Rates Of Other Adverse Events Research Articles

(088) Impact of Testosterone Replacement Therapy on Adverse Cardiovascular Events in Hypogonadism Patients: A Comprehensive Evaluation of Physiological and Supraphysiological T Levels

Abstract Introduction Sustained treatment with elevated levels of exogenous testosterone (T) has been linked to various adverse events, particularly concerning cardiovascular risks. However, there is currently a lack of sufficient literature that comprehensively describes the overall safety profile of supraphysiologic testosterone levels. Objective To compare the safety profiles and rates of polycythemia, venous thromboembolism (VTE), major adverse cardiac events (MACE), deep vein thrombosis (DVT), myocardial infarction (MI), and stroke between hypogonadism patients treated with testosterone replacement therapy (TRT) at physiological and supraphysiological testosterone levels. Methods We identified patients with hypogonadism (<300 ng/dL) who underwent testosterone replacement therapy (TRT) at our institution through electronic medical record review. Patients lacking records of their first encounter, documented medical history, sufficient follow-up, or post-TRT adverse event data were excluded from the analysis. Supraphysiological testosterone levels were defined as >1000 ng/dL. The included patients were retrospectively analyzed using two-way nonparametric testing for continuous variables and chi-square and Fisher exact tests for categorical variables (α = 0.05). Results From a cohort of 537 men diagnosed with hypogonadism, we included 184 patients who underwent testosterone replacement therapy (TRT). Among these patients, 135 (73.4%) were treated to achieve physiological testosterone levels, with a median level of 468.0 ng/dL (interquartile range, IQR = 308.0-644.5), while 49 patients (26.6%) were treated to attain supraphysiologic testosterone levels, with a median level of 1552 ng/dL (IQR = 1279-1700). Before initiating TRT, there was no significant difference in testosterone levels between the two groups (p = 0.11). Moreover, no significant differences were found between the groups in terms of a history of diabetes mellitus (DM; p = 0.422) or prostate cancer (p = 0.29). However, significant differences were observed in the history of hypertension (HTN; p = 0.003) and hyperlipidemia (HLD; p = 0.006), with more patients in the physiologic testosterone group having a diagnosis of HTN and HLD prior to treatment. Regarding adverse events, there were more cases of polycythemia in the supraphysiologic testosterone group compared to the physiologic testosterone group (p < 0.001; 35.4% vs. 7.0%). Interestingly, there was no significant difference in the rate of other adverse events after TRT between the two groups, including venous thromboembolism (VTE; p = 0.285), major adverse cardiovascular events (MACE; p = 0.768), deep vein thrombosis (DVT; p > 0.999), myocardial infarction (MI; p = 0.562), and stroke (p > 0.999). Conclusions Despite widespread concerns, these findings suggest that although patients treated to achieve supraphysiologic testosterone levels had a higher incidence of polycythemia, there were no significant differences in the rates of other adverse events after TRT between patients treated to attain physiological versus supraphysiologic testosterone levels. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Consultant for AbbVie, Marius, Tolmar, Endo, Petros, Boston Scientific, Coloplast Investor: Sprout.

Effect of duloxetine on pain and opioid consumption after total knee and hip arthroplasty: a systematic review and meta-analysis of randomized controlled trials.

Although duloxetine has shown a positive effect on pain relief with hip and knee osteoarthritis, there is no pooled analysis of duloxetine for pain relief and opioid consumption in patients after total hip or knee arthroplasty. This systematic review and meta-analysis aimed to analyze pain control, opioid consumption, and associated adverse events of perioperative administration of duloxetine after total hip or knee arthroplasty. After being registered with PROSPERO (CRD42022323202), the databases of MEDLINE, PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched from inception until March 20, 2023, for randomized controlled trials (RCTs). Primary outcomes were the visual Analog Scale (VAS) pain scores at rest (rVAS) and upon ambulation (aVAS). Secondary outcomes were postoperative opioid consumption quantified as oral morphine milligram equivalents (MMEs) and adverse effects of duloxetine. Nine RCTs with 806 cases were included. Duloxetine was associated with lower VAS scores at different times after surgery (24h, two weeks, and ≥ 3months). Compared to placebo, perioperative daily duloxetine use significantly reduced daily opioid MMEs at 24h (standard mean deviation [SMD] -0.71, 95% confidence interval [95% CI] -1.19 to -0.24,P = 0.003), three days (SMD -1.10, 95% CI -1.70 to -0.50,P = 0.0003), and one week (SMD -1.18, 95% CI -1.99 to -0.38,P = 0.004) after surgery. The duloxetine group had a significantly lower rate of nausea (odds ratio 0.62, 95% CI [0.41 to 0.94], P = 0.02) and a higher rate of drowsiness and somnolence (odds ratio 1.87, 95% CI [1.13 to 3.07], P = 0.01) compared to the placebo group. No significant differences were observed in the rates of other adverse events. Perioperative duloxetine significantly decreased postoperative pain and opioid consumption with good safety profiles. Further high quality designed and well-controlled randomized trials are warranted.

Effect of different timing of letrozole initiation on pregnancy outcome in polycystic ovary syndrome.

To investigate the efficacy of oral letrozole (LE) starting on day 3 or 5 of the menstrual cycle in patients with polycystic ovary syndrome (PCOS). Retrospective cohort study. Reproductive Endocrinology Department of Hangzhou Women's Hospital. In this retrospective analysis, we analyzed patients who received oral LE for ovulation induction (OI) at the Hangzhou Women's Hospital from January 2016 to January 2021. In total, 539 PCOS patients with fertility requirements were classified into the D3 group and D5 group according to the different starting times of oral LE, that is, from the 3rd or 5th day of the menstrual cycle or LE is taken orally for 5 days starting on day 3 or 5 of progesterone withdrawal bleeding. Treatment started with one tablet (LE 2.5 mg), continue the regimen from the previous cycle in non-responders and continued until pregnancy or for up to three ovulatory cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The primary outcome was to compare ovulation rates, conception rates, live birth rates, pregnancy complications, and pregnancy outcomes at different initiation times. Women who started LE on the 5th day of their menstrual cycle had more cumulative conception rates than those who started LE on the 3rd day(173 of 228[75.9%]vs. 201 of 311[64.6%], P= 0.005; rate ratio for conception, 1.174; 95% confidence interval,1.052 to 1.311) without significant differences in overall live birth rate, though there were 142 of 228[62.3%] in the D5 group versus 172 of 311[55.3%] in the D3 group (P= 0.105). The median (IQR) endometrial thickness was significantly (P = 0.013) greater during the D5 group treatment compared to the D3 group, which may be related to higher conception and clinical pregnancy rates. The median (IQR) maximum follicle diameter was not statistically (P = 0.073) different between the two groups. The cumulative ovulation per cycle rate was higher with D5 than with D3 (287 of 405 treatment cycles [70.9%] vs. 388 of 640 treatment cycles [60.6%], P=0.001). There were no significant between-group differences in pregnancy loss (31 of 173 conceptions in the D5 group [17.9%] and 29 of 201 conceptions in the D3 group [14.4%]) or multiples pregnancy (8.2% and 10.5%, respectively). Rates of other adverse events during pregnancy were similar in the two treatment groups. As compared with D3 group, D5 group was associated with higher ovulation and conception rates, shorter time-to-pregnancy among infertile women with the PCOS.

Canadian Cancer Trials Group (CCTG) LY.17: A Randomized Phase II Study Evaluating Novel Salvage Therapy Pre-Autologous Stem Cell Transplant (ASCT) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (RR-DLBCL) - Outcome of Rituximab-Dose-Intensive Cyclophosphamide, Etoposide, Cisplatin (R-DICEP) Versus R-GDP

Introduction: The CCTG LY.12 trial established rituximab combined with gemcitabine, dexamethasone and cisplatin (R-GDP) as a standard salvage chemotherapy option prior to ASCT for patients (pts) with relapsed/refractory (RR) DLBCL (Crump JCO 2014). CCTG LY.17 is an ongoing multi-arm randomized phase II "pick a winner" trial evaluating novel salvage therapy compared with R-GDP in ASCT-eligible RR-DLBCL pts. Methods: The primary endpoint of the study is overall response rate (ORR) using CT imaging. According to the protocol futility rule, any treatment arm with an ORR lower than the R-GDP control arm at the first interim analysis (n = 16), or less than 10% higher at the second interim analysis (n=32) would not continue to full target accrual of 64 pts per treatment arm. Encouraging results could then be pursued in a larger phase III trial designed to detect differences in progression-free survival (PFS). This report involves the component of the trial that randomly allocated pts to either 1 cycle of inpatient R-DICEP (Rituximab 375mg/m2 IV or 1400mg sc days 1 and 5 plus dose-intensive Cyclophosphamide 5.25g/m2, Etoposide 1050mg/m2, Cisplatin 105mg/m2 divided over days 2-4, with daily filgrastim starting day 15 until apheresis of blood stem cells approximately between days 20-22) or to 3 cycles of outpatient R-GDP. This report is the result of the protocol-specified second interim analysis. Results: A total of 67 pts were randomized to R-DICEP (n=32) or to R-GDP (n=35) between April 2016 and April 2021. Table 1 lists baseline pt characteristics. Four pts (R-DICEP=2, R-GDP=2) were not evaluable for response. The ORR was 65.6% for R-DICEP (70.0% for evaluable pts), which was 17% greater than the ORR of 48.6% for R-GDP (51.5% for evaluable pts). Additionally, only 1 (3.1%) R-DICEP pts versus (vs) 11 (31.4%) R-GDP pts experienced progressive disease as best response to salvage therapy. Of interest, the ORR to salvage was 40% (14/35) for pts primary refractory to RCHOP (no response to RCHOP or progressive disease during or <3mo post RCHOP) vs 75% (24/32) for those who relapsed >3mo post RCHOP (p=0.006), with ORR to R-DICEP of 50% vs 81.3% and ORR to R-GDP of 31.6% vs 68.8% for primary refractory vs relapse >3mo, respectively. The ORR based on PET-CT scan was 50.0% vs 31.4% for the R-DICEP (n=26) vs R-GDP (n=25) arms, respectively. Overall, 23 (71.9%) R-DICEP pts and 19 (54.3%) R-GDP pts underwent ASCT. In total, 26 out of 27 (96.3%) R-DICEP, and 18 out of 20 (90%) R-GDP pts underwent successful autologous blood stem cell collection (requiring >1 attempt in 0 R-DICEP and 2 R-GDP pts). The median time to neutrophil engraftment post-ASCT was 13 (1-32) and 12 (1-22) days, and to platelet engraftment was 12 (1-50) and 16 (7-22) days for R-DICEP and R-GDP pts, respectively. Regarding adverse events (AEs) of salvage therapy and subsequent ASCT, R-DICEP pts had higher rates of culture positive infection (84% vs 40%), platelet (96.6% vs 60.0%) and red cell (75.0% vs 42.9%) transfusions, diarrhea (44% vs 14%), serious adverse events (50% vs 34.3%), and treatment-related mortality (3.1% vs 0%) but similar rates of other AEs including arrhythmia (6% vs 9%), bleeding (0 vs 0), fungal infections (0 vs 0) and pneumonitis (0 vs 0). At a median duration of follow-up of 26.9 months (R-DICEP 26.4 months and R-GDP 27.4 months), the 1-year PFS rate was 42% for R-DICEP and 32% for R-GDP (HR 0.59, 95%CI: 0.32-1.09, logrank p=0.09), and 1-year OS rate was 65% for R-DICEP and 55% for R-GDP (HR 0.675, 95%CI: 0.333-1.369, logrank p=0.27). Conclusions: Although the 17% improvement in ORR for R-DICEP vs R-GDP in the second interim analysis exceeded the pre-specified 10% threshold required proceed to full accrual of 64 pts in the R-DICEP arm, we decided to stop accrual to the R-DICEP arm of the LY.17 trial due to slow accrual, higher AE rates, and greater utilization of healthcare resources including hospitalization needed to administer treatment, which limits feasibility of R-DICEP at several Canadian centres. The LY.17 trial continues testing other salvage regimens. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intravenous Iron Isomaltoside for Patients With Iron Deficiency Undergoing Elective Surgery

&#x0D; The results of 1 randomized controlled trial did not find a difference in functional status (6-minute walk distance and New York Heart Association class), hand grip strength, or health-related quality of life for patients who underwent a transcatheter aortic valve implantation treated with iron isomaltoside versus placebo.&#x0D; There was 1 (1.4%) hypersensitivity reaction and 1 (1.4%) episode of chest pain in patients treated with iron isomaltoside in the randomized controlled trial. Rates of other adverse events were similar between patients treated with iron isomaltoside and placebo.&#x0D;

Trends of adverse events and mortality after DMARDs in patients with rheumatoid arthritis: Interrupted time-series analysis.

ObjectivesPatients with rheumatoid arthritis (RA) experience adverse events because of the characteristics of the disease and the side effects of medications. We investigated the trends of adverse events and mortality associated with disease‐modifying antirheumatic drugs (DMARDs).MethodsWe used the Taiwan National Health Insurance Database to enroll patients with incident RA between 2000 and 2017. The 1‐year incident rate of gastrointestinal (GI) bleeding and 3‐year incident rates of other adverse events and mortality for each calendar‐quarter cohort were computed and adjusted using propensity score‐based stabilized weights for fair comparisons. Levels and trends of the conventional DMARD era (2000–2002, Phase 1) were compared with those of the TNFi era (2003–2012, Phase 2) and OMA era (2013–2017, Phase 3) by using interrupted time series (ITS) analysis.ResultsAll patients with RA were prescribed cDMARDs in Phase 1 (2000–2002), and 1%–3% were prescribed either TNFi in phase 2 (2003–2012) or OMAs in phase 3 (2013–2017). The cancer incidence rate was 1.90%, and its mortality rate was 4.19%. After the introduction of TNFi from 2003 to 2012, the main outcomes, except TKA, exhibited a steady or mild decrease in trends. ITS analysis revealed that the slope mildly increased in 2003–2012 compared with that in 2000–2003 by 0.13% for total knee replacement (p = .0322). In 2012–2017 (the OMA era), the events became steady.ConclusionIn patients with RA, the introduction of DMARDs was associated with stable adverse events and mortality rates. Moreover, the introduced new treatment for RA exhibited a good safety profile.

Complications after surgical treatment of pelvic fractures: a five-year follow-up of 194 patients

PurposeSurgical treatment of pelvic fractures is an advanced intervention associated with multiple complications. The primary aim of this study was to investigate the rate of unplanned reoperations after pelvic fracture surgery. Secondary aims included occurrence of other adverse events and mortality.MethodsAll adult patients ≥ 18 years with surgically treated pelvic fracture operated at the Karolinska University Hospital in Sweden between 2010 and 2019 were identified and retrospectively included. Data were collected through review of medical records and radiographs. Logistic regression analysis was performed to evaluate factors associated with unplanned reoperations and other adverse events.ResultsA total of 194 patients were included with mean age (± SD, range) 45.4 (16, 18–83) years. 62% were males (n = 121) and the median (IQR) follow-up time was 1890 (1791) days (4.9 years). Forty-eight patients (25%) had an unplanned reoperation, with infection being the most common cause of reoperation (n = 18, 9.3%). Seventy-eight (40%) patients had an adverse event not requiring reoperation and the most common event was nerve injury (n = 34, 18%). Concomitant abdominal injury was identified as a risk factor for an adverse event (OR 2.5, 95% CI 1.3–4.9, p < 0.01). 30-day mortality was 1.5% and 1-year mortality 6.2%.ConclusionThe rate of unplanned reoperation after pelvic fracture surgery was high, as was the rate of other adverse events not requiring surgery. No identified risk factor was found to predict further surgery, but concomitant abdominal injury was a risk factor for other adverse events. Mortality was low at both 30 days and 1 year.

Pre‐emptive oral clarithromycin to reduce the skin toxicity of panitumumab treatment for metastatic colorectal cancer.

79 Background: Chemotherapy with panitumumab is expected to be well tolerated and improve survival in patients with metastatic colorectal cancer (mCRC). However, skin toxicities are its most common adverse events. The aim of this trial was to evaluate the efficacy and safety of pre-emptive antibiotic treatment with clarithromycin (CAM) to prevent panitumumab skin toxicities. Methods: We conducted a phase lll, multicenter, open-label, randomized clinical trial on mCRC patients treated with pani- tumumab. Eligible patients were randomly assigned 1:1 to pre-emptive antibiotic and control groups. In the pre-emptive group, CAM administration (200 mg twice per day) continued daily through the panitumumab treatment period. The control regimen consisted of skin care only. The primary end point was the incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period. Results: Of 156 enrolled patients, 78 received pre-emptive antibiotic treatment, and 78 received reactive treatment. The number and incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period were 16 (21.3%) and 41 (54.7%) for the pre-emptive and control groups, respectively (HR, 0.32; 95% CI, 0.17–0.56). There was almost no difference in the rate of other adverse events between the two groups, but the incidence of grade ≥ 3 diarrhea in the pre-emptive group was high, at 8% vs. 1.3% in the control group. There were no treatment-related deaths. Conclusions: Prophylactic oral CAM together with relatively simple skin care was found to be effective in suppressing the development of grade ≥ 2 skin toxicities induced by panitumumab. Clinical trial information: UMIN000011485.

Pre-emptive oral clarithromycin reduces the skin toxicity of panitumumab treatment for metastatic colorectal cancer.

Chemotherapy with panitumumab is expected to be well tolerated and improve survival in patients with metastatic colorectal cancer (mCRC). However, skin toxicities are its most common adverse events. The aim of this trial was to evaluate the efficacy and safety of pre-emptive antibiotic treatment with clarithromycin (CAM) to prevent panitumumab skin toxicities. We conducted a phase lll, multicenter, open-label, randomized clinical trial on mCRC patients treated with panitumumab. Eligible patients were randomly assigned 1:1 to pre-emptive antibiotic and control groups. In the pre-emptive group, CAM administration (200mg twice per day) continued daily through the panitumumab treatment period. The control regimen consisted of skin care only. The primary end point was the incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period. Of 156 enrolled patients, 78 received pre-emptive antibiotic treatment, and 78 received reactive treatment. The number and incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period were 16 (21.3%) and 41 (54.7%) for the pre-emptive and control groups, respectively (HR, 0.32; 95% CI, 0.17-0.56). There was almost no difference in the rate of other adverse events between the two groups, but the incidence of grade ≥ 3 diarrhea in the pre-emptive group was high, at 8% vs. 1.3% in the control group. There were no treatment-related deaths. Prophylactic oral CAM together with relatively simple skin care was found to be effective in suppressing the development of grade ≥ 2 skin toxicities induced by panitumumab. UMIN000011485 DATE OF REGISTRATION: Sep 1st, 2013.

BXCL701, first-in-class oral activator of systemic innate immunity pathway, combined with pembrolizumab (Keytruda) in men with metastatic castration-resistant prostate cancer (mCRPC).

124 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP), primarily DPP8 and DPP9, triggers inflammasome mediated pyroptosis in macrophages, leading to induction of IL-18 and IL-1ß, bridging between innate and adaptive immunity. PD-L1 expression correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor growth inhibition was observed with BXCL701 plus checkpoint inhibition. In a prior clinical study, single-agent BXCL701 resulted in objective responses in patients with Stage IV melanoma (unpublished). Methods: Eligible patients included in Phase 1b portion of this multicenter study, had progressing mCRPC (PCWG3), ≥1 prior systemic therapy, ≤2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anticancer therapy. In Phase 2 portion, patients with adenocarcinoma must have received 1 or 2 2nd generation androgen signaling inhibitors; patients with SCNC/t-NEPC must have received ≥1 prior line of chemotherapy. Patients received fixed-dose pembrolizumab (200 mg IV q21-days) with BXCL701 on days 1-14 at recommended Phase 2 dose (RP2D)/schedule. Primary endpoint is Composite Response (RECIST 1.1, PSA, CTC). Change in relevant immune effector cells was also evaluated. Results: In Phase 1b portion 13 patients were treated with BXCL701 in 3 cohorts: 0.4 mg qd (n = 3); 0.6 mg qd (n = 3) and 0.6 mg split dose (n=7). 7 patients had adenocarcinoma, 6 had small cell/neuroendocrine prostate cancer phenotype. Prior treatment included androgen deprivation therapy (n = 10), 2nd-generation androgen signaling inhibitors (n = 9), chemotherapy (n = 11), radiation therapy (n = 11). On-target adverse events (AEs) consistent with cytokine activation were seen at highest dose levels. In 0.6 mg qd cohort, all patients had events consistent with cytokine release syndrome: 3/3 had hypotension, including 1 grade 3 syncope—dose-limiting toxicity (DLT)—and 2 patients each had dizziness and lower extremity edema. Splitting 0.6 mg dose improved tolerability while maintaining total daily dose (TDD) previously associated with objective response; 3/7 patients had fatigue, and 1 patient each had low grade hypotension, dyspnea, chills, myalgia. Preliminary anti-tumor activity was seen with 1 patient achieving a PSA response and 4 patients with RECIST1.1 stable disease. Consistent dose and time dependent increases in serum IL-18 levels were observed. Conclusions: BXCL701 0.3 mg BID (0.6mg TDD) administered on days 1-14 was identified as RP2D when administered with pembrolizumab 200 mg every 21 days. Splitting TDD was associated with improved tolerability as evidenced by no reported DLTs and lower rates of other AEs of interest e.g. hypotension and peripheral edema. Preliminary data from Phase 2 portion will be presented. Clinical trial information: NCT03910660.

The predictive value of preimplant pulmonary function testing in LVAD patients

The predictive value of preoperative pulmonary function testing (PFT) in left ventricular assist device (LVAD) patients remains unknown. This study evaluates the relationship between abnormal PFTs and postimplant outcomes in LVAD patients. LVAD implants from January 2004 to December 2018 at a single institution were included. Patients were stratified based on the presence of abnormal preoperative PFTs, and the primary outcome was respiratory adverse events (AE). Secondary outcomes included 1-year overall postimplant survival, and complications including bleeding, renal failure, thromboembolism, and device malfunction. The total of 333 patients underwent LVAD implant, 46.5% (n = 155) with normal PFTs and 53.5% (n = 178) with abnormal PFTs. Patients with abnormal PFTs were noted to have higher rates of respiratory AEs (25.9% vs. 15.1%, p = .049). In multivariable analysis, the impact of PFTs was most significant when forced expiratory volume in 1 s/forced expiratory volume (FEV1/FVC) ratio was less than 0.5 (hazard ratio [HR] 16.32, 95% confidence interval [CI], 1.70-156.78). The rates of other AEs including bleeding, renal failure, right heart failure, and device malfunction were similar. One-year overall postimplant survival was comparable between the groups (56.8% vs. 68.8%, p = .3183), though patients in the lowest strata of FEV1 (<60% predicted) and FEV1/FVC (<0.5) had elevated risk-adjusted hazards for mortality (HR 2.63, 95% CI, 1.51-4.60 and HR 18.92, 95% CI, 2.10-170.40, respectively). The presence of abnormal preoperative PFTs is not prohibitory for LVAD implantation although it can be used for risk stratification for respiratory AEs and mortality, particularly in patients with severely reduced metrics. The importance of careful patient selection should be underscored in this higher risk patient subset.

Polaprezinc for prevention of oral mucositis in patients receiving chemotherapy followed by hematopoietic stem cell transplantation: A multi-institutional randomized controlled trial.

Oral mucositis is a common and distressing complication in patients receiving high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT). We reported previously in a single-center retrospective analysis that zinc-L-carnosine (polaprezinc [PZ]) reduced the incidence of oral mucositis associated with HSCT. To verify the accuracy of the prophylactic effect of PZ against oral mucositis, we carried out a multi-institutional prospective randomized controlled study. Patients were randomly allocated to either the prevention group, in which PZ lozenge treatment was started before chemotherapy, or the control group, in which administration of PZ lozenges was initiated immediately after the onset of Grade 2 oral mucositis. Oral mucositis was evaluated daily from the start of chemotherapy to 35 days after transplantation. A total of 91 patients were enrolled, and 88 patients (47 in the control group and 41 in the prevention group) were eligible for data analysis. The incidence of Grade ≥2 but not Grade ≥3 oral mucositis was significantly reduced in the prevention group compared to the control group (44.7% in control group vs 22.0% in the prevention group, P = .025). There were no significant differences in the incidence rates of other adverse events or the rate of engraftment (95.6% vs 97.2%, P = .693) between the two groups. These findings suggest that PZ lozenge is effective for prophylaxis against Grade ≥2 oral mucositis associated with chemotherapy in patients undergoing HSCT without any influence on the HSCT outcome.

Efficacy of oral administration of cystine and theanine in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery: a multi-institutional, randomized, double-blinded, placebo-controlled, phase II trial (JORTC-CAM03)

PurposeCapecitabine-based adjuvant chemotherapy for colorectal cancer patients often causes adverse events (AEs), such as diarrhea, stomatitis, anorexia, and hand-foot syndrome (HFS). Cystine and theanine were reported to attenuate some chemotherapy-associated AEs, and hence are also expected to attenuate capecitabine-induced AEs. Therefore, we aimed to investigate the safety and efficacy of cystine/theanine treatment in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery.MethodsA total of 100 colorectal cancer patients treated with capecitabine as an adjuvant chemotherapy after surgery were randomly allocated into the cystine/theanine group (n = 52) or the placebo group (n = 48). The primary endpoint was incidence rate of diarrhea of grade 1 or higher in accordance with the Common Terminology Criteria for AEs (CTCAE) v.4.0, Japanese Clinical Oncology Group (JCOG) version. The secondary endpoints included incidence rates of other AEs (CTCAE v.4.0-JCOG), as well as the incidence rate of HFS according to the HFS grading scale.ResultsThere were no significant differences in capecitabine-induced AEs between the two groups. However, the incidence rate of diarrhea of grade 1 or higher tended to be lower in the cystine/theanine group than the placebo group (18.4% vs. 28.9%, p = 0.169) as well as the incidence rate of HFS of grade 1 or higher (CTCAE v.4.0-JCOG or HFS grading scale) (67.4% vs. 77.8%, p = 0.185, 67.3% vs. 80.0%, p = 0.124, respectively).ConclusionThis trial demonstrated that cystine/theanine treatment of colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery is safe and has the tendency to reduce the incidence rate of diarrhea or HFS.Trial registrationUMIN000024784

Postoperative Corneal Injuries: Incidence and Risk Factors.

Previous studies of postoperative corneal injury rates relied on provider-initiated incident reports, which may underestimate the true incidence. Postoperative administration of proparacaine eye drops is used almost exclusively to diagnose corneal injury; therefore, identifying instances of administration may provide a better estimate of corneal injuries. We compared proparacaine administration versus provider-initiated reports to determine rates of corneal injury. In addition, potential associations between clinical variables and injury were assessed with a matched case-control study. The health records of 132,511 sequential adult postanesthesia recovery room admissions (January 1, 2011 to June 30, 2017) were reviewed to identify postoperative proparacaine administration and incident reports of corneal injury. Patients with corneal injury were matched with control patients at a 1:2 ratio to assess factors associated with injury. Proparacaine drops were administered to 442 patients (425 patients received proparacaine for diagnosis and 17 patients received proparacaine for unrelated reasons). Incident reports identified 320 injuries, and the aggregate corneal injury count was 436 (incidence, 3.3 injuries [95% confidence interval {CI}, 3.0-3.6] per 1000 cases of general anesthesia). Proparacaine administration had a greater case ascertainment percentage than incident reporting (97.5% vs 73.4%; P < .001). The matched case-control analysis found greater risks associated with longer duration of anesthesia (odds ratio, 1.05 [95% CI, 1.03-1.07] per 10 minutes of anesthesia; P < .001) and nonsupine surgical position (odds ratio, 3.89 [95% CI, 2.17-6.98]; P < .001). Patients with injuries also had more evidence of sedation and agitation during anesthesia recovery. Calculation of incidence by using the administration of a medication (proparacaine eye drops) that is almost exclusively used to diagnose a specific injury (corneal injury) showed higher case ascertainment percentage than incident-reporting methods. Similar strategies could be used to monitor the rates of other adverse events.

Digoxin is Associated with Higher Quality of Life in LVAD Recipients

Purpose To examine the effects of digoxin on functional capacity and quality of life as measured by the 6-minute walk test (6MWT) and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ) in patients receiving the Heartware HVAD system. Methods HVAD patients who remained alive on device support at 6 months from the ADVANCE + CAP, ENDURANCE + Supplemental trials were eligible. Pts were separated by digoxin use: those who were discharged from the index hospitalization on digoxin and remained on digoxin through 6 months (DIG, n=161) and those discharged from the index hospitalization not on digoxin and remained off through 6 months (NO DIG, n=533). Differences in 6MWT and KCCQ were compared between groups at baseline, 6, and 12 months. Adverse events were compared between groups from baseline through 6 months. Results Baseline characteristics were similar: Mean age was 59 years and 23% of patients were female. Serum creatinine was 0.9mg/dL ± 0.7. History of atrial fibrillation was more common in the DIG group (57.8% vs 42.9%, p = 0.001). Compared to the NO DIG group, the DIG group had greater improvements in KCCQ score at 6 months (+ 36.8 vs. + 27.7, p=0.0001) and at 12 months (+35.9 vs +29.5, p=0.01). 6MWT was similar between groups (Table 1). Device malfunction within 6 months was more common in the DIG group [18% (0.42 EPPY) vs 9.2% (0.21 EPPY), p = 0.002]. Rates of other adverse events including 6-month re-hospitalization [47.8% (2.21 EPPY) vs 42.9% (1.8 EPPY), p=0.10] were similar. Conclusion LVAD recipients maintained on chronic digoxin for at least 6 mo had greater improvements in QOL scores compared to those not treated with digoxin despite having higher rates of device malfunction and similar improvements in functional capacity. Prospective study is warranted.

Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for stage IV esophageal squamous cell carcinoma: a retrospective controlled study

BackgroundThe purpose of this study is to compare the efficacy and safety of concurrent chemoradiotherapy (CCRT) versus chemotherapy alone for patients with stage IV esophageal squamous cell carcinoma (ESCC).MethodsEligible patients were retrospectively enrolled at the authors’s institution from January 2010 to October 2015. Of the 141 patients enrolled, 55 (39.0%) received CCRT and 86 (61.0%) received chemotherapy alone. The outcomes and adverse events (AEs) were compared between the two groups.ResultsThe baseline clinical characteristics of the two groups were similar. However, the CCRT group showed a significantly better primary tumor objective response rate (ORR) than that of the chemotherapy group (74.5% versus 45.3%, p = 0.001). The 1-year, 2-year, 3-year overall survival (OS) rates and median OS were 58.0% versus 43.0%, 25.5% versus 14.0%, 10.7% versus 4.7%, and 14 months versus 11 months for patients treated with CCRT or chemotherapy, respectively (p = 0.007). The 1-year and median progression-free survival (PFS) were 29.8% versus 14.9% and 8 months versus 6 months (p = 0.005). Multivariate analysis identified CCRT (p = 0.013) and solitary metastasis (p = 0.037) as independent factors for greater OS. The frequency of leucocytopenia (grade 3 or higher) was significantly higher in the CCRT group than in the chemotherapy-alone group (p = 0.040), whereas the rates of other AEs did not differ.ConclusionsIn this study, it is suggested that CCRT is more effective than chemotherapy alone for stage IV ESCC, yielding better primary responses and survival outcomes with tolerable side effects.

Severe Neutropenia is Associated with Better Clinical Outcomes in Patients with Advanced Pancreatic Cancer Who Receive Modified FOLFIRINOX Therapy.

While modified FOLFIRINOX therapy is effective for treating advanced pancreatic cancer, it frequently causes severe neutropenia. The present study investigated the effect of severe neutropenia on clinical outcomes in advanced pancreatic cancer patients who received modified FOLFIRINOX. The study subjects were 51 patients (30 males and 21 females) with advanced pancreatic cancer who received modified FOLFIRINOX (2h bolus injection of oxaliplatin at 85 mg/m2, 2 h bolus injection of L-leucovorin at 200 mg/m2, 90min bolus injection of irinotecan at 150 mg/m2, followed by continuous infusion of 5-fluorouracil for 46 h at 2400 mg/m2 without bolus 5-fluorouracil) during the period from January 2014 to May 2018. No patients had prior history of chemotherapy. Adverse events, including neutropenia, were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. Median overall survival (OS) was the primary endpoint, while median time to treatment failure (TTF), overall response rate (ORR), and the incidence of other adverse events were secondary endpoints. Severe neutropenia (grade ≥3) occurred in 39 patients (76.4%), and Cox proportional hazard analysis identified high total bilirubin level as a significant risk factor. Median duration of OS was significantly longer in patients with severe neutropenia than in those without it (21.3 months versus 8.9 months, p = 0.020). Moreover, there was a significant correlation between OS and the grade of neutropenia (r = 0.306, p = 0.029). ORR tended to be higher, though not significantly, in patients with severe neutropenia. In contrast, the incidence rates of other adverse events were not different between the two groups. Severe neutropenia is an independent predictor of prognosis in advanced pancreatic cancer patients received modified FOLFIRINOX therapy.

Nebulised hypertonic saline for cystic fibrosis.

Background Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline (HS) enhances mucociliary clearance in vitro and may lessen the destructive inflammatory process in the airways. Objectives To investigate the effects of nebulised HS in CF compared to placebo or other treatments for mucociliary clearance. Search methods We searched the Cochrane CF and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 31 July 2008. Selection criteria Controlled trials assessing HS compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity). Data collection and analysis Two authors independently reviewed all identified trials and data; and assessed trial quality. Main results Twelve trials (442 participants, aged 6 to 46 years) were included; five excluded and two await classification. In two placebo-controlled trials, HS (3% to 7%, 10 ml twice-a-day) significantly increased forced expiratory volume at one second (FEV1) at four weeks, mean difference (MD) 4.15 (95% CI 1.14 to 7.16); but not significantly after 48 weeks, MD 2.31 (95% CI -2.72 to 7.34). Two trials compared a similar dose of HS to recombinant deoxyribonuclease (RhDNAse). One three-week trial showed a non-significant difference, MD 1.60 (95% CI -7.96 to 11.16). However, in the second trial, after 12 weeks, RhDNAse led to a greater increase in FEV1 than HS (5 ml twice-daily), in participants with moderate to severe lung disease, MD 8.00 (95% CI 2.00 to 14.00). One 48-week placebo-controlled trial showed significant improvements in frequency of antibiotic use and quality of life; also that HS did not increase the concentration of Pseudomonas aeruginosa or Staphylococcus aureus. Authors' conclusions Treatment with 7% HS for 48 weeks showed a small improvement in FEV1 at four weeks; however, this was not sustained at 48 weeks (primary outcome measure of the only long-term trial). Unlike RhDNAse, HS can't, in the long term, be said to improve lung function. However, it did improve quality of life and reduce pulmonary exacerbations. Delivered following a bronchodilator, HS appears inexpensive and safe with no increased infection risk. We believe there is sufficient evidence to recommend using HS in CF; qualifying this we highlight that the only long-term trial failed to demonstrate a significant difference in its primary outcome (lung function) with improvements only in secondary outcomes.

Efficacy of oral administration of cystine and theanine in patients with colorectal cancer undergoing capecitabine-based adjuvant chemotherapy after surgery: study protocol for a multi-institutional, randomised, double-blinded, placebo-controlled, phase II trial

IntroductionAlthough adjuvant capecitabine therapy for patients with colorectal cancer after surgery often causes adverse events (AEs), such as diarrhoea, stomatitis, anorexia and hand-foot syndrome (HFS), there are no standard prevention...

Efficacy and safety of everolimus plus low-dose calcineurin inhibitor vs. mycophenolate mofetil plus standard-dose calcineurin inhibitor in renal transplant recipients: A systematic review and meta-analysis .

To seek an optimized immunotherapy which can preserve renal function while maintaining low acute rejection rates, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of everolimus (EVR) plus low-dose calcineurin inhibitor (CNI) vs. mycophenolate mofetil (MMF) plus standard-dose CNI regimen after kidney transplantation (KT). We searched for RCTs comparing the outcomes of EVR plus low-dose CNI and MMF plus standard-dose CNI regimen after KT and identified eligible RCTs according to strict inclusion and exclusion criteria. Two authors independently assessed the quality of included studies and performed a meta-analysis using RevMan5.3. Eleven RCTs with 850 renal transplant recipients were included. This meta-analysis showed that EVR plus low-dose CNI regimen was associated with comparable renal function (standardized mean difference (SMD) 0.16, 95% CI (-0.03, 0.35), p=0.09) and a similar rate of acute rejection (risk ratio (RR) 1.16, 95% CI (0.96, 1.42), p=0.13), graft loss (RR 0.89, 95% CI (0.63, 1.24), p=0.49) and mortality (RR 1.19, 95% CI (0.69, 2.08), p=0.53) compared to MMF plus standard-dose CNI regimen. In addition, EVR plus low-dose CNI regimen could reduce the rate of cytomegalovirus and infection, whereas a lower rate of other adverse events were noted in MMF plus standard-dose CNI regimen. EVR plus low-dose CNI regimen was similar in efficacy and safety to MMF plus standard-dose CNI regimen after KT. However, this should be confirmed by further studies. .