Median Time Of Appearance Research Articles

The CXCR4dim/CD5bright Proliferative Fraction Reappears in Relapsed CLL Under Ibrutinib, Enriched in BTK Mutations

BTK inhibitors deeply affect the proliferative capacity, homing and migrations of chronic lymphocytic leukemia (CLL) cells, and cause their redistribution from nodal compartments to the blood stream. Reciprocal expression of CXCR4 and CD5 on circulating CLL cells is an established marker discriminating the proliferative fraction (CD5high/CXCR4dim, PF), recently egressed from the lymph node, from the resting fraction (CXCR4high/CD5dim, RF) of older, quiescent cells navigating the blood stream. We monitored the dynamics of the PF under the course of ibrutinib therapy in 31 CLL cases recruited in the IOSI-EMA-001 study (NCT02827617) with sequential blood sampling (156 samples, median 6 samples/case, range 3-7). PF was monitored through fixed gates, designed on the pre-treatment sample around the population visually detaching from the main cluster (panel A). Longitudinal analysis showed a depletion of the PF over time, from a median of 17.7% at pre-treatment to 4.75, 0.4, 1.5, 0.6, 1.5% at subsequent timepoints (0.5, 6, 12, 18, 24 months; range 0-50; p < 0.001, U test). Loss of proliferative potential was confirmed by concurrent loss of Ki67 expression. We retrospectively analyzed the PF from a second cohort of 99 ibrutinib-treated CLL cases from the real world, referred for routine immunophenotyping (278 samples, median 3 samples/case, range 2-7). Median PF of pre-ibrutinib samples was 12.0% (range 0.7-50%), with a significant drop to 2.7% after 1 year of treatment and to 1.0% after 2 years (p<0.001, U test). Out of 99 cases, 55 discontinued ibrutinib within 5 years (16 toxicity, 38 progression/relapse, 1 death; median time of treatment 29.7 months, range 1-58.6 months). Median PF in samples collected after ibrutinib discontinuation was 1.15% after 2 years of treatment, and increased to 13.3, 7.10, 6.30, 12.0% after 3, 4, 5 and >5 years. Conversely, samples collected under ibrutinib treatment presented a more stable trend of median PF (3.0 and 3.5% after 3 and 4 years respectively). Interestingly, of 27 patients with blood samples collected during the third year of therapy, 11 failed ibrutinib due to relapse/progression within the following two years: these cases presented a higher median PF (10.0%) than cases who stayed on ibrutinib (median PF 1.8%, p=0.045). Mutations of BTK/PLCG2 were detected in 28/99 cases (28.2%); among these, 18 (64.2%) discontinued ibrutinib due to progression/relapse (17/18) or toxicity (1/18), whereas 10 cases, although mutated, remained on treatment. Median time of appearance of BTK/PLCG2 mutations was 48 months (range 16-70). Median VAF was 22.8 (range 1.2-99.0) and 3.5 (range 1.7-17.6) for BTK and PLCG2, respectively. We isolated the PF and RF fractions from 10 cases developing BTK/PLCG2 mutations, who showed reappearance of the PF after prolonged ibrutinib treatment (median 50.7 months). Sequencing revealed 1.7 mean BTK mutations per sample (range 1-4), with a median VAF higher in the PF (23.0%, range 0.3-92.3) than in the RF (5.15%, range 0.1-84.8; p=0.0027, paired rank test); overall, the PF VAF was almost 3 times larger than the RF (average 2.82, range 0.01-38). Accompanying PLCG2 mutations were present in 6 cases, generally more frequent (average 3.7 mutations per case, range 1-8) but with lower burden (median VAF 1.7%, range 0.1-4.3) than BTK mutations; again, average the PF fraction had higher VAF than the RF (average PF: 2.0, range 0.1-6.2; average RF: 1.35, range 0.4-2.8; p=0.0142) (panel B). Finally, we performed mRNA-seq on 6 cases relapsed after ibrutinib, isolating the RF and the newly reconstituted PF, the latter enriched in BTK mutations, with matching fractions isolated from pre-ibrutinib samples. Differential expression signature of PF vs. RF at pre-treatment was concordant with published gene sets (e.g. Calissano et al. Mol Med 2011); application of this signature to post-ibrutinib PF/RF fractions drove co-clustering of 12 out of 13 fractions with their respective pre-treatment counterparts, suggesting that the reconstituted PF fraction at relapse is functionally similar to the original pre-treatment PF. Overall, our data support the hypothesis that, in patients undergoing ibrutinib treatment, BTK/PLCG2 mutations arise within the lymph nodes, the proliferative compartment of CLL; clinically, longitudinal monitoring of the CXCR4/CD5 fractions by flow cytometry may provide a simple tool helping to intercept CLL progression under ibrutinib therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Incidence and Risk Factors for Acute Kidney Injury after Allogeneic Stem Cell Transplantation: A Prospective Study.

(1) Background: Acute kidney injury (AKI) is a serious complication of hematopoietic stem cell transplantation (HSCT). (2) Methods: The aim was to identify the incidence, severity, and risk factors for AKI during the first 100 days after allo-HSCT; we performed a prospective observational study on 135 consecutive patients. (3) Results: The mean age was 38.3 ± 11.9 years (50.6% females), AKI developed in 93 patients (68.9%), the median time of appearance was 28 days, and the mean serum creatinine at the time of AKI was 1.8 ± 0.8 mg/dL. A total of 36 (38.7%) patients developed stage 1 AKI, 33 (35.5%) patients developed stage 2, and 24 (25.8%) patients developed stage 3; eight (8.6%) patients required temporary hemodialysis, and the mortality rate in these patients was 87.5%. Death was twice as frequent in the AKI subgroup, without statistical significance. Cyclosporine overdose (HR = 2.36, 95% CI: 1.45–3.85, p = 0.001), tacrolimus overdose (HR = 4.72, 95% CI: 2.22–10.01, p < 0.001), acute graft-versus-host disease (aGVHD) (HR = 1.96, 95% CI: 1.13–3.40, p = 0.01), and CRP level (HR = 1.009, 95% CI: 1.007–1.10, p < 0.001) were independent risk factors for AKI. Sepsis (HR = 5.37, 95% CI: 1.75–16.48, p = 0.003) and sinusoidal obstruction syndrome (HR = 5.10, 95% CI: 2.02–12.85, p = 0.001) were found as independent risk factors for AKI stage 3. (4) Conclusions: AKI occurs with high incidence and increased severity after allo-HSCT. Careful monitoring of calcineurin inhibitors and proper management of sepsis may reduce this risk.

Clinical Profile of Posterior Reversible Encephalopathy Syndrome(PRES)-Related Epilepsy in Patients Following Haploidentical Hematopoietic Stem Cell Transplantation:a 10-Year Study

AbstractIntroductionPosterior reversible encephalopathy syndrome (PRES) is a clinical-neuroradiological entity characterized by seizures, headache, altered mental status and visual disturbances associated with typical transient lesions on magnetic resonance imaging (MRI). Haploidentical hematopoietic stem cell transplant (haplo-HSCT) is an upfront and effective therapy for hematological patients, but it has a large spectrum of neurological complications including PRES. Epilepsy is a common manifestation but there is no information on epilepsy following PRES. The aim of the present study was to describe clinical characteristics and potentially unrecognized risk factors for PRES-related epilepsy following haplo-HSCT.MethodsA nested case-control study was conducted at the Institute of Hematology, Peking University People's Hospital between January 2007 and July 2017.Forty patients with PRES-related epilepsy were identified, and 122 controls were matched for transplantation type, and time of transplantation. The diagnosis of PRES was based on characteristic clinical findings and characteristic findings of subcortical white matter lesions on CT or MRI of the brain. PRES-related epilepsy was defined as at least two unprovoked seizures occurring >24 h apart more than one month after the inciting episode with complete or near complete resolution of imaging abnormalities (Fisher RS, et al. Epilepsia 2014; Sha Z,et al. Epilepsy Behav 2015; Hinduja,et al. Epilepsy Behav 2016).Additionally, patients with prior history of epilepsy were excluded. A provoked seizure was defined as a seizure that occurred in the context of a precipitating cause that could lower the seizure threshold.ResultsForty patients were defined as PRES-related epilepsy. The cumulative incidences of the disease at 100 days, 1 year and 2 years post-transplantation were 0.4%, 1.7%, 2.2%, respectively.Magnetic resonance imaging (MRI) or computed tomography(CT) was collected during 4 days of the onset of epilepsy seizures. CT was performed in 3 patients. The median time of appearance for PRES-related epilepsy was 107.1 days(rang:15-839). The mean age at the time of presentation was 18 years(range:5-47). Eleven patients had acute myeloid leukemia,12 patients had acute lymphoblastic leukemia,4 patients had chronic myelogenous leukemia,6 patients had aplastic anemia,7 patients had myelodysplastic syndrome.Thirty-two patients (80%) were diagnosed with GVHD, and 8 patients (20%) had grade Ⅲ to IV GVHD before day 100.Five patients died from disease relapse,6 patients from infection.In univariate analysis, an increased risk of PRES-related epilepsy was associated with age (<10years/³10years), mean arterial pressure (MAP), hyponatremia, hypochloremia, serum lactate dehydrogenase (LDH) and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) (³1) were related to the occurrence of PRES-related epilepsy. Multivariate analysis showed that MAP (OR= 1.053,95% CI 1.031 to 1.075,P=0.000), hyponatremia (OR=1.27,95% CI 1.139 to 1.417,P=0.000), hypochloremia (OR=0.77,95% CI 0.692 to 0.856,P=0.000) and HCT-CI (³1) (OR=9.505, 95% CI 1.262 to 71.574,P=0.027) were risk factors for PRES-related epilepsy.The median follow-up for the survivors was 1423 days (rang:95-3018).The 10-year overall survival did not significantly differ between the two groups (PRES-related epilepsy 73.2% and control 82.8%,P = 0.184).ConclusionMAP, hyponatremia, hypochloremia and HCT-CI(³1) are related with the occurrence of PRES-related epilepsy after haplo-HSCT. PRES-related epilepsy had no influence on long-term survival. DisclosuresNo relevant conflicts of interest to declare.

Thyroid dysfunction related to vascular endothelial growth factor receptor tyrosine kinase inhibitors: A real-world study based on FAERS.

The adverse events of thyroid dysfunction caused by the use of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) have not been confirmed in a real-world investigation. The aim of this study was to evaluate the relationship between thyroid dysfunction and treatment using Food and Drug Administration (FDA)-approved VEGFR-TKIs. Four data-mining algorithms were employed to detect thyroid dysfunction signals for VEGFR-TKIs, using data in the FDA Adverse Event Reporting System (FAERS) database from 68 quarters. MySQL Workbench and R were used to conduct statistical analysis. We identified 32679 reports of thyroid dysfunction, of which 1567 listed VEGFR-TKIs as the primary suspected drugs. All four algorithms showed that the strength of the signals for hypothyroidism were greater than those for hyperthyroidism, for all the VEGFR-TKIs. In most cases, the median appearance time was within 100days of initiation of VEGFR-TKIs therapy, except in the case of ponatinib. This indicated the need to actively identify and manage thyroid dysfunction during the early stages of VEGFR-TKIs treatment. This study systematically identified the pharmacovigilance signals of thyroid dysfunction associated with the use of VEGFR-TKIs, using the FAERS database.

Patient-reported shoulder morbidity and fatigue among the breast cancer survivors: An insight from a Tertiary Care Cancer Hospital

Context: Breast cancer is the most common cancer in Indian women with an annual mortality of around 87,000. Treatment for breast carcinoma may lead to swelling of the ipsilateral arm and shoulder stiffness and arm pain and cancer-related fatigue. Very few centers in India have reported the arm and shoulder morbidity treated in their hospital. Aims: The study aims to evaluate the predictive factors of arm and shoulder morbidity and fatigue among the survivors. Settings and Design: Retrospective analysis from a prospectively maintained database. Materials and Methods: Early and locally advanced cases of breast cancer patients were screened for the study during 2015–2018. Eligible participants were invited to fill up the predetermined questionnaire and their demographic and treatment-related information was accrued from a file archive. Follow-up period was estimated from the date of tissue diagnosis to last contact/time of interview. Statistical Analysis Used: Predictive factors of shoulder morbidity and fatigue were analyzed by independent sample t-test and univariate analysis. Significant predictive factors were selected for further validation in the multivariate cox regression model. A P ≤ 0.05 was considered significant. Results: Shoulder stiffness was the most common complaint followed by arm numbness. Obesity and diabetes played a crucial role in most of the morbidities and fatigue. The median fatigue score was 34 and the median time of appearance of lymphedema was 13 months. Modified radical mastectomy, and radiotherapy to axilla were significantly associated with greater shoulder stiffness and arm swelling. Conclusions: Obesity, diabetes, type of surgery, the extent of axillary dissection, and radiation plan are the major predictive factors of arm and shoulder morbidity. Further prospective validation is necessary for future breast cancer survivorship programs.

Patient-Reported Shoulder Morbidity and Fatigue among Breast Cancer Survivors: An Insight from a Tertiary Care Cancer Hospital

Abstract Context: Breast cancer is the most common cancer in Indian women with an annual mortality of around 87,000. Treatment for breast carcinoma may lead to swelling of the ipsilateral arm, shoulder stiffness, arm pain, and cancer-related fatigue. Very few centers in India have reported the arm and shoulder morbidity treated in their hospitals. Aims: The aim was to evaluate the predictive factors of arm and shoulder morbidity and fatigue among breast cancer survivors. Settings and Design: This was a retrospective analysis based on a prospectively maintained database. Materials and Methods: Early and locally advanced cases of breast cancer patients were screened for the study during 2015–2018. Eligible participants were invited to fill up the predetermined questionnaire, and their demographic and treatment-related information was accrued from a file archive. Follow-up period was estimated from the date of tissue diagnosis to last contact/time of interview. Results: Shoulder stiffness was the most common complaint followed by arm numbness. Obesity and diabetes played a crucial role in most of the morbidities and fatigue. The median fatigue score was 34, and the median time of appearance of lymphedema was 13 months. Modified radical mastectomy and radiotherapy to axilla were statistically significantly (P = 0.04 and 0.01, respectively) associated with greater shoulder stiffness and arm swelling. Conclusions: Obesity, diabetes, type of surgery, the extent of axillary dissection, and radiation plan are the major predictive factors of arm and shoulder morbidity. Further prospective validation is necessary for future breast cancer survivorship programs.

Organizing pneumonia secondary to influenza infection: Two case reports and a literature review

BackgroundOrganizing pneumonia (OP) is a rare complication of influenza virus infection but scarce data are available. The recognition of this entity is important because require appropriate treatment. MethodsWe report two cases and perform a systematic review on PubMed database. Only cases with histological confirmation of OP and influenza virus positive laboratory test were included. ResultsWe collected 16 patients. Median age was 52 year, 20% of patients were smokers and 43.8% had not any comorbidity. Influenza A virus infection was diagnosed in 75%. Clinical manifestation consisted on a respiratory deterioration with a median time of appearance of 14 days. Radiological pattern observed was ground-glass opacities with consolidations. Survival was observed in 12 patients (75%). All three patients who did not receive steroid treatment died. ConclusionPhysicians must be aware that patients with influenza infection with a torpid course could be developing OP and prompt corticoid therapy should be instaured.

Organizing pneumonia secondary to influenza infection: Two case reports and a literature review

BackgroundOrganizing pneumonia (OP) is a rare complication of influenza virus infection but scarce data are available. The recognition of this entity is important because require appropriate treatment. MethodsWe report two cases and perform a systematic review on PubMed database. Only cases with histological confirmation of OP and influenza virus positive laboratory test were included. ResultsWe collected 16 patients. Median age was 52 year, 20% of patients were smokers and 43.8% had not any comorbidity. Influenza A virus infection was diagnosed in 75%. Clinical manifestation consisted on a respiratory deterioration with a median time of appearance of 14 days. Radiological pattern observed was ground-glass opacities with consolidations. Survival was observed in 12 patients (75%). All three patients who did not receive steroid treatment died. ConclusionPhysicians must be aware that patients with influenza infection with a torpid course could be developing OP and prompt corticoid therapy should be instaured.

EEG analysis in anti-NMDA receptor encephalitis: Description of typical patterns

ObjectiveTo describe different electroencephalogram (EEG) patterns and epileptic features in patients with anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE), their timeline in the course of the disease, their correlation with clinical data and outcome. MethodsWe retrospectively analyzed EEG recordings between November 2007 and June 2016 in 24 consecutive patients. ResultsThree EEG patterns were described: Excessive Beta Activity range 14–20 Hz (EBA) in 71% of patients, Extreme Delta Brush (EDB) in 58% and Generalized Rhythmic Delta Activity (GRDA) in 50%. They followed a chronological organization in the course of the disease: EBA appeared first, followed by EDB and then GRDA, as the median time of appearance for EBA, EDB and GRDA was respectively 10, 16.5 and 21.5 days. The presence of GRDA was strongly associated with concomitant abnormal movements (p < 0.001). ConclusionThis study focuses on EEG and epileptic abnormalities in anti-NMDARE. Beyond EDB that were already reported (Schmitt et al., 2012), GRDA seems to be a very frequent pattern. Its rhythmic aspect should not be misinterpreted as seizure or status epilepticus, to avoid antiepileptic treatments intensification. SignificanceThis study comforts the importance of EEG in anti-NMDARE, with a better description of EEG abnormalities for a better treatment management.

LONG-TERM FOLLOW-UP STUDY OF JUVENILE DIFFERENTIATED THYROID CARCINOMA TREATED BY RADIOACTIVE IODINE

The overall prognosis in pediatric differentiated thyroid carcinoma (DTC) is excellent. Recurrent disease is frequent, however, and requires additional treatment. In this study we retrospectively analyzed the outcome of juvenile DTC treated by radioactive iodine (I-131) during the long-term follow-up study of 29 years. Methods: 54 DTC patients (34 females, 20 males; ≤20 years old, mean age, 16,5 years) were treated with 131I (RAI) with a median follow-up of 13 years. Patients (pts) underwent different initial treatment: 49 pts, TTx+RAI; 2 pts, TTx; and 3 pts, STTx. The probability of recurrence and prognostic factors were tested by Kaplan-Meier’s method. Results: Initially, 37/54 pts achieved complete remission (CR), 16/54 pts partial remission (PR), 1/54 had progressive disease (PG). During the follow-up 11 pts (20,4%) who achieved CR developed recurrent disease (RD); median appearance time, 4 years (range, 1–25 years). Probability of recurrence was 15,8% at 5 years; 20,3% at 10 years, 25,6% at 15, 20 and 26 years after initial treatment. Strong predictive factors of recurrence were age (p=0,0001), initial treatment (p=0,0001), and tumor multifocality (p=0,004), while gender, nodal metastases at presentation, distal metastases at presentation, histological type of the tumor, tumor or T stage and clinical stage showed no influence on relapse (p=0,176; p=0,757; p=0,799; and p=0,822, respectively). Patients with RD, PR and PG were retreated, with surgery or surgery plus RAI, receiving cumulative activity up to 40 GBq. The overall outcome in our patients was excellent: 88,9% CR, 5,55% SD, 1,85% PG, 1,85% DRD, and 1,85% OCD. Conclusion: Younger age at diagnosis, less radical primary surgery without subsequent RAI, and tumor multifocality are strong prognostic factors for recurrence. In order to reduce relapse rate and to improve surveillance for recurrent disease, TTx followed by RAI appears to be the most beneficial initial treatment for patients with juvenile DTC. The use of RAI seems to be safe without adverse effects on subsequent fertility and pregnancy or secondary malignancy.

Infections in patients after Berlin Heart® EXCOR assist device implantation.

Berlin Heart® EXCOR devices (BHED) are ventricular assist devices (VAD) used mainly as a bridge to heart transplantation (HT) in pediatric population. The aim of our study is to report the infections diagnosed in adult patients undergoing a BHED implantation. Adult patients receiving a BHED between Jul 2009 and Oct 2017 at our institution were included. Infections were classified according to the International Society of Heart and Lung Transplantation definitions in VAD-Specific (VAD-S), VAD-Related (VAD-R) and non-VAD (N-VAD). Fifteen patients underwent BHED implantation, which was maintained for a mean of 92 (19-195) days. Infection occurred in 13 patients who developed 36 infectious episodes: 5 VAD-S (5 cannula infections); 8 VAD-R (5 bloodstream infections and 3 mediastinitis) and 24N-VAD (7 urinary tract infections, 6 Cytomegalovirus diseases and others). Overall, 27 (75%) were bacterial, 7 (19.4%) were viral and there was one (2.7%) fungal infection. Eleven patients underwent HT and all of them developed at least one infection after it. In 3 cases, all VAD-R or VAD-S infections were caused by the same etiology as before HT. Their median time of appearance was on day +6 (3-11) after BHED removal and HT. Overall mortality was 6/15 (40%). None of the deaths were related to VAD Infection. Infection complicated BHED implantation in 86.7% of the patients. Overall, 13.9% were specific of BHED and 22.2% were related. However, infections did not preclude HT in any case and carried no attributable mortality.

Clinical characteristics and risk factors of Intracranial hemorrhage in patients following allogeneic hematopoietic stem cell transplantation.

Intracranial hemorrhage (ICH) is one of the most life-threatening neurological complications after allogeneic hematopoietic stem cell transplantation. Although cerebral complications and its causes after allo-HSCT are well documented, assessment of the incidence and risk factors of intracranial hemorrhage following allo-HSCT are less discussed. A nested case-control study was conducted involving 160 subjects drawn from 2169 subjects who underwent HSCT at Peking University People's Hospital between 2004 and 2014. Thirty-two patients (1.5%) with ICH were identified, and 128 controls were matched for age, gender, transplantation type, and time of transplantation. Intracranial hemorrhage was identified by CT scan and/or MRI by searching hospital records. Among the 32 ICH patients, 27 (82.9%) developed intraparenchymal hemorrhages (IPH), 2 cases (5.7%) suffered subdural hematomas (SDH), and 3 cases (8.6%) had multiple hemorrhage lesions in the brain parenchyma. The median time of appearance for cerebral hemorrhages was 147.5days. Multivariate analysis showed that systemic infections (hazard ratio 2.882, 95% confidence interval 1.231-6.746), platelet count (5.894, 1.145-30.339), and fibrinogen levels (3.611, 1.528-8.532) were independent risk factors for intracranial hemorrhage among HSCT patients. The cumulative survival rate in the intracranial hemorrhage and control groups were 43.3 and 74.7% (P = .001), respectively. Intracranial hemorrhage is associated with high mortality and a decreased overall survival rate. Systemic infections, platelet count, and fibrinogen levels were individual independent risk factors.

Evaluation of cytokine profile and HLA association in benznidazole related cutaneous reactions in patients with Chagas disease.

Benznidazole is the drug of choice for Chagas disease. The major drawback of this drug is the high adverse events rate, being cutaneous reactions the most frequent one, leading to definitive withdrawal of treatment in 15%-30% of patients. Prospective observational study where adult Chagas disease patients accepting to receive benznidazole (100 mg/8 hours for 60 days) were included. The objective was to characterize the skin toxicity of benznidazole in patients with Chagas disease, determine the serum cytokine profile, and evaluate the potential association with specific HLA alleles and benznidazole concentration. Serum cytokine levels were measured at day 0, 15, and 60 of treatment. Class I and II HLA alleles were determined. When cutaneous reaction was detected, a skin biopsy was performed. Serum benznidazole concentration was determined at the time of cutaneous reaction, or at day 15 of treatment. Fifty-two patients were included, 20(38.5%) had cutaneous reaction, and median time of appearance was 9 days. Skin biopsies showed histopathological findings consistent with drug eruption. Patients with cutaneous drug-reaction had higher proportion of eosinophilia during treatment, and higher interleukin (IL)-5 and IL-10 serum concentrations at day 15 of treatment than those without cutaneous reaction. Treatment interruption (that included moderate-severe cutaneous reactions) was more frequent in patients carrying HLA-B*3505 allele (45.5% vs 15.4%, P = .033). No differences in benznidazole serum concentration were found. Benznidazole related cutaneous reaction rate is high, and it was produced by a delayed hypersensitivity reaction with a Th2 response. Carrying HLA-B*3505 allele could be associated with moderate-severe cutaneous reaction.

Results of surgical management of renal cell carcinoma metastatic to the pancreas.

Aim of the studyMetastases from renal cell carcinoma represent between 0.25% and 3.00% of all resected pancreatic tumours. The aim of this study was to review 13 patients with renal cell carcinoma metastatic to the pancreas.Material and methodsClinical data, time from initial presentation, operative outcome, long-term survival, tumour size, presence of lymphatic invasion, and surgical margin status were evaluated.ResultsThe median age of the patients was 62 years (mean 60.9). The median time for appearance of metastatic disease following resection of the primary tumour was 9 years (mean 8.38). Pancreatic metastases were located in the head of the pancreas in four patients, in the body in three, in the tail in two patients, and four patients had multiple pancreatic localisations. Four (30.7%) pancreatoduodenectomies, 5 (38.5%) distal resections, 2 (15.3%) total pancreatectomies, 1 (7.6%) enucleation, and 1 (7.6%) Roux duodenojejunostomy were performed. Two patients (15.3%) had postoperative complications. Operative mortality was 0%. Surgical margins were microscopically positive in 1 (8.3%) patient, and lymph nodes were positive in 2 (16.6%) patients. In our group of 7 deceased patients the mean survival was 19 months (median 16 months).ConclusionsRenal cell carcinoma metastatic to the pancreas can occur several years after nephrectomy. In our series a large number of patients with occurrence of symptoms, advancement of tumours, metastases to lymph node, and positive margin were connected with short survival period. Early detection of primary tumour, long and thorough patient care, and radical resections give patients a chance for a prolonged life.

Recurrent disease in juvenile differentiated thyroid carcinoma: prognostic factors, treatments, and outcomes.

The overall prognosis in pediatric differentiated thyroid carcinoma (DTC) is excellent. Recurrent disease is frequent, however, and requires additional treatment. We analyzed the probability of recurrence, prognostic factors, treatment, and outcome of juvenile DTC. Fifty-one DTC patients (32 girls and 19 boys; ≤ 20 y old; mean age, 16.5 y) were treated with (131)I (radioiodine, or radioactive iodine [RAI]); the median follow-up was 10 y. Patients underwent different initial treatments: 46 patients received total thyroidectomy and RAI, 3 patients received total thyroidectomy, and 3 patients received subtotal thyroidectomy. The probability of recurrence and prognostic factors were tested with the Kaplan-Meier method. Initially, 36 of 51 patients achieved complete remission, 14 of 51 achieved partial remission, and 1 of 51 had progressive disease. By the follow-up, 11 of 51 patients (21.6%) had developed recurrent disease; the median appearance time was 4 y (range, 1-15 y). The probabilities of recurrence were 16.7% at 5 y, 22.3% at 10 y, and 33.3% at 15 and 23 y after the initial treatments. Factors that were strongly predictive of recurrence were age (P = 0.001), initial treatment (P = 0.0001), and tumor multifocality (P = 0.011). Sex, nodal metastases at presentation, distal metastases at presentation, histologic type of the tumor, T stage, and clinical stage had no influence on relapse (P = 0.180, P = 0.786, P = 0.796, P = 0.944, P = 0.352, and P = 0.729, respectively). Patients with recurrent disease, partial remission, and progressive disease were retreated, with either surgery or surgery and RAI, receiving cumulative activities of up to 40 GBq. The overall outcome in our patients was excellent: 90.2% complete remission, 3.92% partial remission, 1.96% stable disease, 1.96% disease-related death, and 1.96% another cause of death. Younger age at diagnosis, less radical primary surgery without subsequent RAI, and tumor multifocality are factors that are strongly prognostic for recurrence. For reducing the rate of relapse and improving surveillance for recurrent disease, total thyroidectomy followed by RAI appears to be the most beneficial initial treatment for patients with juvenile DTC. The use of RAI seems to be safe, with no adverse effects on subsequent fertility and pregnancy or secondary malignancy.

Intracranial Hemorrhage and Mortality In 1461 Patients After Allogeneic Hematopoietic Stem Cell Transplantation For 6-Year Follow-Up: Study Of 44 Cases

▪Although cerebral complications and causes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were well documented, assessment of incidence rates and risk factors of intracranial hemorrhage (ICH) following allo-HSCT are less discussed. The clinical data of 1461 consecutive patients undergoing allo-HSCT in Peking University Institute of Hematology from January 2005 to June 2011 were retrospectively analyzed. Among these patients, 44 developed intracranial hemorrhage (ICH) and matched 176 patients control subjects were accrued. ICH was verified by computed tomography (CT) scan in all patients. Among the 1461 patients, 44 patients (3.0 %) developed ICH, including 29 patients (65.9%) with multiple location hemorrhage, 4 patients (9.1 %) with subdural hematoma (SDH), 8 patients (18.2%) with subarachnoid hemorrhage (SAH), and 3 patients (6.8%) with other hemorrhage in the brain parenchyma. The median time of appearance for ICH was 129 days (1-450). Survival after 6 year was significantly reduced in patients who developed ICH complications compared with control (47.1% vs. 75.7%,p<0.001 ).Multivariate analysis showed that donor type, systemic infections, III-IV aGVHD, platelet count, fibrinogen level were the independent risk factors for ICH among allo-HSCT patients. The ROC curve analysis showed a cutoff value of 13.2×109/L for platelet count and 129.5 g/L for fibrinogen level in patients with ICH. The transplantation-related mortality rate in the ICH and control group were 50% and 22.2%, respectively(p<0.001).ICH is common cerebral complication after allo-HSCT which associated with high mortality and decreased overall survival rate. After allo-HSCT patients with severe thrombocytopenia plus low level of fibrinogen and/or III-IV aGVHD appeared to be at particularly high risk of ICH. Disclosures:No relevant conflicts of interest to declare.

Real-Time Whole-Body Visualization of Chikungunya Virus Infection and Host Interferon Response in Zebrafish

Chikungunya Virus (CHIKV), a re-emerging arbovirus that may cause severe disease, constitutes an important public health problem. Herein we describe a novel CHIKV infection model in zebrafish, where viral spread was live-imaged in the whole body up to cellular resolution. Infected cells emerged in various organs in one principal wave with a median appearance time of ∼14 hours post infection. Timing of infected cell death was organ dependent, leading to a shift of CHIKV localization towards the brain. As in mammals, CHIKV infection triggered a strong type-I interferon (IFN) response, critical for survival. IFN was mainly expressed by neutrophils and hepatocytes. Cell type specific ablation experiments further demonstrated that neutrophils play a crucial, unexpected role in CHIKV containment. Altogether, our results show that the zebrafish represents a novel valuable model to dynamically visualize replication, pathogenesis and host responses to a human virus.

Influence of Initial Treatment on the Survival and Recurrence in Patients With Differentiated Thyroid Microcarcinoma

Differentiated thyroid microcarcinoma (DTM) has a good prognosis and survival, but recurrent disease may appear during follow-up. The aim of this study was to evaluate the influence of initial treatment including surgery and radioactive iodine (131I) on the survival and recurrence in patients with DTM. Between January 1979 and December 2006, 130 patients with DTM were retrospectively evaluated, with a median follow-up of 10 years. Total/near-total thyroidectomy was performed in 121 (93.1%) of 130 patients, followed with 131I ablation in 71 (54.6%) of 130 patients. The probability of disease-specific survival was 97.7% ± 1.3% after 5 and 10 years; the probability of disease-specific survival was 95.9% ± 2.2% after 15, 20, 25, and 28 years after the initial treatment and was significantly influenced by recurrence, clinical stage, and patients' age (P = 0.0001, P = 0.0005, and P = 0.02, respectively). Sex, histopathological type of the tumor, metastases at presentation, initial treatment, performance of radioactive therapy, and risk categories had no influence on survival (P = 0.8, P = 0.6, P = 0.1, P = 0.4, P = 0.5, and P = 0.1, respectively). The overall recurrence rate was 10.8%, (6.9% in lymph nodes, 1.5% in thyroid bed, and 2.3% at distant sites), with a median appearance time of 30 months. Recurrences were significantly influenced by regional metastases at presentation, radioiodine ablation, and initial treatment (P = 0.0002, P = 0.005, and P = 0.003, respectively); there was no relationship based on age, sex, histological type of the tumor, and tumor multifocality. To perform more accurate surveillance for recurrence, total/near-total thyroidectomy followed by radioiodine ablation may be the optimal initial treatment for patients with DTM.

Accelerated Partial Breast Irradiation (APBI) With MammoSite™: An Interim Outcome Analysis With Two Years Follow-up

Accelerated Partial Breast Irradiation (APBI) With MammoSite™: An Interim Outcome Analysis With Two Years Follow-up

Prospective Study of Location and Daily Variation in the Position of Ovaries and its Impact on the Technique for Radiation Ovarian Ablation

developed cellulitis, two of whom did not have a seroma. The total number of infected patients was therefore 7 (11%.) Eleven patients received chemotherapy after completion of APBI, and one of these patients developed radiation recall dermatitis. Forty-four patients had hormonal therapy. The persistence of seroma (clinical and/or radiological) at the median follow-up of 30 months was seen in 44 (67%) patients. The only clinical or dosimetric variable predictive for seroma was intraoperative placement of the catheter (84% vs. 47%, p = .005). Telangiectasia in the treatment area was observed in 9 patients. The median time of appearance of telangiectasia was 23 months (range 4–52 months). Telangiectasia was significantly increased in patients with maximum skin dose of $100% (41% vs. 2%,p = .0002) and $125% (71% vs 6.7%,p = 0.0001). Seven patients had fat necrosis (mammographic and clinical) at a median of 23 months (range 13–48 months.) Cosmetic outcome was excellent in 44 (67%), good in 20 (30%) and fair in 2 (3%) of patients. The presence of telangiectasia had a significant impact on cosmetic outcome grading. The presence of seroma did not affect cosmesis. To date, no patient has had local or systemic recurrence of cancer, although one patient developed contralateral DCIS 10 months after treatment. Conclusions: The MammoSite Radiation Therapy System continues to demonstrate excellent local control and cosmetic outcome with extended follow-up. The maximum skin dose should be kept below 100% to reduce late effects on skin and improve cosmetic outcome. The persistence of seroma is higher with intraoperative placement of the catheter, and at our institution ultrasound guidance is the preferred method of placement.