Incidence Of Disease Progression Research Articles

Radiofrequency ablation for papillary thyroid microcarcinoma with a trachea-adjacent versus trachea-distant location

Objective To evaluate the outcomes of radiofrequency ablation (RFA) for papillary thyroid microcarcinoma (PTMC) adjacent to the trachea and compare them with those of PTMC distant from the trachea. Methods Patients who received RFA for solitary low-risk PTMC between June 2014 and July 2020 were reviewed and classified into adjacent and distant groups. To balance between-group confounders, the propensity score matching approach was employed. Volume, volume reduction ratio (VRR), tumor disappearance, complications, and disease progression were assessed and compared between the groups. Furthermore, factors affecting disease progression were evaluated. Results A total of 122 and 470 patients were included in the adjacent and distant groups, respectively. Overall VRR was 99.5% ± 3.1 and cumulative tumor disappearance rate was 99.4% after a mean follow-up time of 40.1 months ± 16.2. Overall disease progression and complications incidence were 3.7% and 1.0%, respectively. No substantial differences were observed between the two groups in the latest volume (0.8 mm3 ± 4.1 vs. 0.9 mm3 ± 4.2, p = .77), VRR (99.7% ± 1.6 vs. 99.5% ± 2.7, p = .75), cumulative tumor disappearance rate (92.6% vs. 94.2%, p = .58), and incidence of disease progression (4.1% vs. 4.5%, p = .70) and complication (1.7% vs. 0.8%, p = .86) after 1:2 matching. Additionally, tracheal adjacency exhibited no association with disease progression in multivariate Cox regression analysis (p = .73). Conclusion For eligible patients with PTMC located adjacent to or distant from the trachea, RFA may offer a safe and effective alternative treatment method.

Differences in Clinical Outcomes Between Hydroxyurea-Resistant and -Intolerant Polycythemia Vera Patients.

Previous studies have suggested that patients with polycythemia vera (PV) who exhibit hydroxyurea-resistance (HU-R) and -intolerance (HU-I) may have distinct characteristics and clinical outcomes. However, to date, no studies have reported a comparison between these two groups or assessed prognostic factors in these patients. The objective of this study was to evaluate clinical outcomes and identify prognostic factors among PV patients with HU-R or HU-I. We conducted a review of PV patients who received frontline treatment with HU from nine centers and identified 90 patients with HU-R or HU-I. The cumulative incidence of thrombosis after 7 years of HU-R/I was 21.4%, and the incidence of disease progression was 22.5%. Comparing the HU-R and HU-I groups, the HU-R group had a significantly higher rate of disease progression (36.7% vs. 0.56%, P = 0.009), while there was no significant difference in thrombosis incidence (19.0% vs. 22.9%, P = 0.463). Multivariate analysis revealed that HU-R was an independent prognostic factor for progression-free survival (hazard ratio, 6.27, 95% confidence interval, 1.83-21.47, P = 0.003). Additionally, higher lactate dehydrogenase levels, multiple cardiovascular risk factors, and prior thrombosis were identified as unfavorable predictors of overall survival. These findings suggest that patients with HU-R face a higher risk of hematological transformation, but have a comparable risk of thrombosis to patients with HU intolerance. These distinctions should guide decisions on second-line treatment options and clinical trials involving these patients.

Differences in Clinical Outcomes between Hydroxyurea-Resistant and -Intolerant Polycythemia Vera Patients

Previous retrospective studies have revealed that a substantial portion of PV patients experience resistance to hydroxyurea (HU-R) and intolerance to HU (HU-I). Currently, the therapeutic options for both groups of patients do not differ, and most clinical trials investigating second-line therapies have enrolled patients with HU-R or HU-I without considering potential clinical distinctions between the two groups. Direct comparisons between patients with HU resistance and HU intolerance have not been conducted, and prognostic factors related to clinical outcomes, such as thrombosis, bleeding, disease progression, and survival, remain unclear for patients experiencing HU resistance or intolerance. A total of 90 patients with HU-R/I were retrospectively anlyzed in this study. Among them, 44 and 46 patients fulfilled the ELN criteria defining resistance or intolerance to HU, respectively. Patients with HU-R were older at the time of diagnosis of PV (66.7 ± 13.2 years, vs. 59.8 ±11.2 years in the HU-I group, P = 0.016), had longer times to developing HU-R/I, and thus, were older at the time of HU-R/I development compared with those with HU-I. The majority of the study patients continued HU treatment with dose modification or intermittent discontinuation with anagrelide added to control platelet counts until disease progression or death because of limited second-line treatment options during the observed period. The cumulative incidence of thrombosis after 7 years of HU-R/I was 21.4%, and the incidence of disease progression was 22.5%. Comparing the HU-R and HU-I groups, the HU-R group had a significantly higher rate of disease progression (36.7% vs. 0.56%, P = 0.009), while there was no significant difference in thrombosis incidence (19.0% vs. 22.9%, P = 0.463). The type of thrombosis did not differ between the two groups (P = 0.628). Multivariate analysis revealed that HU-R was an independent prognostic factor for progression-free survival (hazard ratio = 5.57, 95% CI: 1.22 - 25.54, P = 0.027). The patients in the HU-R group had significantly lower PFS (40.2% vs. 66.1% in the HU- I group, P < 0.01). They also showed a trend toward lower TFS (51.0% vs. 62.1% in the HU-I group; P = 0.055) and lower OS (57.5% vs. 67.7% in the HU-I group; P = 0.060) compared to patients with HU-I. The mortality at seven years was 42.5% in the HU-R group and 32.3% in the HU-I group (P = 0.06). Higher LDH levels, multiple cardiovascular risk factors, and prior thrombosis were identified as unfavorable predictors of overall survival. These findings suggest that HU-resistant patients have a higher risk of hematological transformation but a comparable risk of thrombosis to HU-intolerant patients. These distinctions should guide decisions on second-line treatment options and clinical trials involving these patients.

Natural history of internal carotid artery stenosis progression

ObjectiveThe aim of this study was to investigate the natural history of internal carotid artery (ICA) stenosis progression. MethodsThis single-institution retrospective cohort study analyzed patients diagnosed with ICA stenosis of 50% or greater on duplex ultrasound from 2015 to 2022. Subjects were drawn from our institutional Intersocietal Accreditation Commission-accredited noninterventional vascular laboratory database. Primary outcomes were incidences of disease progression, and stroke or revascularization after index study. Progression was defined as an increase in stenosis classification category. Imaging, demographic, and clinical data was obtained from our institutional electronic medical record via a database mining query. Cases were analyzed at the patient and artery levels, with severity corresponding to the greatest degree of ICA stenosis on index and follow-up studies. ResultsOf 577 arteries in 467 patients, mean cohort age was 73.5 ± 8.9 years at the time of the index study, and 45.0% (n = 210) were female. Patients were followed with duplex ultrasound for a mean of 42.2 ± 22.7 months. Of 577 arteries, 65.5% (n = 378) at the index imaging study had moderate (50%-69%) stenosis, 23.7% (n = 137) had severe (70%-99%) stenosis, and 10.7% (n = 62) were occluded. These three groups had significant differences in age, hypertension, hyperlipidemia prevalence, and proportion on best medical therapy. Of the 467-patient cohort, 56.5% (n = 264) were on best medical therapy, defined as smoking cessation, treatment with an antiplatelet agent, statin, and antihypertensive and glycemic agents as indicated. Mean time to progression for affected arteries was 28.0 ± 20.5 months. Of those arteries with nonocclusive disease at diagnosis, 21.3% (n = 123) progressed in their level of stenosis. Older age, diabetes, and a history of vasculitis were associated with stenosis progression, whereas antiplatelet agent use trended towards decreased progression rates. Of the 467 patients, 5.6% (n = 26) developed symptoms; of those, 38.5% (n = 10) had ischemic strokes, 26.9% (n = 7) had hemispheric transient ischemic attacks, 11.5% (n = 3) had amaurosis fugax, and 23.1% (n = 6) had other symptoms. A history of head and neck cancer was positively associated with symptom development. Of 577 affected arteries, 16.6% (n = 96) underwent intervention; 81% (n = 78) of interventions were for asymptomatic disease and 19% (n = 18) were for symptomatic disease. No patient-level factors were associated with risk of intervention. ConclusionsA significant number of carotid stenosis patients experience progression of disease. Physicians should consider long-term surveillance on all patients with carotid disease, with increased attention paid to those with risk factors for progression, particularly those with diabetes and a history of vasculitis.

Disease Progression and Leukemic Transformation in Patients With Lower-Risk Myelofibrosis (MF): An Analysis from MOST

Background: Progressive disease (PD) in MF is associated with increased bone marrow fibrosis, worsening anemia, and an increase in circulating blasts and can result in leukemic transformation (LT). LT is a rare (~11% incidence) but fatal complication of MF with a mortality rate of 97% and a median survival of 3.6 months. Real-world data regarding PD and LT in lower-risk MF are limited. This analysis from the Myelofibrosis and Essential Thrombocythemia Observational Study (MOST; NCT02953704) describes the incidence of PD, including LT, in patients with lower-risk MF and compares the baseline characteristics of patients who progressed vs those who did not. Methods: MOST is a longitudinal, noninterventional, prospective, observational study of patients with clinical diagnoses of MF or essential thrombocythemia enrolled at clinical practices in the US. Patients included in this analysis (≥18 years) had low-risk or intermediate-1 (INT-1)-risk MF (by age >65 years alone) stratified by the Dynamic International Prognostic Scoring System (Blood. 2010;115:1703) at enrollment and were followed for at least 3 years. Baseline data were collected as previously described (Gerds A. Clin Lymphoma Myeloma Leuk. 2022;22:e532-e540). PD was defined as physician-reported PD, LT, and/or death by reason of progression. Results: Of the 232 patients with MF enrolled in MOST, 204 patients (low-risk: n=84, 41.2%; INT-1-risk: n=120, 58.8%) were included in this analysis (data cutoff: July 5, 2022). The median (range) time from MF diagnosis to enrollment was 1.8 (0-38) years and the median (range) enrollment duration was 4.2 (3.3-5.4) years. Of 193 patients with available data on disease progression, 46 patients (23.8%) had physician-reported PD; of these, 18 (22.0%) were low-risk and 28 (25.2%) were INT-1-risk. The most commonly reported indicator was change in hematologic parameters (n=27 [58.7%]), followed by change in spleen size (n=19 [41.3%]), MF-related symptoms (n=16 [34.8%]), and blast counts (n=8 [17.4%]). LT was reported in 15 patients (7.8%); of these 4 (4.9%) were low-risk and 11 (9.9%) were INT-1-risk. Death by any cause was reported in 30 patients (14.7%; PD, n=16, without PD, n=9; unknown PD, n=5). Patient baseline characteristics are shown in Table 1. Patients who had PD were older than patients without (median [range] age: PD, 70.0 [35-88] vs without PD, 66.5 [35-88] years). Bone marrow biopsy/aspiration and mutation tests at diagnosis were reported in 98.3% and 80.7% of patients with PD and in 91.8% and 82.8% of patients without PD, respectively. Significant differences in the symptomatology of patients with PD vs without PD were not detected at time of enrollment. More than half of patients with PD and without PD were receiving MF-directed monotherapy at enrollment (59.3% vs 55.2%). The most common monotherapies received in patients with PD vs without PD were hydroxyurea (15.3% vs 28.4%) and ruxolitinib (37.3% vs 17.9%). Six patients (PD, n=3; without PD, n=3) received >1 MF-directed therapy. Conclusion: This real-world analysis of data from patients enrolled in MOST describes the disease evolution of patients with lower-risk MF. After ~3 years of follow-up, a relatively high proportion of patients in this population had physician-reported PD or LT (23.8% and 7.8%, respectively). Baseline characteristics and symptoms did not differ between those who progressed and those who did not; however, further analysis of molecular and post-baseline data may provide insight into risk factors for disease progression in this lower-risk population. Identification of patients with higher risk of PD is likely to improve disease management and outcomes for patients with lower-risk MF. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Tenofovir disoproxil fumarate therapy in patients with chronic hepatitis B and advanced fibrosis or compensated cirrhosis

Tenofovir disoproxil fumarate (TDF) is the first-line therapy for chronic hepatitis B. This interim analysis presents the efficacy and safety data for TDF at Week 144 in patients with chronic hepatitis B and advanced fibrosis or compensated cirrhosis from China. Patients were assessed for incidence of newly diagnosed hepatocellular carcinoma (HCC) and disease progression, liver stiffness measurement (LSM), virological suppression (serum hepatitis B virus DNA <20 IU/mL), alanine aminotransferase normalization, hepatitis B e antigen (HBeAg) loss and seroconversion, histological liver fibrosis score, and safety at Week 144. Overall, 197 patients were enrolled. At Week 144, the incidence of newly diagnosed HCC was observed in 2.1% patients, and the incidence of disease progression was observed in 3.6% patients. The mean (standard deviation) change in LSM from baseline was −5.1 (5.85) kPa. Serum hepatitis B virus DNA <20 IU/mL was observed in 94.1% patients, alanine aminotransferase normalization in 33.5% patients, HBeAg loss in 35.6% patients, and HBeAg seroconversion in 14.4% patients. Among patients with stage F3 or F4 fibrosis at baseline by LSM, 38.3% patients regressed to stage F0/1, and 22.0% of patients regressed to stage F2 at Week 144. Overall, 67.7% patients experienced ≥1 adverse events, 13.8% patients experienced TDF-related adverse events, and 16.4% patients experienced serious (none were TDF-related). At Week 144 of TDF treatment, low incidence of HCC and disease progression were reported. Virological suppression was observed in 94.1% patients, which was associated with fibrosis regression. No new safety events were identified. • Tenofovir disoproxil fumarate (TDF) lowered hepatocellular carcinoma incidence. • TDF resulted in reduced disease progression after 144 weeks of treatment. • Virological suppression occurred in 94.1% of patients after 144 week TDF treatment.

Clinical features and outcomes of newly diagnosed follicular lymphoma concurrent with diffuse large B-cell lymphoma component

Objective: To explore the clinical features and survival of newly diagnosed follicular lymphoma (FL) patients with diffuse large B-cell lymphoma (DLBCL) component. Methods: 1845 newly diagnosed FL patients aged ≥ 18 years with grades 1-3a in 11 medical centers in China from 2000 to 2020 were included, and patients with DLBCL component were screened. The clinical data and survival data of the patients were retrospectively analyzed, and the prognostic factors were screened by univariate and multivariate analysis. Results: 146 patients (7.9% ) with newly diagnosed FL had DLBCL component. The median age was 56 (25-83) years, 79 males (54.1% ) . The pathology of 127 patients showed the proportion of DLBCL component. Patients were divided into two groups according to whether the proportion of DLBCL component was ≥ 50% . The study found that patients with DLBCL component ≥ 50% had higher grade 3 ratio (94.3% vs 91.9% , P=0.010) , Ki-67 index ≥ 70% ratio (58.5% vs 32.9% , P=0.013) and PET-CT SUVmax ≥ 13 ratio (72.4% vs 46.3% , P=0.030) than patients with DLBCL component<50% . All patients received CHOP or CHOP like ± rituximab chemotherapy. The overall response rate (ORR) was 88.2% , and the complete response (CR) rate was 76.4% . In the groups with different proportions of DLBCL component, there was no significant difference in the remission rate after induction treatment and the incidence of disease progression within 2 years after initiation of treatment (POD24) (P<0.05) . The overall estimated 5-year progression free survival (PFS) rate was 58.9% , and the 5-year overall survival (OS) rate was 90.4% . The 5-year OS rate of POD24 patients was lower than that of non POD24 patients (70.3% vs 98.5% , P<0.001) . Compared with non maintenance treatment of rituximab, maintenance treatment of rituximab could not benefit the 5-year PFS rate (57.7% vs 58.8% , P=0.543) , and the 5-year OS rate had a benefit trend, but the difference was not statistically significant (100% vs 87.8% , P=0.082) . Multivariate analysis showed that failure to reach CR after induction treatment was an independent risk factor for PFS (P=0.006) , while LDH higher than normal was an independent risk factor for OS (P=0.031) . Conclusion: FL patients with DLBCL component ≥50% have more invasive clinical and pathological features. CHOP/CHOP like ± rituximab regimen can improve the clinical efficacy of patients. Rituximab maintenance therapy can not benefit the PFS and OS of patients. Failure to reach CR after induction therapy was the independent unfavorable factor for PFS.

FGL2 expression and relation with survival and prognosis in patients treated with concurrent temozolamide and radiotherapy in high-grade glioma.

e14019 Background: FGL2 is a member of the fibrinogen-related protein, Literature suggests that FGL2 contributes to the progression of glioblastoma multiforme (GBM) through inducing multiple immunosuppression mechanisms. The present study aimed at evaluation of the expression and the prognostic value of FGL2 in high grade glioma. Methods: In our study, we analysed sixty specimens retrieved at diagnosis of high grade glioma patients. They received concurrent Temozolamide and radiotherapy, as a standard of care, during the period from October 2019 to December 2020 and and were followed up for 12 months . Evaluation of FGL2 expression done by using FGL2 Immunohistochemistry .ClinicalTrials.gov Identifier: NCT04113278. Results: Mean age of studied patients was (48.88± 12.45) . Majority (75%) of patients were males. Mean FGL2 expression was 61 ± 31.80 (%) with range between 3% and 95%. It was found that 7 (11.7%) patients had negative FGL2. Over the period of follow up, incidence of disease progression was significantly higher among the patients with higher percentage of FGL2 in comparison to those with lower FGL2 percentages (76.54 ± 18.52 vs. 56.17 ± 33.41(%); P= 0.04). number of deaths was also significantly higher among the high FGL2 percentage group (64.86 ± 31.58 vs. 54.16 ± 31.71(%); P= 0.03). Intensity of FGL2 was mild 16 (26.7%), moderate 20 (33.3%) and strong 17 (28.3%) . Intensity of FGL2 was more among patients with disease progression. All patients with progression had either moderate intensity (46.2%) or strong intensity (53.8%). Seven (14.9%) patients without disease progression had negative FGL2 expression with ( P= 0.01). Disease free progression (DFP) was significantly negatively correlated with increasing in the intensity of FGL2. Patients with strong intensity had the lowest DFP (14 month) while patients with negative FGL2 and mild intensity had the highest DFP (25 month) with ( P &lt;0.001). Overall survival was significantly worse with increasing in the intensity of FGL2 where patients with strong intensity had the lowest overall survival (19 month), while patients with negative FGL2 and mild intensity had the highest overall survival (27and 26 month, respectively) with ( P &lt;0.001). For prediction of progression among patients with high grade glioma, FGL2 at cut off point &gt; 60% has 92.3% sensitivity and 28% specificity with ( P= 0.04). For prediction of mortality among patients with high grade glioma, FGL2 at cut off point &gt; 70% has 67% sensitivity and 61% specificity with ( P= 0.03). Conclusions: FGL2 expression in high grade glioma patients can be used as a prognostic factor but additional studies are required to clarify the prognostic value.

Claims-Based Network Analysis of Disease Progressions in Complex and Non-Complex Older Adults

Older adults are the fastest growing subset of complex patients with high medical, behavioral, and social needs. Understanding differences in disease progression patterns between complex and non-complex older adults is critical for understanding disease risk and tailoring patient-centered interventions. We identified complex patients as those having frequent medical encounters and multiple chronic conditions within the first year of the study period and non-complex patients as the converse. This study compares the disease progression patterns of (a) complex and (b) non-complex older adults by creating disease progression networks (DPN) from claims data of 762,362 patients (mean age = 73) from 2016 to 2020. We characterized the network size and density between the complex patient DPN (C-DPN) and non-complex patient DPN (NC-DPN), and compared disease progression incidence, time-to-progression, and age- and gender-related risk. Results show that the C-DPN was denser and had a wider range of values for risk of progression compared to the NC-DPN. This implies more varied disease progression patterns occurring in the complex adults. We were also able to compare (median) time-to-progressions of diseases relative to each subpopulation and found variation in disease progression time. Furthermore, k-means clustering on the network allowed us to identify highly connected diseases involved in many disease pathways that are prevalent among older adults. (e.g., lipoprotein disorders, hypertension, major depressive disorder). Our results suggest that DPNs can be used to identify important conditions and time-points for tailoring care to the complex and non-complex older adults.

Debulking before Initiation of Venetoclax Therapy in Untreated Patients with Chronic Lymphocytic Leukemia: Results from a Phase 3b Study

Debulking before Initiation of Venetoclax Therapy in Untreated Patients with Chronic Lymphocytic Leukemia: Results from a Phase 3b Study

Real-World Outcomes of Ruxolitinib for Polycythemia Vera

BackgroundRuxolitinib (RUX) is a JAK1/JAK2 inhibitor approved for the treatment of hydroxyurea (HU)-resistant or intolerant patients with polycythemia vera (PV). Approval followed the results of the phase III RESPONSE trial, which demonstrated significant benefits of ruxolitinib in this population, including decreased phlebotomy requirements, reduction in splenomegaly, and amelioration of symptom burden. Although the results from the RESPONSE trial are positive in this selected patient population, no follow-up investigation has evaluated the real-world outcomes of patients with PV treated with RUX.MethodsWe conducted a retrospective case series of patients at a single-center tertiary-care institution who were prescribed RUX for the indication of PV between January 1st, 2013 and January 1st, 2017. Inclusion criteria included: 18 years of age or older, follow up at the study institution, and a diagnosis of PV without progression to myelofibrosis (MF) or other hematologic malignancy at time of initiation of RUX. Primary outcome measures included phlebotomy requirements, change in spleen size, and symptom burden (all assessed at 32 weeks after initiation of RUX), as well as the incidence of disease progression, and adverse events including infections, thromboses and cytopenias.ResultsBaseline disease characteristics and history are summarized in Table 1. Twenty-five (16 men and 9 women) eligible patients were identified. The average age was 65.8 years (range, 51-89 years) at initiation of RUX. Patients started RUX, on average, 9.2 years after their diagnosis. Fourteen patients (56%) had follow up at or beyond 32 weeks of initiation (4 were lost to follow up, 3 started treatment before 32-week data could be captured and 4 discontinued RUX).Primary outcomes relating to burden of disease are summarized in Table 2. Seven (50%) patients with 32-week follow-up data achieved phlebotomy freedom and four (29%) patients achieved a reduction in palpable splenomegaly of at least 50% (6 remained non-palpable, and the remaining 4 patients experienced reductions in palpable splenomegaly of less than 50%.Four (16%) of 25 patients were deemed intolerant of RUX. Intolerance was reported as headache (2 patients), weight gain (1 patient), and dizziness/diarrhea (1 patient). The average time to discontinuation of the medication was 12.6 weeks. Excluding the 4 patients who discontinued RUX, patients were on the medication for an average of 70.4 weeks (range, 8.1-182 weeks). All patients who continued RUX past 32 weeks remained on the drug at their last known follow-up visit.Three (13%) of 23 patients had leukopenia while on RUX, of which only 1 (4.3%) was grade III. Seven (30%) of 23 patients had thrombocytopenia while on RUX, of which only 1 (4.3%) was grade III. Eight (32%) of patients reported headaches while on RUX, 7 (28%) reported dizziness and 7 (28%) reported diarrhea. All reported adverse events were grade I/II. Two patients progressed to MF (on average 40.7 weeks after starting RUX). None progressed to AML or MDS. One patient, who had a previous thrombotic event, had a transient ischemic attack (grade I) while receiving RUX. No patient developed a secondary malignancy during the study period. Five (20%) patients had documented infections. Two were grade II (herpes recurrence and UTI), and one grade III (colitis), which were managed in clinic or the emergency department. Two infections, both pneumonia (grade III and V), required hospitalization.One of these patients passed away from complications of a suspected lobar pneumonia 174.2 weeks after starting RUX. The patient, who had JAK2V617F-negative/exon 12-positive disease, presented with fever and cough, and was managed in the intensive care unit with broad-spectrum antibiotics before transitioning to hospice care.ConclusionsThis is the first study to evaluate the real-world effects of RUX for the treatment of PV. Patients in our case series, most of whom had failed therapy with HU, experienced an overall reduction in phlebotomy requirement, splenomegaly, and symptom burden after the initiation of RUX. The intolerance rate to RUX in this case series was comparable to, or lower than, the reported rates for HU. Although over half of patients reported an adverse effect of RUX, less than 20% discontinued the drug for this reason. The results of this case series are largely congruous with the positive results of the original RESPONSE trial. [Display omitted] DisclosuresMascarenhas:Novartis: Other: DSMB member , Research Funding; Promedior: Research Funding; Merck: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Incyte: Other: Clinical Trial Steering Committee , Research Funding.

Potential Utility of Event-Free Survival (EFS) As Surrogate Endpoint for Overall Survival (OS) in Relapsed Diffuse Large B-Cell Lymphoma (DLBCL) after Autologous Stem Cell Transplantation (ASCT): A Subgroup Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Randomized Phase III Trial

Background: EFS at 24 months (EFS24) in newly diagnosed patients with DLBCL following first line rituximab containing anthracycline-based chemotherapy has been shown to be a surrogate marker for long-term OS. In patients achieving EFS24, subsequent OS is nearly equivalent to that of the general population, suggesting that these patients will have a near normal life expectancy if they have not experienced disease relapse by this time point. (Maurer et al. JCO 2014, Jakobsen et al. JCO 2017). In this study, we aim to determine the value of EFS as a surrogate endpoint for OS among patients with relapsed and refractory de novo or transformed DLBCL undergoing ASCT.Methods: Patients with de novo or transformed DLBCL undergoing ASCT in the CCTG LY.12 trial (Crump et al. JCO 2014) were included in the analysis. This multi-center study enrolled patients from August 2003 to November 2011. Analyses were conducted on the updated locked database of June 30th, 2017. Data for an age and sex-matched control group were taken from the Statistics Canada (http://www.statcan.gc.ca) life tables, which provide the survival rate of the general Canadian population. EFS was defined as time from ASCT until relapse, progression, initiation of new lymphoma therapy, or death from any cause. Standardized mortality ratio (SMR) was calculated for each subgroup of patients achieving EFS0 (date of ASCT) to EFS72, with increments of 12 months. All statistical calculations were performed using the SAS version 9.2 and R version 3.3.2.Results: A total of 267 patients were included. The mean age at study entry was 54 years (range 24 to 70); 68% were age <60 years; 61% male; relapse IPI 0-1: 43.8%, 2: 31.5 %, >3: 24.7%; de novo DLBCL 82.8%. Sixty-seven percent of patients received prior rituximab; 70% received rituximab as part of salvage chemotherapy (gemcitabine, cisplatin, dexamethasone or dexamethasone, cytarabine, cisplatin). At a median follow-up of 8.5 years, the total recorded number of deaths was 124; 59 occurred within the first year of follow up, 21 occurred among patients achieving EFS 24, and 6 occurred in patients achieving EFS60. The SMR decreased with each year of follow up, at EFS0 it was 12.55 (95% CI 10.44-14.96), 3.27 (95% CI 2.03-5.00) at EFS24, and 1.92 (95% CI 0.70-4.18) at EFS 60 (Table and Figure). The incidence of disease progression also decreased with each year of follow up, with 88 occurring within the first year of follow up, 21 within year 2, and only 3 after 5 years. More deaths were caused by non-lymphoma conditions, including second malignancy, for patients achieving EFS24 or greater. The 5-year OS was 59.4% for patients at EFS0, 87.1% at EFS24, and 94.3% at EFS60. A multivariate analysis including age at ASCT, IPI, de novo vs transformed DLBCL, and response to prior therapy did not reveal any predictors of survival once patients had achieved EFS24 or EFS60.Conclusion: This study demonstrates that the SMR decreases over time among patients with relapsed DLBCL undergoing ASCT, and remains significant until these patients have achieved EFS60. Thus, earlier EFS cannot be used as a surrogate marker of OS in this clinical context. A larger sample size and a validation study are needed to establish the predictive value of EFS60 for OS following ASCT. [Display omitted] DisclosuresHay:Celgene: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Kite: Research Funding; Abbvie: Research Funding; Roche: Research Funding. Crump:Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Ortho: Consultancy, Membership on an entity's Board of Directors or advisory committees. Baetz:Merck: Honoraria; Novartis: Honoraria; Roche: Honoraria. Robinson:Abbvie: Honoraria; Lundbeck: Honoraria; Janssen: Honoraria; Roche: Honoraria; Gilead: Honoraria. Assouline:Bristol Myer Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Novartis Canada Inc.: Honoraria; Paladin: Speakers Bureau; Janssen: Honoraria.

Clinicopathological and prognostic features of young onset patients with middle-low rectal cancer received neoadjuvant chemoradiotherapy

Objective: To explore the clinicopathological and prognostic features of young onset patients with middle-low rectal cancer who received neoadjuvant chemoradiotherapy (NCRT). Methods: After NCRT, a total of 441 patients with primary middle-low rectal cancer treated with radical surgery at the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS) from January 2004 to December 2016 were included. According to the age of disease onset, the patients were divided into the young group (51cases) and the middle-old group (390 cases), and the clinicopathological characteristics and survival of these patients were analyzed. Results: In the young group, 68.6% of patients received radical surgery within 7 weeks after NCRT, which was higher than 52.8% in the middle-old group (P=0.047). The stage ypTNM Ⅲ in the young group was 51.0%, higher than 34.1% in the middle-old group (P=0.027). The stage ypN+ in the young group was 51.0%, higher than 34.1% in the middle-old group (P=0.047), The incidence of disease progression in the young group was 39.2%, higher than 25.1% in the middle-old group (P=0.049). The incidence of distant metastasis in the young group was 35.3%, higher than 21.5% in the middle-old group(P=0.044). Most cases of disease progression occurred in the first 3 years after surgery for the young group, especially in the second year after surgery, the incidence of disease progression in the young group was 55.0%, higher than 26.5% in middle-old group (P=0.025). The 3-year and 5-year disease-free survival (DFS) rates for the young group were 63.7% and 58.2%, lower than 81.0% and 74.3% in the middle-old group (P=0.016), respectively. The 3-year and 5-year overall survival in the middle-old group (OS) rates for the young group were 85.4% and 69.2%, lower than 93.6% and 84.1% in the middle-old group (P=0.033), respectively. The multivariate analysis showed that, response of primary tumor (HR=4.804, 95% CI: 1.360-16.973) and total number of dissected lymph nodes (HR=4.336, 95% CI: 1.739-10.809) in the young group were independent prognostic factors related to DFS. The total dissected number of lymph nodes(HR=3.295, 95% CI: 1.076-10.091)was an independent prognostic factor related to OS. In the middle-old group, response of primary tumor (HR=2.626, 95% CI: 1.354-5.091), ypTNM stage (ypTNM Ⅲ: HR=5.837, 95% CI: 2.968-11.479) and tumor location distance from the anal verge (HR=0.500, 95% CI: 0.308-0.812) were independent prognostic factors related to DFS. Lymphovascular invasion (HR=0.500, 95% CI: 0.308-0.812) and ypTNM stage (ypTNM Ⅲ: HR=16.322, 95% CI: 5.049-52.771) were independent prognostic factors related to OS. Conclusions: Young onset rectal cancer patients are associated with shorter operation time interval, advanced pathological stage and poorer prognosis. More intensive adjuvant treatment and post-treatment surveillance should be conducted to young onset rectal cancer with NCRT.

Chondrosarcoma of the hands and feet.

A multicentre retrospective study was carried out at two tertiary sarcoma centres. A database search identified all patients with a CS treated between January 1995 and January 2018. There were 810 CSs of which 76 (9.4%) were located in the fingers, toes, metacarpals, and metatarsal bones. The median age of the study population was 55 years (36 to 68) with a median follow-up of 52 months (22 to 87) months. Overall, 70% of the tumours were in the hand (n = 54) and 30% in the foot (n = 22). Predictors for LR were margin (p = 0.011), anatomical location (p = 0.017), and method of surgical management (p = 0.003). Anatomical location (p = 0.026), histological grade between 1 and 3 (p = 0.004) or 2 and 3 (p = 0.016), and surgical management (p = 0.001) were significant factors for LR-free survival. Disease-specific survival was affected by histological grade (p < 0.001), but not by LR (p = 0.397). Intralesional curettage of a low-grade CS is associated with an increased risk of LR, but LR does not affect disease-specific survival. Therefore, for low-grade CSs of the hands and feet, surgical management should aim to preserve function. In grade 2 CS, our study did not show any decreased disease-specific survival after recurrence; however, we suggest a more aggressive surgical approach to these tumours to prevent local recurrence, especially in the metacarpal and metatarsal bones. In high-grade tumours, the incidence of progressive disease is high and, therefore, the treatment of the primary tumour should be aggressive where possible, and patients observed closely for the development of metastatic disease. Cite this article: Bone Joint J2021;103-B(3):562-568.

Negative impact of antibiotic administration on the clinical activity in patients with advanced gastric cancer

Antibiotics (ATBs) induce dysbiosis of the gut microbiota by altering the diversity and composition of the microbiota, which mediates the efficacy and toxicity of cancer therapy. The influence of dysbiosis induced by ATB administration on primary resistance to chemotherapy in patients with advanced gastric cancer (GC) has been rarely studied. We evaluated the effect of ATB administration on chemotherapy efficacy in patients with advanced GC. Patients with GC were divided into two groups according to the status of ATB administration: ATB-treated and control groups. Tumor responses, progression-free survival (PFS) and overall survival (OS) were assessed. We found that the incidence of progressive disease in the ATB-treated group was significantly higher when compared with that in the control group that received no ATB treatment (72.73% vs. 29.55%, p = 0.007). In addition, ATB administration was associated with shorter PFS [median PFS: 1.47 vs. 4.97 months, hazard ratio (HR): 2.296, 95% confidence interval (CI): 1.214 − 4.342, p = 0.011] and reduced OS (median OS: 9.97 vs. 13.3 months, HR: 2.101, 95% CI: 1.030 − 4.286, p = 0.041) based on univariate analysis. Subsequent multivariate analysis also indicated that ATB administration was an independent prognostic factor for PFS (HR: 3.361, 95% CI: 1.592 − 7.097, p = 0.001) and OS (HR: 2.280, 95% CI: 1.042 − 4.991, p = 0.039). ATB administration is associated with reduced chemotherapy efficacy and poor prognosis in patients with advanced GC. Modulations in ATB-related dysbiosis and gut microbiota composition improve the clinical outcomes of chemotherapy. Supplemental data for this article is available online at https://dx.doi.org/10.1080/13102818.2021.1953400 .

Association of Morbid Progression With Overall Survival Among Patients With Multiple Myeloma: Validation of the Progression-free Survival Endpoint

IntroductionMultiple myeloma (MM) is an incurable malignancy, marked by end-organ damage that is frequently irreversible. Progressive disease (PD) can be defined as morbid PD, associated with new-onset hypercalcemia, renal insufficiency, anemia, or lytic bone lesions (CRAB symptoms), or as asymptomatic biochemical progression. The frequency of morbid versus asymptomatic PD and its effect on survival is unknown. Our aim was to determine the incidence of morbid PD, and to evaluate if this influences survival. Patients and MethodsData from 2 phase III trials of transplant-ineligible patients with newly diagnosed MM were included in a post hoc analysis. ResultsOf 2082 patients enrolled, 1243 (59.7%) experienced PD. At first progression, 543 (43.7%) patients had morbid PD; 12 (2.2%) had hypercalcemia, 271 (49.9%) had renal insufficiency, 370 (68.1%) developed anemia, and 79 (14.5%) developed new or enlarged bone lesions. A total of 700 (56.3%) patients had asymptomatic PD. Patients with morbid PD had worse second progression-free survival (PFS) versus patients with asymptomatic biochemical PD (median second PFS, 11.5 months vs. 20.0 months; hazard ratio, 1.63; 95% confidence interval, 1.43-1.85; P < .0001) and worse overall survival (OS) (median OS, 23.2 months vs 39.3 months; hazard ratio, 1.51; 95% confidence interval, 1.30, 1.74; P < .0001). ConclusionsMorbid PD occurs frequently and is associated with inferior second PFS and OS. As CRAB symptoms may not reverse with therapy, morbid PD is a meaningful event, and its association with a shortened PFS adds validity to PFS as a relevant endpoint in patients with MM.

Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis

BackgroundThe efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown.MethodsWe evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease.ResultsA total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine–sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine–sulindac as compared with sulindac (P=0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine–sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups.ConclusionsIn this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.)

Timing of antiretroviral therapy for HIV-infected patients with moderate to severe Pneumocystis pneumonia: study protocol for a multi-centre prospective randomised controlled trial

BackgroundPneumocystis pneumonia (PCP) is a common acquired immune deficiency syndrome (AIDS)-related opportunistic infection. Recent reports estimate that more than 400,000 patients with human immunodeficiency virus (HIV) develop PCP each year globally. However, the timing of antiretroviral therapy (ART) initiation for HIV-infected patients with PCP is still controversial, and the benefits and risks of early initiation of ART are not completely clear. We thus designed this study in order to determine the optimal timing for ART initiation for HIV-positive patients with moderate to severe PCP.MethodsThis study will be an open-label, multi-centre, prospective randomised controlled trial. A total of 200 subjects will be randomly assigned to an early ART initiation group (≤14 days after PCP diagnosis) and a deferred ART initiation group (>14 days after PCP diagnosis) at a 1:1 ratio. All subjects will be followed up for 48 weeks after starting ART. The primary endpoint is incidence of disease progression (including new or relapsing opportunistic infections and death) at week 48. The secondary endpoints are the changes in CD4 counts from baseline at weeks 12, 24 and 48; the degree of virological suppression (HIV RNA < 50 copies/mL) at weeks 24 and 48; the rate of development of PCP-associated immune reconstitution inflammatory syndrome; and adverse events over 48 weeks.DiscussionWe hope that the results of this study will reveal the optimal timing for initiation of ART in HIV-infected patients with moderate to severe PCP.Trial registrationThis trial was registered as one of the 12 trials under the name of a general project at chictr.org.cn on February 1, 2019. The registration number of the general project is ChiCTR1900021195.

Outcomes of combined radiotherapy in high-risk prostate cancer

Radiotherapy is one of the radical treatment options used in patients with prostate cancer (PC). Many studies of combined radiotherapy (CRT) for PC have demonstrated good results in respect of response to treatment; however, the sequence of CRT steps and optimal interval between them have not been determined so far. Few randomized studies have been conducted in order to confirm the advantages of brachytherapy at the first or second step or determine the most effective interval between the contact and external beam RT. Therefore, it appears reasonable to evaluate different CRT techniques.Purpose. The goal of the study was to evaluate the outcomes of PC treatment depending on the sequence of CRT steps and the interval between them.Materials and methods. 53 patients with PC received 125I radiation therapy in combination with long-term hormone therapy (HT). Median follow-up was 38 months. Patients’ age varied from 54 to 81 years. All patients were in a high-risk group according to the D’Amico Risk Classification System. The patients were allocated to two groups: in Group 1, brachytherapy was used as the first step (n=31); in Group 2, it was applied after external beam therapy (EBT). The interval between the CRT steps could be less than 4 weeks (n=6), 4 – 7 weeks (n=17) and more than 8 weeks (n=30). Standard fractionation EBT with a total dose of 46 Gy using the VMAT technique was conducted. 125I prostate implants were inserted to reach a total dose of 110 Gy. Neoadjuvant (2 – 4 months) and adjuvant (not less than 24 months) regimens of HT were applied.Results. Five (9.4 %) patients had disease progression; two of them experienced only biochemical recurrence; distant metastases were diagnosed in three patients. Median time to disease progression was 29.9 months. One patient with a biochemical relapse died of acute myocardial infarction (1.9 %). Median five-year disease-free survival was 84.5±11.7 % in Group 1 and 83.5±9.1 (p=0.73) in Group 2. There were no significant differences in the incidence of toxicity depending on the sequence of CRT steps.Conclusion. EBT using 125I radiation sources in combination with long-term hormone therapy is an effective and safe treatment option for high-risk PC patients. No significant increase in the incidence of disease progression was observed when the interval between the CRT steps was increased to more than 8 weeks. Changes in the sequence of CRT steps do not affect response to treatment or incidence of radiation-related complications.

Analysis of the Relationship between Cytogenetic Changes and Course Evolution of Patients with CML during TKI Treatment

To analyze the relationship between cytogenetic changes and the progression in the patients with chronic myeloid leukemia (CML) during the treatment with tyrosine kinase inhibitor (TKI).The chromosome G banding of 150 patients with CML treated in our hospital, was carried out to analyze the karyotype by the 24 h short-term culture or direct method of bone marrow cells, and the point mutation of the ABL kinase area was detected, the relationship between cytogenetic changes and the evolution of the disease course was analyzed.The indirect fluorescence in situ hybridization showed that the BCR-ABL fusion gene of 150 patients was positive, out of which 142 cases showed positive Philadelphia (Ph) (94.67%), 8 cases with Ph negative (5.33%). Among 142 cases with Ph positive on the first diagnosis, and 14 cases (9.86%) with additional chromosome abnormality (9.86%), 4 cases (2.82%) with mutation translocation with 124 cases (87.32%), standard translocation t (9; 22) (q34; Q11) were found. Out of the 14 patients with additional chromosomal abnormalities, 8 cases with "main pathmay" abnormalities, 2 case with -Y abnormalities, and 4 cases with "secondary pathway" abnormalities were observed. During TKI treatment, additional chromosomal abnormalities were found in 46 patients with standard translocation and abnormal number of chromosomes, and the incidence of disease progression and point mutation were higher (P＜0.05). Compared with patients with the standard translocation, the disease-free survival rate of the patients diagnosed as CML at 1st visit and with additional chromosome abnormality was significantly decreased (P＜0.05), but the overall survival rate showed no significantly different (P＞0.05). Compared with patients without additional cvtogenetic aberrations, the disease free and overall survival rate of the patients with additional cytogenetic aberrations during the TKI treatment of CML in chronic phase were significantly decreased (P＜0.05).Some CML patients may have additional chromosomal abnormalities during the onset and development of the disease, and these patients are at higher risk of disease progression.CML患者在TKI治疗过程中的细胞遗传学变化与病程演进的关系分析.分析慢性髓系白血病（CML）患者在酪氨酸激酶抑制剂（TKI）治疗过程中的细胞遗传学变化与病程演进的关系.对本院收治的150例初诊CML患者，通过骨髓细胞24 h短期培养法或直接法，行染色体G显带技术核型分析；经ABL激酶区点突变检测，分析细胞遗传学变化与其病程演进的相关性.间接荧光原位杂交技术检测结果发现，150例患者BCR-ABL融合基因均为阳性，其中费城（Ph）染色体阳性142例（94.67%），阴性8例（5.33%）；142例Ph染色体阳性患者中，初诊Ph阳性且伴有额外染色体异常14例（9.86%），变异易位4例（2.82%），标准易位t（9；22）（q34；q11）124例（87.32%）。14例伴有额外染色体异常的患者中，“主要路径”异常8例，-Y异常2例，“次要路径”异常4例。在TKI治疗期间，46例标准易位患者出现额外染色体异常，以染色体数目异常为主，此类患者疾病进展和出现点突变的比例较高（P＜0.05）。与标准易位患者比较，初诊CML慢性期伴有额外染色体异常患者无病生存率明显降低（P＜0.05），而与总生存率的比较，并无明显差异（P＞0.05）。与无额外染色体异常患者比较，CML慢性期TKI治疗期间出现额外染色体异常者无病生存率及总生存率明显下降（P＜0.05）.部分CML患者在疾病发生和发展过程中可出现额外染色体异常，此类患者发生疾病进展的风险性较高.