823 by detecting the change trend of CTC 1-month after treatment (P<0.001). When the DOG-1 content decreased by more than 57.5% 1-month after treatment, it can be used as an indicator to judge the effectiveness of the treatment, whose sensitivity was 72.2% and specificity was 100%. Conclusion: The detection of peripheral blood CTC can evaluate the efficacy of targeted therapy in GIST patients and can provide decision-making basis for further clinical treatment.

Adherence to adjuvant with therapy imatinib in patients with gastrointestinal stromal tumor: a national multi-center cross-sectional study / 中华胃肠外科杂志

Objective: To analyze the current adherence to imatinib in patients with gastrointestinal stromal tumors (GIST) in China and its influencing factors. Methods: A cross-sectional survey was conducted. Study period: from October 1, 2020 to November 31, 2020. Study subjects: GIST patients taking imatinib who were diagnosed and treated in public tertiary level A general hospitals or oncology hospitals; those who had not been pathologically diagnosed, those who never received imatinib, or those who had taken imatinib in the past but stopped afterwards were excluded. The Questionnaire Star online surgery platform was used to design a questionnaire about the adherence to adjuvant imatinib therapy of Chinese GIST patients. The link of questionnaire was sent through WeChat. The questionnaire contained basic information of patients, medication status and Morisky Medication Adherence Scale. Results: A total of 2162 questionnaires from 31 provinces, autonomous regions, and municipalities were collected, of which 2005 were valid questionnaires, with an effective rate of 92.7%. The survey subjects included 1104 males and 901 females, with a median age of 56 (22-91) years old. Working status: 609 cases (30.4%) in the work unit, 729 cases (36.4%) of retirement, 667 cases of flexible employment or unemployment (33.3%). Education level: 477 cases (23.8%) with bachelor degree or above, 658 cases (32.8%) of high school, 782 cases (39.0%) of elementary or junior high school, 88 cases (4.4%) without education. Marital status: 1789 cases (89.2%) were married, 179 cases (8.9%) divorced or widowed, 37 cases (1.8%) unmarried. Two hundred and ninety-four patients (14.7%) had metastasis when they were first diagnosed, including 203 liver metastases, 52 peritoneal metastases, and 39 other metastases. One thousand eight hundred and sixty-nine patients underwent surgical treatment, of whom 1642 (81.9%) achieved complete resection. The median time of taking imatinib was 25 (1-200) months. Common adverse reactions of imatinib included 1701 cases (84.8%) of periorbital edema, 1031 cases (51.4%) of leukopenia, 948 cases (47.3%) of fatigue, 781 cases (39.0%) of nausea and vomiting, 709 cases (35.4%) of rash, and 670 cases (33.4%) of lower extremity edema. The score of the Morisky Medication Adherence Scale showed that 392 cases (19.6%) had poor adherence, 1023 cases (51.0%) had moderate adherence, and 590 cases (29.4%) had good adherence. Univariate analysis showed that gender, age, work status, economic income, residence, education level, marriage, the duration of taking medication and adverse reactions were associated with adherence to adjuvant imatinib therapy (all P<0.05). Multivariate analysis showed that female (OR=1.264, P=0.009), non-retirement (OR=1.454, P=0.001), monthly income ≤4000 yuan (OR=1.280, P=0.036), township residents (OR=1.332, P=0.005), unmarried or divorced or widowed (OR=1.362, P=0.026), the duration of imatinib medication >36 months (OR=1.478, P<0.001) and adverse reactions (OR=1.719, P=0.048) were independent risk factors for poor adherence to adjuvant imatinib. Among patients undergoing complete resection, 324 (19.7%) had poor adherence, 836 (50.9%) had moderate adherence, and 482 (29.4%) had good adherence. Meanwhile, 55 patients with good adherence (11.4%) developed recurrence after surgery, 121 patients with moderate adherence (14.5%) developed recurrence, 61 patients with poor adherence (18.8%) developed recurrence, and the difference was statistically significant (P=0.017). Conclusions: The adherence to adjuvant therapy with imatinib in Chinese GIST patients is relatively poor. Females, non-retirement, monthly income ≤4000 yuan, township residents, unmarried or divorced or widowed, the duration of imatinib medication >36 months, and adverse reactions are independently associated with poor adherence of GIST patients. Those with poor adherence have a higher risk of recurrence after surgery. Positive interventions based on the above risk factors are advocated to improve the prognosis of patients with GIST.

Definition of tumor rupture in gastrointestinal stromal tumor / 中华胃肠外科杂志

Tumor rupture is a common clinical event in the process of tumorigenesis, progression, diagnosis and treatment of gastrointestinal stromal tumor, which is closely associated with tumor recurrence, metastasis and poor prognosis. Tumor rupture may be associated with some intrinsic biological aggressiveness qualities, such as large tumor size, high mitotic count, and KIT exon 11 deletion mutations involving codons 557 and 558, and may be relatively more frequent with small intestine GIST and excellent response to imatinib neoadjuvant therapy resulting in tumor tissue rapid liquefacient and necrosis. The triggering factors involve sudden increase in abdominal pressure, external pressure, collision and improper surgical operation, etc. Tumor rupture is considered as an important risk factor of recurrence after macroscopically complete resection of tumor, and an indication for determining interval or even lifelong adjuvant therapy with imatinib according to guidelines. However, there is no consensus or universally accepted definition of tumor rupture, and, consequently, its incidence varies greatly across reported series and lacks detailed epidemiological data. Without pre-defined criteria, it is difficult to assess the clinical significance of rupture. We reviewed the relevant literature and international guidelines, and generally divided tumor rupture into spontaneous rupture and iatrogenic rupture. Based on the Oslo criteria, we proposed the following six definitions for tumor rupture: (1) tumor fracture or spillage; (2) blood-stained ascites; (3) gastrointestinal perforation at the tumor site; (4) microscopic infiltration of an adjacent organ; (5) intralesional dissection or piecemeal resection; (6) incisional biopsy. The following types of minor defects of tumor integrity should not be defined as rupture: (1) mucosal defects or spillage contained within the gastrointestinal lumen; (2) microscopic tumor penetration of the peritoneum or iatrogenic damage only to the serosa; (3) uncomplicated transperitoneal needle biopsy; (4) R1 resection. In addition, we further emphasize the importance of identifying risk factors of tumor rupture, prevention and positive intervention.

Renal tuberculosis in an imatinib-treated chronic myeloid leukemia / Tuberculose renal em paciente com leucemia mieloide crônica tratado com imatinibe

ABSTRACT Imatinib, which inhibits tyrosine kinase activity of Bcr-Abl protein, is a standard form of treatment for chronic myeloid leukemia (CML). Through its immunomodulatory effect it affects T cell function in a number of ways. It inhibits antigen-induced T cell activation and proliferation. Antigen-specific T-cells and macrophages are vital for protection against Mycobacterium tuberculosis. Here we present a case of renal tuberculosis associated with imatinib therapy in the maintenance phase of CML. With granulomatous interstitial nephritis and positive tubercular DNA on renal biopsy, the condition was successfully treated with anti-tubercular therapy. This case provides support to the hypothesis that imatinib therapy in CML increases the susceptibility to tuberculosis and strict vigilance is required to enable its early detection and treatment.

RESUMO O imatinibe, um inibidor da atividade da tirosina-quinase da proteína BCR-ABL, faz parte do padrão de tratamento para leucemia mieloide crônica (LMC). Por conta de seu efeito imunomodulador, o imatinibe afeta a função dos linfócitos T de várias maneiras ao inibir a sua ativação e proliferação induzidas por antígenos. Linfócitos T e macrófagos antígeno-específicos são vitais para a proteção contra o Mycobacterium tuberculosis. O presente artigo relata um caso de tuberculose renal associada a terapia com imatinibe na fase de manutenção da LMC. Com nefrite intersticial granulomatosa e positividade para DNA de M. tuberculosis na biópsia renal, o paciente foi tratado com sucesso com terapia antituberculínica. O presente caso corrobora a hipótese de que a terapia com imatinibe na LMC aumenta a suscetibilidade à tuberculose, exigindo vigilância rigorosa para permitir sua detecção e tratamento precoces.

Informe diário de evidências COVID-19: busca realizada em 2 de julho de 2020 / COVID-19 daily evidence report: search conducted on July 2, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 17 artigos e 9 protocolos.

A rectal gastrointestinal stromal tumor - a plea for neoadjuvant imatinib and TAMIS / Tumor estromal gastrointestinal no reto - um caso de uso de imatinibe neoadjuvante e TAMIS

Abstract Here we describe an infrequent case of gastrointestinal stromal tumor of the rectum in a 57 year-old man with spindle cell neoplasm probably gastrointestinal stromal tumor and CT scan showed tumor from the anterior rectal wall and offered abdominoperineal resection for the same. The patient was started on imatinib and had a significant reduction in symptoms. The patient was reassessed with the CT scan, which showed a reduction in tumor size and Transanal minimally invasive surgery was planned for the patient. Use of imatinib prior to surgical resection to attain the reduced size of the tumor within the limit of resection is an attractive approach. Since tumor development can happen rapidly again after substantial tumor shrinkage, the best time to operate depending on resectability and the maximum therapeutic outcome remains divisive.

Resumo No presente estudo, os autores descrevem um caso raro de tumor estromal gastrointestinal no reto em um homem de 57 anos que se apresentou com neoplasia de células fusiformes, com provável tumor estromal gastrointestinal. A tomografia computadorizada demonstrou tumor na parede anterior do reto e foi sugerida sua ressecção abdominoperineal. O paciente iniciou tratamento com imatinibe e apresentou uma redução significativa nos sintomas. O paciente foi reavaliado por tomografia computadorizada, que evidenciou redução do tamanho do tumor; portanto, foi indicada cirurgia transanal minimamente invasiva. O tumor era ressecável e foi necessário um extenso acompanhamento para romper o órgão, de forma a alcançar a ressecção máxima; caso contrário, o tumor estromal gastrointestinal também seria irressecável. O uso de imatinibe antes da ressecção cirúrgica para reduzir o tamanho do tumor dentro do limite de ressecção é uma abordagem interessante. Como o tumor pode se crescer rapidamente após ser substancialmente reduzido, a literatura ainda apresenta controvérsias quanto ao melhor momento para operar e quanto ao melhor desfecho terapêutico.

Clinic-pathological aspect of gastro-intestinal stromal tumors at tertiary care Hospital India / Aspecto clínico e patológico dos tumores estromais gastrointestinais em hospital terciário da Índia

Abstract Background This study defines the disease profile in south Indian population and determine the clinic-pathological aspects of Gastro-Intestinal Stromal Tumors. Method In this prospective study patients diagnosed of gastrointestinal stromal tumors were taken thorough clinical examination and a database of Anthropometric details and clinical details were analyzed. Pathological data included tumor size, presence or absence necrosis, mitotic counts, immunohistochemistry for CD-117, CD-34. Results There were 44 patients with confirmed diagnosis of gastro-intestinal stromal tumor. The highest incidence was found in the 6th decade. The most common symptoms were abdominal pain and gastrointestinal bleed. Stomach was most frequent site for gastro-intestinal stromal tumors. Immunochemistry for CD-117 was positive in 93.18% cases. Majority of tumors (79.5%) had pure spindle cell morphology and mitotic activity showed that 34% of the GISTs were of the high risk group. Forty two patients were suggestive of surgery as the primary treatment after presentation. Conclusion Abdominal pain was the most common presenting complaint. Majority of the tumors aroused from the stomach. The majority of the tumors had pure spindle cell morphology and 93% of the tumors were CD-117 positive. A significant relationship between tumor size, tumor necrosis and mitotic activity with large tumors having necrosis and high mitotic rate having high risk of malignancy, was observed. Surgical resection is considered mainstay of treatment of gastro-intestinal stromal tumor. Imatinib therapy should be given to patients in moderate to severe risk categories.

Resumo Justificativa Este estudo define o perfil da doença na população do sul da Índia e determina os aspectos clínicos e patológicos dos tumores estromais gastrointestinais. Método Neste estudo prospectivo, os pacientes diagnosticados com tumor estromal gastrointestinl foram submetidos a um exame clínico completo, e uma série de dados dos pacientes, incluindo detalhes antropométricos e clínicos, foram analisados. Os dados patológicos incluíram tamanho do tumor, presença ou ausência de necrose, contagem mitótica e imuno-histoquímica para CD-117, CD-34. Resultados Havia 44 pacientes com diagnóstico confirmado de tumor estromal gastrointestinal. A maior incidência foi encontrada na 6ª década de vida. Os sintomas mais comuns foram dor abdominal e sangramento gastrointestinal. O estômago foi o local mais frequente para tumores estromais gastrointestinais. A imuno-histoquímica para CD-117 foi positiva em 93,18% dos casos. A maioria dos tumores (79,5%) apresentava morfologia pura de células fusiformes e a atividade mitótica mostrou que 34% dos GISTs pertenciam ao grupo de alto risco. Quarenta e dois pacientes receberam indicação para cirurgia como tratamento primário após a apresentação. Conclusão A dor abdominal foi a queixa mais comum. A maioria dos tumores afetava o estômago, apresentava morfologia pura de células fusiformes e 93% eram CD-117 positivos. Foi observada uma relação significativa entre o tamanho do tumor, a necrose tumoral e a atividade mitótica, com os tumores grandes apresentando necrose e alta taxa mitótica com alto risco de malignidade. A ressecção cirúrgica é considerada o principal tratamento do tumor estromal gastrointestinal. A terapia com imatinibe deve ser administrada a pacientes em categoria de risco de moderadas a grave.

Evaluation of anemia after long-term treatment with imatinib in chronic myeloid leukemia patients in chronic phase

ABSTRACT Introduction: The incidence of grade 3-4 anemia was reported to be 3% with imatinib therapy for newly diagnosed chronic myeloid leukemia (CML) in the chronic phase (CP). However, there are few data regarding the causes and the development of anemia after long-term treatment. This study aimed to evaluate the incidence of anemia after at least two years of imatinib treatment of CML patients in the CP and to identify other contributing causes of anemia in this population. Patients and methods: We performed a retrospective analysis of 97 CML patients in the CP treated with imatinib for at least two years. We analyzed the hemoglobin (Hb) levels of CML patients at diagnosis, upon initiation of treatment with imatinib and after two years of imatinib treatment, and investigated other causes of anemia in this population. Results: Most of the patients presented Hb levels below the normal range (80.4%) after the second year of treatment, 17.9% grade 2 and 1.3% grade 3. In 13 cases (16.7%), anemia was attributed to resistance and in 13 cases (16.7%) the following causes were identified: iron deficiency (n = 5), hypothyroidism (n = 2), vitamin B12 deficiency (n = 3), acquired immune deficiency syndrome (AIDS) (n = 1), pulmonary tuberculosis (n = 1) and renal toxicity (n = 1). In 52 patients (66.6%), there were no other factors contributing to anemia, except imatinib treatment. Conclusion: Regular follow-up is required to identify the causes of anemia not related to CML or imatinib toxicity. The importance of investigating secondary causes of anemia should be emphasized, especially in patients with good adherence to treatment and satisfactory therapeutic response.

Isocromosoma Filadelfia en dos pacientes con leucemia mieloide crónica / Philadelphia isochromosome in two patients with chronic myeloid leukemia

RESUMEN El cromosoma Filadelfia (Ph por su abreviatura del inglés "Philadelphia") se presenta en más del 90 % de los pacientes con leucemia mieloide crónica. Un cromosoma Ph extra es una de las alteraciones secundarias comúnmente observada como evolución clonal de la enfermedad y se puede presentar como un derivativo adicional o un isocromosoma del 22 derivativo. Es una alteración adquirida durante la progresión de la enfermedad con implicación pronóstica. Se presentan dos casos con diagnóstico de leucemia mieloide crónica, resistentes al tratamiento con mesilato de imatinib. En el estudio cromosómico con técnica de banda G se observaron en ambos pacientes líneas celulares con dos isocromosomas del derivativo del 22, 2ider (22) t (9; 22). El primer caso falleció en crisis blástica y el segundo luego de no responder al tratamiento de primera línea, se le indicó nilotinib pero su evolución fue no satisfactoria. Las alteraciones cromosómicas secundarias están asociadas con un impacto negativo en la supervivencia y progresión a fase acelerada y crisis blástica de la enfermedad.

ABSTRACT The Philadelphia chromosome (Ph) is present in more than 90% of patients with chronic myeloid leukemia. An extra Ph chromosome is one of the secondary alterations commonly observed in clonal evolution and it could be as na additional derivative or anisochromosome of the derivative. It is na alteration acquired during the progression of the disease with prognostic implications. We present two cases with a diagnosis of chronic myeloid leukemia, Who showed resistance to treatment with imatinib mesylate. In both patients,the chromosomal study with G-band technique, show cell lines with two isochromosomes from the derivative of 22, 2ider(22)t(9; 22). The first case died in blast crisis and to the second after not responding to the first line treatment, was precribed nilotinib but the evolution was unsatisfactory. Secondary chromosomal alterations are associated with a negative impact on survival and the progression to accelerated phase and blast crisis of the disease.

Modificación del abordaje quirúrgico en tumores estromales gástricos posterior a neoadyuvancia con Imatinib / Change of surgical approach in gastrointestinal stromal tumors after neoadyuvant therapy with Imatinib

Resumen Introducción: El tratamiento de los tumores estromales gastrointestinales (GIST) de alto riesgo es quirúrgico. Su resultado podría variar al usarse neoadyuvancia. Objetivo: Evaluar si el uso de la terapia neoadyuvante con imatinib puede cambiar el abordaje quirúrgico en los tumores estromales gastrointestinales de alto riesgo. Materiales y Métodos: Se realizó un análisis retrospectivo en el Hospital Clínic de Barcelona entre enero de 2002 y mayo de 2016. Resultados: Se obtuvo un total de 8 pacientes. La edad media fue 66,1 ± 13,3 años. La ubicación del tumor fue de 37,5% (3) en el tercio superior, el 50% (4) en el tercio medio y el 12,5% (1) en el tercio inferior. Debido a la clasificación de riesgo alto, la ubicación y/o la necesidad de resecciones multiviscerales, se indicó, previa evaluación comité oncológico, realizar terapia neoadyuvante. La mediana de tiempo de neoadyuvancia fue de 30 semanas. En el 100% (8) de los casos se logró un cambio de enfoque quirúrgico después de la utilización de imatinib. En todos los casos se realizó un resección local (7 laparoscópica y 1 endolaparoscópica) con márgenes negativos La biopsia posoperatoria mostró un promedio de 51,2% de reducción del tamaño tumoral inicial, lo que resultó en una diferencia estadística (p < 0,01) con el tamaño inicial de las lesiones. Durante el seguimiento, tanto la sobrevida relacionada al tumor como la global, fue de un 100%. Conclusión: La terapia neoadyuvante podría cambiar el abordaje quirúrgico de los pacientes con GIST gástrico de riesgo intermedio o alto mediante la reducción del tamaño tumoral, permitiendo realizar cirugías más económicas y logrando resultados oncológicos adecuados.

Introduction: The treatment of high-risk gastrointestinal stromal tumors (GIST) is surgical. Results may change when using neoadjuvant. Objetive: To evaluated if the use of neoadjuvant therapy with imatinib can change the surgical approach in high risk gastrointestinal stromal tumors (GIST). Materials and Methods: A retrospective analysis was performed from a prospective collected database in Hospital Clinic of Barcelona between January 2002 and May 2016. Results: A total of 8 patients were analyzed with a mean age of 66.1 ± 13.3 years. The tumor location was upper third 37.5% (3) cases, 50% (4) in the middle third and 12.5% (1) in lower third. Because of high risk classification, location and the need of multivisceral resections, neoadjuvant therapy was indicated. The median time of neoadjuvant therapy was 30 weeks. In 87.5% (7) cases a change of surgical approach was achieved after the use of imatinib. In 100% of our series laparoscopic wedge resection was performed achieving negative margins of resection. The postoperative biopsy showed 51.2% of reduction of initial tumor size, resulting in statistical difference (p < 0.01). All patients are alive and 100% of tumor related survival was achieved. Conclusion: Neoadjuvant therapy maybe can change the surgical approach of patients with high-intermediate risk gastric GIST by reducing tumor size. This response also eventually can achieve optimal oncological outcome.

Tumor del estroma gastrointestinal y trasplante renal / Gastrointestinal stromal tumor and renal transplant

El tumor estromal gastrointestinal (GIST) representa alrededor del 1% de todos los tumores digestivos y su aparición en pacientes trasplantados renales es infrecuente. Aproximadamente el 95% muestra tinción positiva para c-kit/CD117. DOG1 es un anticuerpo recientemente descrito que se sobre-expresa en los GIST, incluso en c-kit/ CD117 negativos. El diagnóstico preciso de GIST resulta imperativo, debido a la disponibilidad y la creciente eficacia de los inhibidores de la tirosina quinasa en estos tumores, incluso en el subgrupo c-kit/ CD117 negativo. Se presenta el caso de una mujer trasplantada renal inicialmente con GIST en intestino delgado y débil positividad para CD117 tratada con cirugía y recidiva tumoral a los tres años, pérdida de la expresión CD117 y tinción positiva para DOG1. Recibió tratamiento exitoso con imatimib sin presentar recaída tumoral durante un seguimiento de cinco años.

Gastrointestinal stromal tumor (GIST) accounts for nearly 1% of all gastrointestinal tumors. Its association with renal transplantation is not frequent. Approximately 95% of GIST show staining for CD177. DOG1 is a recently described monoclonal antibody that shows positivity even in the absence of CD177 staining. The diagnosis of GIST should be pursued because of the availability of very effective treatments with tyrosine-kinase inhibitors. Herein, we describe the case of a woman with renal transplant who presented a small bowel GIST and weak positivity for CD177, treated initially with surgery. Tumor recurrence was documented 3 years later and histopatology showed loss of CD177 staining and positivity for DOG1. She was treated with imatimib without further recurrence after five years of follow up.