Primary prophylaxis implementation and long-term joint outcomes in Swedish haemophilia A patients.

INTRODUCTION: Primary prophylaxis is the gold standard in severe haemophilia A (SHA) but time to escalate the prophylaxis regimen varies. AIM: Assess prophylaxis implementation and long-term joint health outcomes in SHA with primary prophylaxis. METHODS: Adult male patients born after 1980, with SHA on primary prophylaxis, started before the age of 3 years and second joint bleed, and no history of FVIII inhibitors, were enrolled. Repeated joint-health examinations were performed with HJHS or HEAD-US; VERITAS-PRO assessed adherence. RESULTS: Thirty patients were enrolled with, at inclusion, median age 33.5 years, annualized bleed rate and joint bleed rate 0, and FVIII consumption 4232 IU/kg/year, respectively. The median age was 1.2 years, at prophylaxis start once weekly with a median FVIII dose of 47.7 IU/kg, and 1.7 years, by the time escalation to a final regimen had occurred, with a median infusion frequency of thrice weekly and FVIII dose 41.7 IU/kg, respectively. Older age correlated with later transition to escalated prophylaxis (p < .001). Longer time to escalated prophylaxis correlated to more bleeds (p < .001). Median HJHS increased slowly, reaching 4 at 35-40 years. HJHS at 15-20 years correlated with higher HJHS afterwards. Median total HEAD-US score was 1 and correlated with HJHS (p < .001). Median VERITAS-PRO score was 36, indicating good treatment adherence. CONCLUSION: Primary prophylaxis is effective but does not completely prevent the gradual development of arthropathy in SHA. Joint assessments with HJHS should start at an early age, as they correlate with arthropathy in later life. Prophylaxis escalation should proceed expeditiously to prevent bleeds.

Outcome of Pneumocystis Jirovecii pneumonia (PcP) in post-CAR-T patients with hematological malignancies.

BACKGROUND: Pneumocystis jirovecii pneumonia (PcP) is an opportunistic infection associated with immunocompromised patients. The development of novel immunotherapies has promoted the incidence of PcP. This study describes the clinical course and outcome of PcP in chimeric antigen receptor (CAR) T cell recipients with hematological malignancies. METHODS: This is a retrospective case series of CAR-T recipients diagnosed with PcP in our center. The cases were all confirmed by metagenomic next-generation sequencing of clinical samples. The demographic, clinical, and outcome data were retrieved from the patients' medical charts and electronic medical record system. RESULTS: In total, 8 cases of PcP were identified. The underlying malignancies included T-acute lymphoblastic leukemia (ALL) (n = 1), diffuse large B cell lymphoma (DLBCL) (n = 4), and B-ALL (n = 3). One patient received short-term sulfamethoxazole-trimethoprim (SMZ-TMP) while the others had no prophylaxis. Four patients had neutropenia/lymphopenia at the diagnosis of PcP, and two patients had immunosuppressants within one month before PcP manifestation. The median time from CAR-T infusion to PcP diagnosis was 98.5 days (range 52-251). Seven patients recovered from PcP after proper management while one died of septic shock. CONCLUSION: PcP can occur after different CAR-T product, and the long-term depletion of immune cells seems to be related to PcP. SMZ-TMP is effective in this setting. More real-world experience of CAR-T therapy is required to assess the incidence and outcome of PcP in this population.

Impact of timing of prophylaxis commencement, F8 genotype and age on factor consumption and health-related quality of life in patients with severe haemophilia A.

INTRODUCTION: The timing of prophylaxis and F8 genotype can impact treatment outcomes in adults with severe haemophilia A (HA). AIM: To investigate how F8 genotype, timing, and type of prophylaxis influence arthropathy, bleeding rates, factor consumption and health-related quality of life (HRQoL). METHODS: Thirty-eight patients with severe HA were enrolled. Bleeding events were recorded retrospectively during median 12.5 months. F8 gene variants were classified as null or non-null. Joint health and HRQoL were assessed with HJHS and EQ-5D-5L, respectively. RESULTS: The median age at prophylaxis start was 1.25 years in the primary prophylaxis group (N = 15, median age 26 years) and 31.5 years in the secondary group (N = 22, 45 years), respectively. There were significant differences in the medians of HJHS (4 vs. 20, p < .001), EQ-5D-5L index (0.9647 vs. 0.904, p = .022), EQ VAS (87 vs. 75, p = .01) and FVIII consumption (3883 vs. 2737 IU/kg/year, p = .02), between the primary and secondary groups, respectively. Median annualized bleeding rate (ABR) was 0 for both groups. Twenty-five null and thirteen non-null F8 gene variants were identified. In the secondary prophylaxis group, lower median FVIII consumption (1926 vs. 3370 IU/kg/year) was shown for non-null compared to null variants, respectively, with similar ABR and HJHS. CONCLUSION: Delayed prophylaxis start with intermediate dose intensity prevents bleeds but at a cost of more arthropathy and reduced HRQoL, compared to higher intensity primary prophylaxis. Non-null F8 genotype may allow lower factor consumption with similar HJHS and bleeding rates, compared to null genotype.

Norfloxacin versus alternative antibiotics for prophylaxis of spontaneous bacteria peritonitis in cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a life-threatening complication in patients with advanced cirrhosis. Prophylactic Norfloxacin used to be considered effective in SBP prevention, but in recent years its efficacy has been partially compromised by increasing quinolone-resistant bacteria. However, whether the effects of alternative prophylactic regimens are superior to norfloxacin remains controversial. The goal of this study is to compare the effects of norfloxacin with other antibiotics in SBP prophylaxis for cirrhotic patients. METHODS: We systematically searched Pubmed, Embase, and Cochrane Library Databases. Two reviewers independently identified relevant random control trials (RCTs) comparing the role of norfloxacin and other antibiotics in SBP prevention. RESULTS: Eight studies comprising 1043 cirrhotic patients were included in this study. Norfloxacin and alternative antibiotics displayed comparable effects in SBP prophylaxis, survival benefit, overall infection prevention, and safety. Subgroup analyses revealed that rifaximin prophylaxis could reduce the recurrence of SBP with fewer adverse events but failed to improve overall survival compared with norfloxacin. CONCLUSIONS: Other antibiotics are a reasonable alternative to norfloxacin in the prophylaxis of SBP. Rifaximin prophylaxis could be an alternative choose of antibiotic for SBP prevention because of its better protective effect and safety.

Efficacy of regional cooling + oral dexamethasone for primary prevention of hand-foot syndrome associated with pegylated liposomal doxorubicin.

PURPOSE: Pegylated liposomal doxorubicin (PLD)-induced hand-foot syndrome (HFS) frequently lowers the quality of life of ovarian cancer patients. Wrist and ankle cooling, having a limited preventive effect, has been the commonest supportive HFS care. In this study, we retrospectively assessed the primary preventive effect of a combination of regional cooling and oral dexamethasone therapy (cooling + oral Dex) on HFS. METHODS: This study is a single-arm retrospective, observational study. Recurrent ovarian cancer patients were administered PLD ± bevacizumab. We retrospectively examined the efficacy of hands and feet cooling (from the start of PLD to the end) + oral Dex (day 1-5: 8 mg/day, day 6, 7: 4 mg/day) for primary HFS prevention. RESULTS: This study included 74 patients. The initial dose of PLD was 50 mg/m2 and 40 mg/m2 for 32 (43.2%) and 42 (56.8%) patients, respectively. HFS of Grade ≥ 2 and Grade ≥ 3 developed in five (6.8%) and one (1.4%) patient(s), respectively. The incidence of ≥ Grade 2 and ≥ Grade 3 HFS was much lower than those reported in previous studies. Dose reduction was required in 13 patients (17.6%) mainly because of neutropenia or mucositis; there was no HFS-induced dose reduction. Meanwhile, PLD therapy was discontinued mainly because of interstitial pneumonia (4 patients) and HFS (one patient). CONCLUSIONS: We demonstrated the efficacy of regional cooling and oral Dex for primary prevention of PLD-induced HFS. Although future prospective studies are needed to confirm its efficacy, this combination therapy can be considered for primary prevention of HFS in ovarian cancer patients on PLD.

Comparison of endoscopic ultrasound-guided primary and secondary prophylaxis for gastric variceal bleeding.

OBJECTIVES: Endoscopic ultrasound (EUS)-guided injection of cyanoacrylate (CYA) for primary prophylaxis (PP) of gastric varices (GV) is controversial. This study evaluates the safety and efficacy of this intervention. METHODS: Patients treated for PP of GV bleeding by EUS injection of CYA with or without coils were identified. Endoscopic techniques, outcomes, and adverse events (AEs) were reviewed and compared with a group treated for secondary prophylaxis (SP). Patients were followed until: (i) loss to follow-up; (ii) GV bleeding; (iii) interventional radiology or surgery decompression; (iv) liver transplant; or (v) death or comfort care. RESULTS: One hundred and nineteen patients (61 men; mean 59 ± 12 years) underwent EUS for PP (n = 24) or SP (n = 95). The PP group was treated with CYA alone (n = 18) or with coils (n = 4). Eight (33%) mild (n = 6) or moderate (n = 2) AEs and no index GV bleeding occurred during a mean of 6.1 ± 5.9 months follow-up. Repeat EUS in 22 (92%) PP patients showed 7 (32%) residual GVs, which were retreated with CYA alone (n = 6) or with coils (n = 1). Two (29%) mild (n = 1) or moderate (n = 1) AEs occurred after repeat EUS and 1/22 (5%) index GV bleed occurred during a mean 23 ± 25 months follow-up. Compared to the SP group, the PP group had lower Model for End-stage Liver Disease (MELD) score (P = 0.03), fewer GV stigmata (P < 0.001), required less CYA (P = 0.019) during index EUS, and had a longer time between index and surveillance EUS (P = 0.014). The incidence of AEs and GV bleeding between the two groups were similar. CONCLUSION: Posttreatment GV bleeding and AEs are similar following EUS-guided primary and secondary GV prophylaxis.

Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis.

BACKGROUND & AIMS: Whether non-selective ß-blockers can prevent decompensation of cirrhosis warrants clarification. Carvedilol might be particularly effective since its intrinsic vasodilatory activity may ameliorate hepatic vascular resistance, a major mechanism of portal hypertension in early cirrhosis. We assessed whether carvedilol may prevent decompensation and improve survival in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH). METHODS: By systematic review we identified randomized-controlled trials (RCTs) comparing carvedilol vs. control therapy (no-active treatment or endoscopic variceal ligation [EVL]) in patients with cirrhosis and CSPH without previous bleeding. We performed a competing-risk time-to-event meta-analysis using individual patient data (IPD) obtained from principal investigators of RCTs. Only compensated patients were included. Primary outcomes were prevention of decompensation (liver transplantation and death were competing events) and death (liver transplantation was a competing event). Models were adjusted using propensity scores for baseline covariates with the inverse probability of treatment weighting (IPTW) approach. RESULTS: Among 125 full-text studies evaluated, 4 RCTs were eligible. The 4 provided IPD and were included, comprising 352 patients with compensated cirrhosis, 181 treated with carvedilol and 171 controls (79 received EVL and 92 placebo). Baseline characteristics were similar between groups. Standardized differences were <10% by IPTW. The risk of developing decompensation of cirrhosis was lower with carvedilol than in controls (subdistribution hazard ratio [SHR] 0.506; 95% CI 0.289-0.887; p = 0.017; I2 = 0.0%, Q-statistic-p = 0.880), mainly due to a reduced risk of ascites (SHR 0.491; 95% CI 0.247-0.974; p = 0.042; I2 = 0.0%, Q-statistic-p = 0.384). The risk of death was also lower with carvedilol (SHR 0.417; 95% CI 0.194-0.896; p = 0.025; I2 = 0.0%, Q-statistic-p = 0.989). CONCLUSIONS: Long-term carvedilol therapy reduced decompensation of cirrhosis and significantly improved survival in compensated patients with CSPH. This suggests that screening patients with compensated cirrhosis for CSPH to enable the prompt initiation of carvedilol could improve outcomes. PROSPERO REGISTRATION NUMBER: CRD42019144786. LAY SUMMARY: The transition from compensated cirrhosis to decompensated cirrhosis is associated with markedly reduced life expectancy. Therefore, preventing decompensation in patients with compensated cirrhosis would be associated with greatly improved patient outcomes. There has been controversy regarding the use of non-selective ß-blockers (portal pressure-lowering medications) in patients with cirrhosis and elevated portal blood pressure (portal hypertension). Herein, using a competing-risk meta-analysis to optimize sample size and properly investigate cirrhosis as a multistate disease and outcomes as time-dependent events, we show that carvedilol (a non-selective ß-blocker) is associated with a reduced risk of decompensating events and improved survival in patients with cirrhosis and portal hypertension.

Long-acting granulocyte colony-stimulating factor in primary prophylaxis of early infection in patients with newly diagnosed multiple myeloma.

PURPOSE: This study sought to compare the efficacy of prophylactic long-acting and standard granulocyte colony-stimulating factor (G-CSF) on febrile neutropenia, early infections, and treatment delay in patients with newly diagnosed multiple myeloma (MM) receiving the therapeutic regimen of bortezomib, lenalidomide, and dexamethasone (VRd). METHODS: A prospective study with 68 consecutive patients with MM was conducted in three regional hospitals. Participants were randomly treated with the VRd regimen in combination with prophylactic long-acting G-CSF (treatment group) or prophylactic standard G-CSF (control group). The primary endpoints were the incidence rates of febrile neutropenia, early infection, and treatment delays. The secondary endpoint was clinical outcomes. RESULTS: Thirty-three patients were assigned to the treatment group, and thirty-five patients were assigned to the control group. The incidence of febrile neutropenia was 6.1% and 17.1% in the treatment and control groups, respectively (p = 0.297). However, the rates of early infection and treatment delay were markedly lower in the treatment group than in the control group (6.1% vs. 25.7% and 9.1% vs. 31.4%; p < 0.05). Notably, all early infections occurred during the first four cycles of VRd therapy, and the most common type of infection was pneumonia. No significant difference in clinical efficacy was found between the two groups. All participants achieved at least partial remission. CONCLUSIONS: Prophylactic administration of domestic long-acting G-CSF markedly reduced the rates of early infection and treatment delay as compared with standard G-CSF in patients newly diagnosed with MM. Notably, all early infections occurred during the first four cycles of VRd therapy. As such, it seems appropriate to administer long-acting G-CSF with the aim of primary prophylaxis of early infection in the setting of newly diagnosed MM.

A retrospective review of the real-world experience of the Pegfilgrastim biosimilar (Lapelga®) to the reference biologic (Neulasta®).

INTRODUCTION: Cancer patients receiving myelosuppressive chemotherapy are vulnerable to febrile neutropenia (FN) which contributes to poor treatment outcomes. The use of granulocyte colony-stimulating factors is administered to prevent chemotherapy-induced neutropenia. The introduction of biosimilars has allowed for greater cost-savings while maintaining safety and efficacy. This retrospective study assessed the incidence of FN and related treatment outcomes and the cost minimization of a pegfilgrastim biosimilar and its reference. METHODS: A retrospective chart review of breast cancer patients receiving (neo) adjuvant chemotherapy from February 2017 to May 2020 was conducted. The endpoints included the incidence of FN, the occurrence of dose reduction (DR), dose delay (DD) and pain. A cost minimization analysis was performed from a third-party payer perspective. RESULTS: One hundred Neulasta® and 74 Lapelga® patients were included in the first-cycle analysis. The rate of FN in cycle 1 for Neulasta® and Lapelga® was 2/100 and 4/74, respectively; risk difference (RD) = 3.4%; 95% CI: -2.4 to 9.2%. Eighty-three Neulasta® and 59 Lapelga® patients were included in the all-cycle analyses, where DR was reported in 76 (15%) Neulasta® cycles vs 33 (10%) Lapelga® cycles (RD = -3.6, 95% CI: -10.2 to 2.9). DD was reported in 20 (4%) Neulasta® cycles vs. 11 (3.5%) Lapelga® cycles (RD = -0.3; 95% CI: -2.7 to 2.0). Adverse events were similar between groups. Cost minimization using a cohort of 20,000 patients translated into an incremental savings of $21,606,800 CAD for each cycle. CONCLUSION: The biosimilar pegfilgrastim was non-inferior to the reference biologic based on FN incidence in addition to related outcomes including DR and DD.

Primary endoscopic variceal ligation reduced acute variceal bleeding events but not long-term mortality in pediatric-onset portal hypertension.

BACKGROUND/PURPOSE: Esophageal variceal bleeding (EVB) is a medical emergency in patients with portal hypertension (PHT). However, studies on the long-term outcomes of prophylactic endoscopic variceal ligation (EVL) in pediatric-onset PHT are lacking. METHODS: Between 1999 and 2020, patients who received EVL in the Electronic Report System of the Pediatric Endoscopy Unit were included in this retrospective study. EVL was classified as primary prophylaxis when it was performed for esophageal varices (EVs) without previous bleeding. If it was implemented in acute EVB, the subsequent EVL was classified as secondary prophylaxis. RESULTS: Fifty-eight patients aged 10 months to 33 years with 31 males were included. Thirty-eight patients were classified as primary prophylaxis group, and twenty, secondary prophylaxis group. The primary prophylaxis group experienced fewer 5-year EVB events than the secondary prophylaxis group (cumulative risk: 14.4% versus 32.4%). Still, it didn't significantly affect overall survival and biliary atresia transplant-free survival. Long-term mortality was significantly associated with higher serum direct bilirubin levels (≥0.55 mg/dL) and lower albumin levels (≤2.54 mg/dL) at the first EVL. Aspartate aminotransferase-to-platelet ratio index (APRI) with a cut-off value of 1.24 helped to predict EV presence at the initial esophagogastroduodenoscopy (EGD) (AUROC = 0.762, sensitivity 75.0%, and specificity 66.7%). CONCLUSION: Primary prophylactic EVL, despite reducing acute EVB, may not change overall survival and biliary atresia transplant-free survival. APRI > 1.24 may predict EV presence at the first EGD and help to schedule a surveillance EGD. Higher direct bilirubin and lower albumin levels at the first EVL may relate to long-term mortality.

Bacterial infections adversely influence the risk of decompensation and survival in compensated cirrhosis.

BACKGROUND & AIMS: The prognosis of compensated cirrhosis is good until decompensation. In decompensated cirrhosis, bacterial infections (BIs) are common and increase the risk of death. The incidence and prognostic implications of BIs in compensated cirrhosis are less-well characterized. This study aimed to assess whether BIs influence the risk of decompensation and survival in patients with compensated cirrhosis. METHODS: This is a cohort study nested to the PREDESCI study, a double-blind, multicenter, randomized controlled trial designed to assess whether ß-blockers could prevent decompensation of cirrhosis. Patients with compensated cirrhosis and hepatic venous pressure gradient ≥10 mmHg were included. Development of BIs during follow-up was prospectively registered. Using a competing-risk time-dependent regression analysis, we investigated whether BIs affect the risk of decompensation and survival. Decompensation was defined as development of ascites, bleeding or overt encephalopathy. RESULTS: A total of 201 patients were randomized and followed for a median of 36 months (IQR 24-47 months); 34 patients (17%) developed BIs, which occurred before decompensation in 33 cases, and 29 (14%) developed ascites. Respiratory and urinary tract infections were the most frequent BIs. Decompensation occurred in 26% patients with BIs vs. 16% without BIs. Patients with BIs were at higher risk of decompensation (subdistribution hazard ratio [SHR] 2.93; 95% CI 1.02-8.42; p = 0.047) and of developing ascites (SHR 3.55; 95% CI 1.21-10.47; p = 0.022) than those without BIs. Risk of death was also higher in patients with BIs (subdistribution HR 6.93; 95% CI 2.64-18.18; p <0.001), although decompensation occurred before death in 71% of such cases. CONCLUSIONS: BIs have a marked impact on the natural history of compensated cirrhosis, significantly increasing the risk of decompensation, mainly that of ascites, and increasing the risk of death, which usually occurs after decompensation. Our results suggest that BIs may constitute a target to prevent decompensation. LAY SUMMARY: It is widely known that bacterial infections are common and increase the mortality risk in patients with decompensated cirrhosis. However, the relevance of bacterial infections in compensated cirrhosis has not been well studied. This study shows that in patients with compensated cirrhosis and clinically significant portal hypertension, bacterial infections occur as frequently as the development of ascites, which is the most frequent decompensating event. Bacterial infections increase the risk of progression to decompensation, mainly by increasing the risk of ascites, and also increase the risk of death, which usually occurs after decompensation. CLINICALTRIALS. GOV IDENTIFIER: NCT01059396.

Effects of filgrastim versus pegfilgrastim on outcomes of DA-R-EPOCH for non-Hodgkin's lymphoma.

PURPOSE: Our study aimed to compare the median and average last dose level reached with DA-R-EPOCH, which includes the chemotherapy agents etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab, in patients using filgrastim versus pegfilgrastim as febrile neutropenia primary prophylaxis. METHODS: A retrospective, single-center chart review from January 1, 2014, to September 30, 2019, at The University of Kansas Health System identified patients > 18 years old who received at least four cycles of DA-R-EPOCH in an inpatient or outpatient setting for any subtype of lymphoma along with at least one dose of filgrastim or pegfilgrastim. Data was collected to compare dosing levels reached, appropriate discontinuation of daily filgrastim when ANC > 5000 cells/mm3, completion of at least twice weekly complete blood count (CBC) monitoring after chemotherapy administration, the incidence of infections, FN, hospitalizations from infections or FN, and bone pain. RESULTS: We hypothesized that patients receiving pegfilgrastim will achieve similar median and average dose levels of DA-EPOCH, event-free survival rates, overall response rates, completion of at least twice weekly CBC monitoring, and incidence of infections, FN, hospitalizations for infections or FN, and bone pain compared to patients receiving filgrastim. CONCLUSIONS: The use of pegfilgrastim as a supportive care agent resulted in similar efficacy and safety outcomes compared to filgrastim with DA-R-EPOCH in terms of dose intensity levels and incidence of infections, FN, and bone pain.

First-line combination chemotherapy with etoposide, ifosfamide and cisplatin for the treatment of disseminated germ cell cancer: Efficacy and feasibility in current clinical practice.

OBJECTIVES: To evaluate the efficacy and safety profiles of first-line etoposide, ifosfamide and cisplatin and primary prophylaxis with pegfilgrastim as first-line chemotherapy for disseminated germ cell cancer. METHODS: This study reviewed 154 consecutive patients with previously untreated disseminated germ cell cancer who received first-line etoposide, ifosfamide and cisplatin between 1995 and 2020. Of these, 54 patients were managed with primary prophylaxis using pegfilgrastim (primary prophylaxis group), and 100 were managed with the therapeutic use of short-acting granulocyte colony-stimulating factor (non-primary prophylaxis group). RESULTS: The International Germ Cell Cancer Collaborative Group classification identified 90 (58%)/40 (26%)/24 (16%) patients with good/intermediate/poor prognosis, respectively. Overall, 139 patients (90%) were disease free after etoposide, ifosfamide and cisplatin with/without post-chemotherapy surgery. The median relative dose intensity of etoposide, ifosfamide and cisplatin was 96%, and there was a significant difference between the primary prophylaxis and non-primary prophylaxis groups (100% vs 90%, P < 0.01). The 5-year salvage treatment-free and overall survival rates were 83% and 94%, respectively. In total, 138 patients (90%) developed grade 4 hematological toxicities, and there were no treatment-related deaths due to myelosuppression. Grade 4 neutropenia was less commonly observed in the primary prophylaxis group compared with the non-primary prophylaxis group (80% vs 95%, P < 0.01). CONCLUSIONS: This is the largest study of first-line etoposide, ifosfamide and cisplatin, and its sufficient efficacy and safety profiles are confirmed in current clinical practice. Primary prophylaxis using pegfilgrastim might further improve the feasibility of etoposide, ifosfamide and cisplatin.

Predictors of Clostridioides difficile Infection Among Asymptomatic, Colonized Patients: A Retrospective Cohort Study.

BACKGROUND: Asymptomatic patients colonized with Clostridioides difficile are at risk of developing C. difficile infection (CDI), but the factors associated with disease onset are poorly understood. Our aims were to identify predictors of hospital-onset CDI (HO-CDI) among colonized patients and to explore the potential benefits of primary prophylaxis to prevent CDI. METHODS: We conducted a retrospective cohort study in a tertiary academic institution. Colonized patients were identified by detecting the tcdB gene by polymerase chain reaction on a rectal swab. Univariate and multivariate logistic regression analyses were used to identify predictors of HO-CDI. RESULTS: There were 19 112 patients screened, from which 960 (5%) colonized patients were identified: 513 met the inclusion criteria. Overall, 39 (7.6%) developed a HO-CDI, with a 30-day attributable mortality of 15%. An increasing length of stay (adjusted odds ratio [aOR] per day, 1.03; P = .006), exposure to multiple classes of antibiotics (aOR per class, 1.45; P = .02), use of opioids (aOR, 2.78; P = .007), and cirrhosis (aOR 5.49; P = .008) were independently associated with increased risks of HO-CDI, whereas the use of laxatives was associated with a lower risk of CDI (aOR 0.36; P = .01). Among the antimicrobials, B-lactam with B-lactamase inhibitors (OR 3.65; P < .001), first-generation cephalosporins (OR 2.38; P = .03), and carbapenems (OR 2.44; P = .03) correlated with the greatest risk of HO-CDI. By contrast, patient age, the use of proton pump inhibitors, and the use of primary prophylaxis were not significant predictors of HO-CDI. CONCLUSIONS: This study identifies several factors that are associated with CDI among colonized patients. Whether modifying these variables could decrease the risk of CDI should be investigated.

Beneficial effects of L-ornithine L-aspartate for prevention of overt hepatic encephalopathy in patients with cirrhosis: a systematic review with meta-analysis.

The present systematic review with meta-analysis was undertaken to review the evidence base in support of a beneficial effect of L-ornithine L-aspartate (LOLA) for the prevention/prophylaxis of overt hepatic encephalopathy (OHE) in patients with cirrhosis. Using appropriate keywords and electronic and manual searches together with established inclusion/exclusion criteria, six randomized controlled trials (RCTs) for a total of 384 patients were identified five of which were of high quality and low risk of bias according to Jadad-Cochrane criteria. Treatment with LOLA resulted in significant reductions in the risk of progression to OHE in MHE patients (3 studies) with RR: 0.23 [95% CI: 0.07, 0.73], p < 0.01. LOLA was also effective for secondary OHE prophylaxis with RR: 0.389 [95% CI: 0.174-0.870] p < 0.002 as well as for primary prophylaxis for OHE following acute variceal bleeding [RR: 0.42 [95% CI: 0.16-0.98] p < 0.03 and for OHE prophylaxis post-TIPSS [RR: 0.30 [95% CI: 0.03-2.66] compared to placebo/no intervention in all cases. OHE prevention/prophylaxis was accompanied by significant reductions of blood ammonia. Both oral and intravenous formulations of LOLA appeared to be effective for the prevention of progression to OHE in patients with MHE. These findings provide the first direct evidence of potential benefit of LOLA for the prevention of OHE in cirrhosis across a range of clinical presentations.

[Cost-effectiveness of primary prophylaxis with PEG-rhG-CSF in early-stage breast cancer patients receiving chemotherapy in China].

Objective: To evaluate the cost effectiveness of primary prophylaxis (PP) with pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF), PP with recombinant human granulocyte colony stimulating factor (rhG-CSF) and no prophylaxis in women with early-stage breast cancer in China. Methods: Two phase Markov models were constructed for a hypothetical cohort of patients aged 45 with stage Ⅱ breast cancer. The first phase modelled costs and outcomes of 4 cycles docetaxel combined with cyclophosphamide [TC×4, febrile neutropenia (FN) risk>20%] chemotherapy, which assumptions based on literature reviews, including FN rates [base-case (deterministic sensitivity analysis range), 0.29 (0.24-0.35)] and related events [FN case-fatality, 3.4 (2.7-4.1)]. Second phase modelled the long term survival which was link with the relative dose intensity (RDI) [mortality hazard ratio (HR) of RDI < 85% vs ≥85%, 1.45 (1.00-2.32)]. Clinical effectiveness, therapeutic costs, and economic utilities were estimated from peer-reviewed publications and expert opinions in case of unavailability of published evidences. Results: Compared to rhG-CSF PP and no prophylaxis, the cost of PEG-rhG-CSF PP increased to 5 208.19 RMB and 5 222.73 RMB, respectively. The quality-adjusted life-years (QALYs) enhanced to 0.066 and 0.297, respectively. Accordingly, the incremental cost effectiveness ratios (ICERs) are 79 146.3 RMB and 17 558.77 RMB per QALY, which were both below the willingness to pay (WTP) threshold of three times GDP per capita (18, 000 RMB) recommended by the WHO. Sensitivity analysis suggested that the more clinically effective the primary prophylaxis with PEG-rhG-CSF is, the more cost-effective primary prophylaxis with PEG-rhG-CSF will be. And the lower the mortality HR of RDI<85% vs ≥85% is, the more cost-effective primary prophylaxis with PEG-rhG-CSF will be. Conclusion: Although the cost of PP PEG-rhG-CSF is higher, considering the additional benefits, the administrating of PP PEG-rhG-CSF is likely to be a cost-effective alternative to PP rhG-CSF and no prophylaxis in patients with early stage breast cancer whose FN risks are more than 20% in China.

Post-ERCP Pancreatitis: Risk factors and role of NSAIDs in primary prophylaxis.

OBJECTIVE: To determine efficacy of diclofenac suppository in reducing post-ERCP pancreatitis (PEP) and identify risk factors for PEP. METHODS: This is a placebo-based prospective study at Department of Medicine & Gastroenterology, Services Institute of Medical Sciences / Services Hospital, Lahore performed from January 2018 to June 2019. Patients were randomized to receive diclofenac suppository or glycerine suppository before ERCP. Both groups were compared for PEP using chi square x2 test while risk factors for PEP were determined using binary logistic regression. RESULTS: Total of 165 patients with mean age 49.1(±15.2) and male to female ratio 1/1.6 (63/102) were included. Among 82 (49.7%) patients in diclofenac group, 8 (9.7%) developed pancreatitis while 19(22.9%) of 83(50.3%) in placebo group had PEP (p value 0.02). After multivariate analysis, age>45 years (p value 0.014, OR 3.2), Bilirubin >3 mg/dl (p value 0.004 OR 3.58), time to cannulation> 5 minutes (p value<0.000 OR 9.2), use of precut (p value< 0.000 OR 4.9), pancreatic duct cannulation (p value 0.000 OR 5.46) and total procedure time >30 minutes (p value 0.01 OR 3.92) were risk factors for PEP. CONCLUSION: Pre-procedure Diclofenac suppository reduces post-ERCP pancreatitis. Age > 45 years, serum bilirubin > 3 mg/dl, cannulation time > 5 minutes, use of precut, pancreatic duct cannulation and procedure time > 30 minutes are risk factors for post-ERCP pancreatitis.

Prophylaxis of chemotherapy-induced neutropenia and febrile neutropenia with lipegfilgrastim in patients with non-Hodgkin lymphoma (NADIR study).

OBJECTIVE: The prospective non-interventional study (NIS) NADIR was designed to evaluate both effectiveness and safety of prophylactic use of lipegfilgrastim (Lonquex® ), a glycopegylated granulocyte colony-stimulating factor, in cancer patients with different tumor entities undergoing chemotherapy in routine clinical practice. The primary objective was incidence of severe neutropenia, febrile neutropenia (FN), and neutropenia-associated complications. METHOD: NADIR was a national, multicenter, prospective NIS. RESULTS: Here, we present the data on patients with non-Hodgkin lymphoma (NHL). Final analysis comprised 337 NHL patients having received ≥1 administration of lipegfilgrastim. Primary prophylaxis with lipegfilgrastim was documented in 78.7% of patients with high risk to develop FN. In total, ≥1 severe neutropenia (grade 3/4) was reported in 115 (34.1%) patients and ≥1 event of FN documented in 15 (4.5%) patients. Grade 3/4 infections were reported in 22 (6.5%) patients overall. Most frequently reported adverse events (AEs) related to lipegfilgrastim in total were bone pain (5.4%), leukocytosis (2.1%), back pain (1.8%), platelet count decreased (1.2%), and myalgia (1.2%). Fatal serious AEs were documented in 9 (2.7%) patients; none were attributable to lipegfilgrastim. CONCLUSION: Prophylaxis or therapeutic intention with lipegfilgrastim in NHL patients in routine clinical practice showed similar effectiveness and safety as demonstrated in the pivotal trials.

Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: Real-world experience.

Cytomegalovirus (CMV) is associated with significant morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) patients. We evaluated the efficacy of letermovir as primary and secondary prophylaxis in 53 CMV-seropositive hematopoietic stem cell transplant recipients. 70% of patients were at high risk for CMV reactivation and disease (primarily ex vivo T-cell-depleted HCT [n = 18; 34%] or haploidentical T-replete HCT [n = 12; 23%]). This was a retrospective, single-center study which identified patients transplanted between January 2018 and June 2018. Patients were followed through September 2018. The primary outcome was the incidence of clinically significant CMV infection (CMV viremia requiring preemptive treatment or CMV disease). Primary letermovir prophylaxis started at a median of 7 days (range, 7-40) after allo-HCT. The median duration of primary letermovir prophylaxis was 116 days (range, 12-221). With primary prophylaxis in 39 patients, the observed CMV reactivation rate was 5.1%. Twenty-nine patients continued primary prophylaxis beyond 14 weeks with a reactivation rate of 3.4%. No recurrent reactivation was seen with secondary prophylaxis of an additional 14 patients. Our experience demonstrates the efficacy of letermovir in a real-world setting for CMV prevention for the first 14 weeks and continued efficacy when given longer than 14 weeks after allogeneic stem cell transplantation or as secondary prophylaxis.

Filgrastim prophylaxis in elderly cancer patients in the real-life setting: a French multicenter observational study, the TULIP study.

PURPOSE: Few studies are currently available among elderly patients, justifying the need for better understanding of daily medical practices in terms of use of growth factors to prevent chemotherapy (CT)-induced neutropenia. The primary objective of this study was to describe the use of filgrastim in the elderly. METHODS: Cancer patients aged 65 years and above, undergoing CT and initiating a prophylactic treatment with filgrastim, were enrolled. Patients were followed according to routine medical practice from filgrastim initiation until the end of the CT or after a maximum of 6 cycles. RESULTS: One thousand one hundred nineteen evaluable patients were documented in the study (mean age 73.9 ± 6.2 years, 52.1% men). The majority were suffering from solid tumor (73%) with ECOG 0-1 for 80% of them. Approximately two-third had a global risk for FN ≥ 20%, and one third < 20%. Through all CT cycles, no differences were observed between age classes ([65-74], [75-85], or > 85) in dose, duration, and time to first injection from CT start. Most patients (84%) received primary prophylaxis (PP) and 70% were administered during the first CT cycle. The median time from CT start until filgrastim was 4 days. The median duration of filgrastim treatment was 5 days. Dose reductions and CT delays were less frequent in patients receiving PP (4.8% and 7.1% respectively) than secondary prophylaxis (9.2% and 13.3% respectively). CONCLUSIONS: Filgrastim use was consistent with French Market Authorization terms. No difference was shown compared with younger patients. Safety data were consistent with the known safety profile.