Patients Receiving Combination Therapy Research Articles

Evaluation of the Comparative Effectiveness of Three Therapeutic Drug Regimens in the Treatment of Medication Overuse Headache in the Patients with Headache

Background and Aim: Medication overuse headache (MOH) is the second leading cause of chronic headaches. This study aimed to compare the efficacy of three medication regimens in the treatment of MOH in the patients referring to the neurology clinic of Imam Khomeini Hospital in Urmia in 2018. Material and Methods: This was a randomized clinical trial. Participants in this study selected from MOH patients referring to neurology clinic of Imam Khomeini Hospital in Urmia from Feb to Aug 2018. Our study included 60 patients. Patients were randomly assigned to one of the following 3 groups; prednisolone, celecoxib or a combination of both medications. The duration of treatment was 15 days for all the patients. At the end of the study period, the patients provided the information in regard to the severity, duration, and the number of headache days. Results: The mean duration of headache was 3.55 ± 1.58 months. Gender had no significant relationship with age and the duration of headache. The mean values for severity of headache were 8.2 ±0.71, 2.33 ± 0.84 and 2.3 ±0.95 at the first, second and third visits respectively. The mean values for severity of headache at first visit was higher in the patients receiving celecoxib compared to those in the other two treatment groups. At the second and third visits, the mean values for severity of headache were lower in the patients receiving combination therapy. Difference between the scores of severity of headache at the first visit was higher than those at the second and third visits in the combination group which indicated greater effect of this treatment regimen on reducing the severity of the headache compared to the other treatment groups. Conclusion: All three-treatment regimens were effective in reducing headaches, but the combination regimen was more effective. Both celecoxib and prednisolone had beneficial effects on reducing the severity of headache, but celecoxib was more effective. © 2018 the Author (s).

Laser and cellular technologies in treatment of patients with focal alopecia

Alopecia areata (OA) is the most common cause of hair loss, occurring in approximately 4.5 million people. The incidence of OA in the structure of dermatological diseases is approximately 2.1 %. Promising in terms of the treatment of alopecia is low-intensity laser therapy and cell technology.Material and methods. The clinical study involved 98 patients with a verified diagnosis of focal alopecia (OA). Among them, 53 (53.9 %) women and 45 (46.1 %) men aged 18 to 52 years. Patients received combination therapy, including laser plasma therapy for lesions and percutaneous laser irradiation of blood.Results. The use of combined laser therapy in patients with focal alopecia promotes the relief of inflammation in the foci, the growth of core hair and the restoration of trace elements, according to dermatoscopy, phototrichogram and biochemical studies of hair composition.

Effectiveness of combination endoscopic therapy for colonic anastomotic leaks.

Colonic anastomotic leaks are associated with significant morbidity and mortality. Whereas small case series suggest that fully covered self-expandable metal stents (FCSEMS) are effective, no larger studies have examined the impact of combination endoscopic therapy on colonic anastomotic leaks. Our retrospective cohort study reviewed 51 patients undergoing endoscopic therapy for colonic anastomotic leaks between 2011 and 2018. Patients receiving combination therapy involving FCSEMS plus local closure (n = 24) were compared with patients receiving FCSEMS alone (n = 18) or endoscopic suturing alone (n = 9). The primary outcomes were technical and clinical success (resolution of leak, removal of percutaneous drains, avoidance of surgical reoperation, and reversal of temporary diversion). Clinical success was achieved in 55 % of patients. Clinical success was achieved in 18/24 patients (75 %) with combination therapy compared with 6/18 patients receiving FCSEMS alone (33 %, adjusted risk ratio [RR] 2.16, 95 % confidence interval [CI] 1.10 - 4.24; P = 0.02) and 4 /9 patients undergoing endoscopic suturing alone (44 %, RR 1.91, 95 %CI 0.84 - 4.31; P = 0.10). Stent migration occurred in 40 % of patients. This large series demonstrates that combination therapy was associated with a higher rate of clinical success, and future prospective studies are warranted.

Does combination therapy work in chronic thromboembolic pulmonary hypertension?

The current experience with combination therapy in chronic thromboembolic pulmonary hypertension (CTEPH) is limited. We present the first survival results up to 5years for dual combination therapy versus monotherapy in CTEPH. All consecutive, non-operated CTEPH or residual PH after pulmonary endarterectomy patients treated with PH-specific medical therapy between January 2002 and November 2019 were included. We report and compare survival between monotherapy and (upfront or sequential) dual combination therapy until five years after medication initiation. In total, 183 patients (mean age 65±14years, 60% female, 66% WHO FC III/IV, 86% non-operated) were included, of which 83 patients received monotherapy and 100 patients received dual combination therapy. At baseline, patients receiving combination therapy had a higher NT-proBNP (p=0.02) mean pulmonary artery pressure (p=0.0001) and pulmonary vascular resistance (p=0.02), while cardiac index was lower (p=0.03). Total follow-up duration was 3.3±1.8years, during which 31 (17%) patients died. Estimated 1-, 3- and 5-year survival for monotherapy were 99%, 92% and 79%, respectively. For combination therapy percentages were 98%, 89% and 70%, respectively. Survival did not significantly differ between both groups (p=0.22). Survival up to 5years for patients treated with combination therapy, regardless of the combination strategy, was similar as patients with monotherapy, despite worse clinical and haemodynamic baseline characteristics.

P-02-18 Estimation of Combined Treatment Efficiency of Sexual Dysfunctions in Patients after Surgery for Benign Prostatic Hyperplasia

The purpose of the study was to evaluate the effectiveness of the combined treatment of sexual dysfunctions (SD) in patients with benign prostatic hyperplasia. 160 men who underwent surgery for BPH and had manifestations of SD were examined, they were divided into two groups: group A 77 patients (48.1%), operated byTURP and having SD up to surgery; group B included 83 (51.9%) patients in whom SD occurred after TURP. The period between surgery and inclusion in the study was ≥3 months. After surgery, patients received combination therapy: tamsulosin 0.4 mg OD and Serenoa repens (SR) extract 320 mg OD for 12 months. Evaluated on 1, 3, 6 and 12 months. After 12 months of observation, a strong linear relationship (r=0.96) was revealed between the severity of LUTS and the degree of ED, which accounted for 91.5% in the structure of SD. SD appeared in 85.0% of cases with orgasmic dysfunction, retrograde ejaculation mainly in the operated patients (90.6% versus 73.3%; p< 0.05) and a decrease in their libido (69.4% versus 30.7% among others ; p< 0.05). Characteristic was a decrease in the quality of life on the scales of the physical (with the existence of SD before surgery) and the mental components (the occurrence of SD after surgery). In 89% of cases, subclinical personal and situational anxiety was detected in all groups. The inclusion of individual rational psychotherapy in treatment, depending on the prevalence of depression form, was used in 70.0%, in 61.0% in the presence of SD before TUR and in 74.7% of SD development after surgery.

Brucellar reproductive system injury: A retrospective study of 22 cases and review of the literature.

ObjectiveWe aimed to describe the clinical characteristics and prognosis of 22 patients with Brucella-induced reproductive system injury.MethodsWe assessed 22 patients with reproductive system injury between 2010 and 2018 at The First Affiliated Hospital of Xinjiang Medical University.ResultsThe disease is predominant in men. Male patients had orchitis, erectile dysfunction, prostatitis, and urethral stricture, while female patients had vaginitis and cervicitis. Some patients had laboratory abnormalities and liver injury. Patients received combination therapy of rifampicin and doxycycline. Doxycycline combined with levofloxacin or moxifloxacin was administered to patients with rifampicin intolerance. All patients had received antibiotic therapy for at least 6 weeks. One patient was lost to follow-up, one patient relapsed because of osteoarthropathy, and one patient had dysuria resulting from chronic prostatitis. The clinical symptoms resolved in the other patients, and the overall patient prognosis was good.ConclusionClinicians should pay attention to brucellosis-induced reproductive system damage. The two-drug regimen of rifampicin+doxycycline is recommended for these patients. Doxycycline combined with levofloxacin or moxifloxacin should be used in patients with brucellosis-induced reproductive system damage who have rifampicin intolerance. The treatment course should be at least 6 weeks.

Anlotinib, a multitarget tyrosine kinase inhibitor, for advanced lung cancer patients: Efficacy in real-world study.

e15652 Background: Anlotinib is an novel small molecule multi-target tyrosine kinase inhibitor, which has been approved as a third-line therapy for patients with advanced NSCLC by CFDA in May 2018, and also approved as third-line therapy for patients with advanced SCLC in China in 2019. The objective of this study was to assess the efficacy of Anlotinib for patients with advanced lung cancer in the real world. Methods: We reviewed the patients who were diagnosed as advanced lung cancer and had received anlotinib in Jiangsu Caner Hospital from May 2018 to Sep 2019. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was objective response rate (ORR), disease control rate (DCR) and safety. Results: A total of 465 patients were included in our study, containing 384 cases of NSCLC and 81 cases of SCLC. Among patients with NSCLC, 85 cases received anlotinib alone or anlotinib based therapy as first-line and second-line treatment, whereas 299 cases received anlotinib alone or anlotinib based therapy as third-line or later treatment. There were no significant differences in PFS, ORR and DCR between cohort of 1st /2nd line treatment and those with 3rd /later treatment. However, patients received combination therapy (including anlotinib combined with PD1 inhibitors such as Nivolumab, pembrolizumab, or chemotherapy such as platinum, docetaxel, pemetrexed, paclitaxel, tegafur, etc.) showed a significant longer PFS and higher ORR and DCR (P &lt; 0.001, table). In patients with SCLC, 44 cases received anlotinib alone or anlotinib based therapy as first-line and second-line treatment. There were no significant differences in PFS, ORR and DCR between cohort of anlotinib monotherapy and other combination therapies (P &gt; 0.05, table). No additional safety profile was observed. Conclusions: Anlotinib shows similar effect in patients with NSCLC and SCLC in real world. Anlotinib provides more significant benefits when combining with PD1 inhibitor or chemotherapy comparing with monotherapy in patients with advanced NSCLC. [Table: see text]

HBcrAg and pg RNA and the therapeutic effect in HBeAg-positive patients receiving anti-viral therapy, baseline serum HBV-RNA is a powerful predictor of response.

We used HBV core antigen (HbcrAg), pre-genomic RNA (pg RNA) and other biomarkers to evaluate the therapeutic effect in HBV infected patients receiving anti-viral therapy. 127HBeAg-positive patients were enrolled: 35 patients received nucleotide therapy, 14 patients received interferon and 78 patients received combination therapy with both. HBcrAg, pg RNA and other biomarkers were detected at different time points, we defined the decreased titre of HBcrAg and HBeAg from baseline to 6 and baseline to 12months as ∆HBcrAg and ∆HBeAg, which were used to predict HBeAg seroconversion. Furthermore, we used the time-dependent receiver operator curve of different markers to analyse HBeAg seroconversion. For HBeAg seroconversion: at 6months, 0.75 log10 U/mL of ∆HBcrAg and 1.47 log10 PEI U/mL of ∆HBeAg showed maximum predictive value in receiver operator curve analysis (Youden's index values for area under the curve of 0.687 and 0.646, respectively). At 12months, 2.05 log10 U/mL of ∆HBcrAg and 1.92 log10 PEI U/mL of ∆HBeAg showed improved prediction (maximum Youden's index values, with areas under the curve of 0.688 and 0.698, respectively).pg RNA was a better predictor of outcome due and the concentrations of 6.20 log10 I U/mL of pg RNA and 8.0 log10 U/mL of HBcrAg were cut-off values for response in a Kaplan-Meier curve analysis. Our results may be used to identify the pg RNA concentration in patients at baseline and ∆HBcrAg during therapy who are likely to achieve HBeAg seroconversion according to the cut-off value at different time points, thus helping to evaluate the therapeutic effect.

SUN-127 Diagnostic Challenges Associated with the Rising Incidence of Endocrine Toxicity in the Era of Combination Immunotherapy

Background: Immune checkpoint blockade is now established as standard of care in several malignancies. Trials involving combined cytotoxic T lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD1) blockade demonstrate improved tumour responses in melanoma but at the cost of severe grade 3-4 immune related adverse events (irAEs) in 55%, and endocrine irAEs in up to 10% [1]. Immune-mediated damage to endocrine glands can be a diagnostic and management challenge. We aimed to review the incidence, biochemical evolution and imaging findings of endocrine toxicity related to combined anti CTLA-4 and anti-PD-1 therapy. Methods: We undertook a retrospective chart review of patients who received combined ipilimumab and nivolumab for metastatic melanoma at a tertiary referral centre between 2016-2019. We recorded onset and duration of abnormal biochemistry in endocrine irAEs, reviewed all available MRI images for pituitary size (mm) and appearance and 18-F FDG PET images for features of hypophysitis, thyroiditis and pancreatitis. Results: 162 patients received combination therapy. At least one irAE was recorded in 135 patients (83%), 100 (62%) required glucocorticoids, and 84 (52%) had an unplanned hospital presentation due to irAEs. Thyroiditis occurred in 50 (30.9%), with median time to onset of 30.9 days (range 1-234 days). 35 cases were identified with routine biochemistry performed every 4-6 weeks. TSH receptor antibody was measured in 13 patients and all were negative. 29 (58%) developed permanent hypothyroidism. Central cortisol deficiency was documented in 31 (19%) with a median time to diagnosis of 67.5 days (range 5-286). 4 cases were diagnosed on routine biochemistry and 14 presented with symptoms prompting investigation. 13 were diagnosed after routine neuroimaging demonstrated a pituitary abnormality, and a further 27 patients without the clinical syndrome had features of hypophysitis on neuroimaging. New onset diabetes occurred in 3 people, in which pancreatic inflammation on imaging was found in 2. A further 3/5 patients with an asymptomatic elevated lipase were found to have abnormal pancreatic imaging. In one patient with no features of endocrine or exocrine failure, there was a significant increase in FDG uptake and a subsequent loss of pancreatic volume. Conclusion: We report real world incidence of endocrine irAEs with combination immunotherapy. Routine biochemistry leads to the detection of some but not all cases. Early recognition and avoidance of unplanned presentations remains a challenge. Opportunistic assessment of endocrine gland appearance on routine imaging studies may provide useful early diagnostic information. Reference: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. (2015) 1:23-34. 10.1056/NEJMoa1504030

The role of distinct co-mutation patterns with TP53 mutation in immunotherapy for NSCLC

TP53 mutations was reported to be correlated to the efficacy of program death-1 (PD-1) and program death ligand-1 (PD-L1). The role of co-mutations of TP53 with other recurrently mutated genes in outcome of anti-PD-(L)1 treatment for non-small cell lung cancer (NSCLC) is unknown. Here we mined a previously generated dataset to address the effect of co-mutations on the progression free survival (PFS) of NSCLC patients. Non-synonymous mutations and clinical data of 240 NSCLC patients with anti-PD-(L)1 based therapy was downloaded from cBioPortal. Totally 206 patients received monotherapy and 34 patients received combination therapy. In 240 NSCLC patients, TP53 mutation rate was 59.2%. For the monotherapy cohort, TP53 mutated NSCLC patients have a significantly longer PFS (4.3 vs. 2.5 months, P = 0.0019) compared with TP53 wild type NSCLC patients. The same tendency was also observed in the combination therapy cohort, but the difference in PFS (6.3 vs. 5.4 months, P = 0.12) was not significant. Ever-smoker had a longer PFS compared to never-smokers (4.0 vs. 2.7 months). For further co-mutation analysis with TP53 including KEAP1 mutation (53/240, 22.1%), KMT3C mutation (26/240, 10.8%), STK11 mutation (56/240, 23.3%), EGFR mutation (28/240, 11.7%) and KRAS mutation (86/240, 35.8%). Patients with both TP53 plus KEAP1 mutations in all 240 patients had a longer PFS compared with co-wild population (PFS 9.2 vs. 4.2 months, P = 0.012) when treated with PD-1/PD-L1 inhibitors. TP53 might be the dominating mutation correlating with longer PFS in PD-1/PD-L1 monotherapy. Different genes displayed distinct effect when co-mutated with TP53 in NSCLC patients.

Prospects of systemic enzyme therapy for treatment of male immune infertility

The study objective is to evaluate the effectiveness and safety of systemic enzyme therapy drugs (Wobenzym, Phlogenzym) and the natural complex of multi-component dietary supplement Spermstrong in the treatment of immune infertility.Materials and methods. Sixty-four men with immune infertility, high levels of antisperm antibodies (ASA) in ejaculate, serum and reproductive disorders were examined. All patients were divided into 2 groups. For 8 weeks, 32 patients in the group 1 received systemic enzyme therapy drugs in combination with a natural complex of multi-component dietary supplement Spermstrong (combined therapy), and 32 patients of the group 2 received only Spermstrong (monotherapy), and their comparative assessment was carried out. Immediate results of treatment were evaluated 4 weeks later and remote 8 weeks after treatment.Results. Increased ejaculate volume was observed in patients receiving combination therapy and Spermstrong only: by 19.0 and 10.0 %, respectively, after 4 weeks of treatment and by 42.9 and 15.0 % after 8 weeks. Mean sperm count increased only in patients receiving combination therapy (by 55.4 % after 8 weeks of treatment, p &lt;0.05). Sperm motility increased more after combination therapy (by 11.9 and 129.8 % after 4 and 8 weeks, respectively). Decrease in abnormal spermatozoa was slightly faster for combination treatment compared to Spermstrong monotherapy: after 4 weeks by 12.2 and 0.3 %, respectively, after 8 weeks by 24.8 and 6.5 %. The level of ASA IgG in the ejaculate decreased by 26.3 and 59.0 % after 4 and 8 weeks of combination treatment, and by 3.4 and 13.2 % after Spermstrong monotherapy. Serum level of ASA IgG/IgM significantly decreased only in patients receiving combination therapy (by 36.4 and 76.5 % after 4 and 8 weeks, respectively, p &lt;0.05). No adverse effects were observed in patients in both treatment groups.Conclusion. The results confirm that the use of combination therapy with Wobenzym, Phlogenzym and Spermstrong statistically significantly reduced ASA levels and increased the effectiveness of treatment.The authors declare no conflict of interest.All patients gave written informed consent to participate in the study.

Long-Term Survival in Patients Receiving Combination Therapy with Resection and Radiofrequency Ablation for Multi-Focal Hepatocellular Carcinoma Classified as Barcelona Clinic Liver Cancer Stage B: A Retrospective Controlled Study.

ObjectiveTo evaluate the survival outcomes of combined liver resection (LR) and radiofrequency ablation (RFA) on multi-focal hepatocellular carcinoma (HCC) in patients with Barcelona clinic liver cancer (BCLC) stage B.MethodsA total of 210 cases of HCC were included in this study. In 42 cases, patients were treated with combination therapy using LR and RFA (LRCRFA). In 84 cases, patients underwent transarterial chemoembolization (TACE), and in another 84 cases, patients underwent LR; both the TACE and LR groups served as controls. It both categorized as BCLC stage B for LRCRFA and TACE groups but as BCLC stage A for LR group.ResultsThe overall survival (OS) rate of the LRCRFA group was significantly higher than that of the TACE group (P<0.001) but was not significantly different when compared with the LR group (P=0.544). The disease-free survival (DFS) rate of the LRCRFA group was significantly lower than that of the LR group (P=0.029). Patients with ≤4 tumors or those with ≤5 tumors no larger than 6 cm in diameter experienced better long-term outcomes than other patients in the same LRCRFA group. The OS rates and DFS rates were not significantly different from those of patients in the LR group (P>0.05). Having more than 2 existing tumors was an independent risk factor for OS rate.ConclusionCombination therapy using LR and RFA can more effectively improve the prognosis of these patients than TACE. Patients with BCLC stage B HCC with ≤4 tumors or ≤5 tumors smaller than 6 cm in diameter are the ideal candidates for the application of LRCRFA.

Outcomes of Mechanical Circulatory Support Therapy for Cardiogenic Shock Associated with Late Allograft Failure after Heart Transplantation

Treatment of cardiogenic shock associated with late allograft failure after heart transplant (HT) is poorly characterized and infrequently reported. In this study, we examined the role of mechanical circulatory support (MCS) as a method to treat patients with severe late graft failure. From 2000 - 2018, there were 1275 adult HT at our institution. Of those, 26 patients (2.0%) were identified who required MCS for cardiogenic shock due to late allograft failure. Patient demographics and outcomes were retrospectively reviewed. Median age of the cohort was 37.3 years (IQR: 17.3) and 69% were male. Median time from initial transplant to MCS was 2.9 years. At the time of shock, median hemodynamic values were as follows: CVP 18 mmHg, mean PA pressure 29 mmHg, PCWP 25 mmHg, and CI 1.87 L/min/m2. On echocardiogram, median LVEF was 25% and 77% of patients had moderate or severe right ventricular dysfunction. Seven patients (27%) had severe allograft coronary disease, while all remaining patients had chronic or acute worsening rejection. Initial MCS used included veno-arterial extracorporeal membrane oxygenation in 15 patients (58%), biventricular assist device in 10 patients (38%), and total artificial heart in 1 patient (4%). 8 patients underwent revision of MCS during the same hospitalization, on average 18 days after initial placement. While on MCS, the most common treatments for rejection were pulse dose steroids (69%), thymoglobulin (54%), and plasmapheresis (31%), with nearly all patients receiving combination therapy. Six patients (23%) weaned from MCS following medical therapy. Median duration of MCS was 33 days (IQR 55). Major morbidities included bleeding events in 39%, new renal replacement therapy in 23%, major infection in 27%, and stroke in 23%. Eight patients (31%) underwent re-heart transplant, all within one year of MCS, and survival for this cohort was 100% at 1 year. However, for those patients who were not offered re-transplant or who died while awaiting re-transplant, 1 year survival was only 22%, with 61% of deaths occurring in the hospital. Late graft failure resulting in cardiogenic shock carries significant morbidity and mortality, despite use of contemporary MCS.

Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study

Talacotuzumab, a humanized anti-CD123 monoclonal antibody, was evaluated in combination with decitabine in elderly patients with acute myeloid leukemia (AML) not eligible for intensive chemotherapy. A multicenter, phase 2/3 study was initiated to determine the recommended phase 2 dose (RP2D) of talacotuzumab (Part A) followed by an open-label, randomized comparison of talacotuzumab in combination with decitabine versus decitabine alone to assess achievement of complete response (CR) and overall survival (OS) in Part B. Ten patients were enrolled in Part A and 316 in Part B; the results presented here are based on a database lock on January 25, 2018. Part A confirmed the RP2D of talacotuzumab to be 9 mg/kg. In Part B, CR was achieved in 12/80 (15%) patients receiving combination therapy and in 9/82 (11%) patients receiving decitabine alone (odds ratio: 1.4; 95% confidence interval [CI]: 0.6–3.6; p = 0.44). Median (95% CI) OS was 5.36 (4.27–7.95) months for combination therapy versus 7.26 (6.47–8.64) months for decitabine alone (hazard ratio: 1.04; 95% CI: 0.79–1.37; p = 0.78). Combination therapy showed no improvement in efficacy versus decitabine alone, resulting in the Independent Data Monitoring Committee’s recommendation of early termination of enrollment and discontinuation of talacotuzumab treatment.

Outcomes among patients with infantile spasms treated with hormonal therapy and adjuvant topiramate versus hormonal therapy alone.

Hormonal therapy is the first-line treatment for infantile spasms and is sometimes used in combination with topiramate for better seizure control and potentially improved developmental outcomes. Retrospective review of pediatric patients with infantile spasms, with data compiled on patient sex, age at onset, etiology, electroencephalographic and imaging findings, topiramate use, spasm resolution (at one, six, and 12 months), and developmental outcome (at 12 months). Of 105 patients screened, 55 (28 female) met inclusion criteria (28 [51%] had spasms with known etiology and 27 [49%] had spasms with unknown etiology). Forty-six patients were followed for 12 months or longer to determine seizure outcome; a 12-month developmental assessment was documented for 49 patients. Thirty-seven patients (67%) received combination therapy; 18 (33%) received hormonal therapy alone. Resolution of spasms was comparable among treatment groups, with no difference relative to spasm etiology (p>0.18 for all). No difference was found in developmental outcomes with and without adjunct topiramate (p=0.38). Combination therapy was the most common treatment at our institution. However, combination therapy was not found to be beneficial for the treatment of spasms or developmental outcomes when compared to hormonal therapy alone.

SAT-151 A DILEMMA OF CALCITRIOL IN PRE-DIALYTIC CHRONIC KIDNEY DISEASE: A 1-YEAR STUDY FOR COMBINATION THERAPY OF CALCITRIOL AND RENIN-ANGIOTENSIN ALDOSTERONE BLOCKER IN CHRONIC KIDNEY DISEASE

Renin-angiotensin aldosterone system blockers (RASB) is main stream of management of chronic kidney disease (CKD). Vitamin D (vitD) is known as a potent negative regulator of renin-angiotensin aldosterone system via vitamin D receptor. VitD deficiency often presents, even in early CKD. However, there is no a definite guideline of use of vitD in CKD. In addition, the use of vitD should be given a careful attention due to development of hypercalcemia or vascular calcification in CKD. Now, we report results of a 1-year study for combination therapy of calcitriol and RASB in patients with pre-dialytic CKD and vitD deficiency. Forty five patients with pre-dialytic CKD and proteinuria >500 mg/day despites of RASB during at least 6 months were enrolled. We prescribed calcitriol of 0.5 μg, thrice weekly only in patients with serum calclium <10 mg/dL and 25(OH)vitD of <15 ng/mL. Only a total 27 patients received combination therapy of calcitriol and RASB, and laboratory data were retrospectively analyzed. Urine albumin-creatinine ratio (UACR) at baseline was measured. UACR and serum creatinine were followed with 6-month interval. We also divided the enrolled patients into two groups, early CKD and advanced CKD group, based on eGFR of 60 mL/min/1.73m2. We performed a comparative analysis for impacts of combination therapy on albuminuria and renal function in the groups based on eGFR. Total 27 patients used calcitriol and RASB. Eleven patients among the 27 patients were classified into early CKD group and sixteen patients were classified into advanced CKD group. Total 18 patients used only RASB. Twelve patients among the 18 patients were classified into early CKD group and six patients were classified into advanced CKD group. (Table 1,2: not shown in the abstract) In combination group, UACR were 3.15 g/g ± 3.82 at baseline and fell to 2.28 g/g ± 2.90 and 1.91 g/g ± 2.75 after 6 and 12 months. (p=0.031 and p=0.096, respectively) (Table 3) Moreover, in RASB only group, UACR were 1.05 g/d ± 1.71 at baseline and fell to 0.34 g/g ± 0.37 and 0.74 g/g ± 1.13 after 6 and 12 months. (p=0.039 and p=0.133, respectively) (Table 4) Change of UACR after 6 months from baseline did not show statistical significance in both groups. However, in combination group, when subgroup analyses were performed in early CKD and advanced CKD, UACR were 3.61 g/g ± 4.13 at baseline and significantly fell to 2.44 g/g ± 3.04 and 1.17 g/g ± 1.68 after 6 and 12 months (p=0.005 and p=0.022, respectively) in only early CKD. In addition, change of GFR in early CKD patients received combination therapy did not decrease significantly during 12 months. (p=0.099) (Table 3) Moreover, we performed a comparative analysis between combination and RASB only to identify effect of calcitriol on UACR according to time. The difference of decreasing UACR between combination and RASB only group was not statistically significant in both groups, however, in early CKD patients, the difference based on time between both groups seemed to be significant. (p=0.05) (Table 4 and Figure 1) View Large Image Figure ViewerDownload Hi-res image Download (PPT) Our study didnot show a significant impact on albuminuria of vitD combination therapy compared with only RASB therapy. However, if sample size and study-duration are expanded, combination therapy might show negative impact on albuminuria, particularly in early CKD patients with persistent proteinuria despites of use of RASB.

Comparison of the Efficacy and Safety of Rosuvastatin/Ezetimibe Combination Therapy and Rosuvastatin Monotherapy on Lipoprotein in Patients With Type 2 Diabetes: Multicenter Randomized Controlled Study.

IntroductionEzetimibe/statin combination therapy has been reported to provide additional cardioprotective effects compared to statin monotherapy. The apolipoprotein B/A1 (apoB/A1) ratio is an effective predictor of cardiovascular diseases. The aim of this study was to compare the efficacy and safety of rosuvastatin/ezetimibe combination therapy versus rosuvastatin monotherapy using the apoB/A1 ratio in patients with diabetes and hypercholesterolemia.MethodsIn this randomized, multicenter, open-label, parallel-group study, patients were randomly assigned to receive the combination therapy of rosuvastatin 5 mg/ezetimibe 10 mg once daily (n = 68) or monotherapy with rosuvastatin 10 mg once daily (n = 68), for 8 weeks.ResultsAfter the 8-week treatment, percentage change (least-square means ± standard error) in the apoB/A1 ratio in the rosuvastatin/ezetimibe group was significantly decreased compared to the rosuvastatin group (− 46.14 ± 1.58% vs. − 41.30 ± 1.58%, respectively; P = 0.03). In addition, the proportion of patients achieving > 50% reduction in low-density lipoprotein-cholesterol (LDL-C) and in the comprehensive lipid target (LDL-C < 70 mg/dL, non-HDL-cholesterol [non-HDL-C] < 100 mg/dL, and apoB < 80 mg/dL) was significantly different between the two groups (76.5 and 73.5% in the rosuvastatin/ezetimibe group and 47.1 and 45.6% in the rosuvastatin group, respectively; P < 0.001). The reduction in total cholesterol, non-HDL-C, LDL-C, and apoB were greater in the rosuvastatin/ezetimibe group than in the rosuvastatin group. Both treatments were well tolerated, and no between-group differences in drug-related adverse events were observed.ConclusionThe apoB/A1 ratio was significantly reduced in patients receiving combination therapy with ezetimibe and rosuvastatin compared to those receiving rosuvastatin monotherapy. Both treatments were well tolerated in patients with type 2 diabetes and hypercholesterolemia.Trial RegistrationNCT03446261.Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-020-00778-1) contains supplementary material, which is available to authorized users.

Abstract P5-01-06: Cell-free DNA (cfDNA) analysis of ESR1-mutant advanced breast cancer (aBC): Impact of subsequent therapy on mutation persistence

Abstract Background: Acquired ESR1 mutations (ESR1MUT) are common resistance mechanisms in estrogen receptor positive (ER+) aBC following aromatase inhibitor (AI) therapy. ESR1MUT can be identified using plasma-based cfDNA testing in patients with progressive aBC and may be cleared (i.e. become undetectable) following response to effective therapeutic interventions. Optimal treatment for ESR1MUTaBC has not been established. We retrospectively examined the impact of various treatments on ESR1MUT detection among patients with aBC undergoing serial cfDNA testing. Methods: The deidentified Guardant Health database was queried for patients with aBC (stage IIIB/IV) with multiple cfDNA samples, at least one of which had an ESR1MUT detected (patients tested between March 2014-March 2019 using a 54-73 gene cfDNA next-generation sequencing panel, Guardant360™). Consecutive sample pairs were identified in which the first sample had ≥1 ESR1MUT and subsequent treatment could be determined from the test request form. For patients receiving combination therapy, each therapy was counted individually (e.g. a patient receiving a CDK4/6 inhibitor and an AI would be counted once for each). Each sample pair was classified as to whether any ESR1MUT persisted in the subsequent cfDNA sample. Additionally, the change in ESR1 variant allele fraction (αVAF) between the first and subsequent sample was calculated for each ESR1MUT identified. We considered ESR1MUT that had lower VAF on the subsequent sample (e.g. a negative αVAF) as evidence of a therapeutic response against ESR1MUT for the purpose of this study. The proportion of sample pairs in which the ESR1MUT was cleared, as well as the proportion of any ESR1MUT with decreased VAF was compared by treatment type using Fisher’s exact test. Results: A total of 262 ESR1 mutations were found in 167 unique sample pairs from 124 aBC patients. The median time between sample collection for each pair was 17 weeks (range: 0.7 - 133 weeks). ESR1MUT were cleared in a minority (30/167, 18%) of sample pairs with an overall minimal change in observed VAF (median αVAF of -0.01). A negative ESR1MUT VAF was observed for more than half of all ESR1MUT in patients receiving certain endocrine therapies, including fulvestrant, tamoxifen, and goserelin, and non-endocrine therapies, including chemotherapy, anti-HER2, and CDK4/6 inhibitors, suggesting these agents may still have some efficacy against ESR1MUT (Table 1). The proportion of sample pairs with ESR1MUT clearance was not significantly different for those on endocrine therapy versus those not on endocrine therapy (16% vs 19%). Similarly, there was no significant difference between these groups when examining the proportion of ESR1MUT with decreased VAF (50% vs 50%). Conclusions: In this exploratory analysis of serial cfDNA testing of ESR1MUTin aBC, some variation was observed in the efficacy of commonly used therapies as measured by the proportion of sample pairs with clearance of ESR1MUT and by the proportion of all ESR1MUT with a decreased VAF. We believe these data may be useful in guiding future analysis into optimal therapy for patients with ESR1MUTaBC. Notably, none of the therapies stood out as having promising efficacy against a large proportion of ESR1MUT subclones suggesting that additional therapeutic options may be needed to effectively target and provide long-term disease control of ESR1MUT aBC. Table 1. Temporal changes in ESR1MUT in cfDNA by therapy in aBCTreatmentNo. Sample PairsESR1MUT ClearedNo. ESR1MUTESR1MUT with VAF DecreaseMedian αVAFAI2520%3842%0.09SERD (Fulvestrant)3312%4553%-0.03Estrogen Receptor Agonist (Tamoxifen)30%667%-0.18GnRH Agonist (Goserelin)813%1464%-0.09Chemotherapy8319%13052%-0.09Anti-HER2229%2752%-0.02Everolimus2512%3749%0.05CDK4/6 Inhibitor3119%4953%-0.05Immune Checkpoint520%838%0.02Any Endocrine Therapy6316%9250%-0.01No Endocrine Therapy10419%17050%-0.01OVERALL16718%26250%-0.01 Citation Format: Caroline M. Weipert, Thereasa A. Rich, Rebecca J. Nagy, Sarah Croessmann, Ben H. Park, Joyce O'Shaughnessy, Mohammad Nezami, Massimo Cristofanilli, Aditya Bardia, Richard B. Lanman. Cell-free DNA (cfDNA) analysis of ESR1-mutant advanced breast cancer (aBC): Impact of subsequent therapy on mutation persistence [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-06.

Sub-acute Toxicity in Non-cancerous Tissue and Immune-Related Adverse Events of a Novel Combination Therapy for Cancer.

Brain, lung, and colon tissue experience deleterious immune-related adverse events when immune-oncological agents or radiation are administered. However, there is a paucity of information regarding whether the addition of radiation to immuno-oncological regimens exacerbates the tissue inflammatory response. We used a murine model to evaluate sub-acute tissue damage and the systemic immune response in C57Bl/6 mice when administered systemic anti-programmed cell death protein 1 (αPD-1) immunotherapy alone or in combination with stereotactic fractionated 10 gray/5 X-ray radiation to normal brain, lung or colon tissue. The model indicated that combinatorial αPD-1 immunotherapy and radiation may alter normal colon cell proliferation and cerebral blood vasculature, and induce systemic thrombocytopenia, lymphopenia, immune suppression, and altered immune repertoire (including interleukin-1β). Therein our data supports close monitoring of hematological and immune-related adverse events in patients receiving combination therapy.

Ventricular repolarization indexes in patients treated with hydroxychloroquine - azithromycin combination for COVID-19.

Combination of hydroxychloroquine and azithromycin for the treatment of coronavirus disease 2019 (COVID-19) carries increased risk of corrected QT (QTc) prolongation and cardiac arrhythmias. To characterize the ventricular repolarization indexes which are associated with malignant ventricular arrhythmias in patients treated with hydroxychloroquine and concomitant azithromycin for COVID-19. A total of 81 patients who had hydroxychloroquine and azithromycin combination therapy because of possible or reverse-transcription polymertase chain reaction (RT-PCR) confirmed diagnosis of COVID-19 were included in the study. Baseline and control electrocardiograms (before and after treatment) were analyzed retrospectively. Tp-e interval, Tp-e/QT and Tp-e/QTc ratios, which are ventricular repolarization indexes, were calculated. While there was no significant increase in QTc interval in patients receiving combination therapy, there was a significant increase in ventricular repolarization indexes. The increase in ventricular replarization indexes is associated with the risk of arrhythmia. In patients using QTc prolonging medication for COVID-19 treatment, QTc monitoring alone may not be sufficient to follow-up for arrhythmia. Even if there is no prolongation in QTc, an increase in ventricular repolarization indexes may be seen (Tab. 5, Ref. 37).