Case Report: Neurobrucellosis Presenting as Malignancy.

Neurobrucellosis, caused by Brucella species, is a zoonotic infection that may involve the central nervous system. Although uncommon, it can manifest as a solitary intracranial mass. We report a case of neurobrucellosis in a 25-year-old woman from Peru who presented with headache, weight loss, and right-side hemiparesis and paresthesia. A contrast-enhanced magnetic resonance imaging scan revealed an intracerebral mass in the left temporal lobe. Serum testing subsequently were positive. Brain biopsy demonstrated non-necrotizing granulomas without malignant cells. Neurobrucellosis should be considered in the differential diagnosis of brain space occupying lesions in endemic countries.

On the fence: Combining multimodal imaging and laparoscopy for diagnosing tuberculous peritonitis.

Tuberculous peritonitis (TB peritonitis) is one of the most challenging forms of extrapulmonary TB to diagnose. While tumor markers can be elevated in patients with TB peritonitis, FDG-PET/CT can aid in distinguishing TB peritonitis from malignancies, if an apron-like omentum pattern is seen. Laparoscopy is crucial for accurate and early diagnosis.

Disseminated Mycobacterium chimaera infection successfully treated with a clofazimine-containing regimen and long-term follow-up after discontinuing treatment.

Mycobacterium chimaera is a slow-growing member of the Mycobacterium avium complex. It can contaminate tap water and has been detected in water tanks of heater-cooler devices used during open-heart surgery. Herein we report a case of a 67-year-old- male with disseminated M. chimaera infection who presented with fevers, significant weight loss and was found to have bacteremia with prosthetic valve endocarditis, chorioretinitis, bone marrow and splenic granulomas two years after an open-heart surgery. He developed multiple drug adverse events over the course of treatment but was successfully treated using a clofazimine containing regimen along with aortic valve replacement. He has remained symptom-free with no signs of recurrence three years after completion of antimicrobials. Clofazimine is an effective alternative that can be used as part of a multi-drug regimen in M. chimaera infection when there is resistance to first-line drugs or when adverse drug reactions occur.

Low skeletal muscle mass index is independently associated with low bone mineral density in kidney transplant recipients: a retrospective observational cohort study.

BACKGROUND: Osteoporosis and osteopenia are more frequent in patients who have received kidney transplants than in healthy individuals. Although osteoporosis and sarcopenia are closely related, only few studies have considered them in the post-transplantation period. We aimed to investigate the relationship between lower bone mineral density and skeletal muscle in kidney transplant recipients. METHODS: We included 371 patients in the maintenance phase of kidney transplantation (> 6 months after transplantation) followed-up at our institution from January to December 2019. The primary endpoint was the association between bone mineral density and skeletal muscle mass index. As secondary endpoints, in addition to skeletal muscle mass index, we investigated other factors associated with low bone mineral density, including kidney function and 25-hydroxy vitamin D (25(OH)D) concentration. Considering the possibility that factors affecting bone mineral density differ between men and women, we explored these factors separately for both sexes. RESULTS: Of the 371 participants, 243 (65.4%) were men. The median age and time after transplantation were 52 and 14 years, respectively. Univariate analysis showed that age, female sex, time since transplantation, cystatin C-based estimated glomerular filtration rate (eGFRcysC), 25(OH)D, and skeletal muscle mass index were associated with bone mineral density. Multivariate analysis showed associations of bone mineral density with eGFRcysC, 25(OH)D, and skeletal muscle mass index. Multivariate analysis by sex showed significant associations with eGFRcysC, hemoglobin, and skeletal muscle mass index in men and with age, eGFRcysC, albumin, and skeletal muscle mass index in women. Bone mineral density was not associated with history of dialysis prior to transplantation or time since transplantation. CONCLUSIONS: In kidney transplant recipients, an independent association between lower bone mineral density and skeletal muscle mass index was observed in both sexes.

A case of prosthetic valve endocarditis and aortic abscess due to Bacillus cereus.

Bacillus cereus (B. cereus) is commonly found in the environment and is often considered a blood culture contaminant. However, in patients with specific risk factors such as intravenous drug use, central venous access catheters, immunosuppression, or prosthetic valves, B. cereus can cause severe infections. Herein, we present a case of prosthetic valve endocarditis (PVE) caused by B. cereus in an 84-year-old woman with a history of aortic valve replacement for aortic stenosis five years earlier. She presented with anorexia, and her physical examination revealed tenderness in the left upper quadrant of the abdomen. Blood culture grew B. cereus, and a CT scan showed splenic infarction, raising suspicion of PVE. Transesophageal echocardiogram (TEE) revealed an abscess around the left coronary cusp of the aortic valve and a 15 mm vegetation. Due to the patient's high risk for post-operative complications and her unwillingness to undergo surgery, the surgery was deferred. Instead, she was successfully treated with six weeks of intravenous vancomycin and discharged home. Follow-up TEE demonstrated resolution of the vegetation and valvular abscess. At her six-month post-discharge evaluation, no signs of active infection were noted including fever or worsening heart failure. Although surgery is typically recommended for most cases of PVE, conservative treatment can be considered as an alternative option for selected patients.

Safety and efficacy of S-IROX (S-1, irinotecan and oxaliplatin combination therapy) in patients with advanced pancreatic cancer: A multicenter phase 1b dose-escalation and dose-expansion clinical trial.

BACKGROUND: This phase 1b trial evaluated the toxicity and efficacy of S-1, irinotecan, and oxaliplatin combination therapy (S-IROX) as first-line chemotherapy in patients with advanced pancreatic cancer (APC). METHODS: Patients aged 20-75 years with APC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible to receive escalating doses of S-1 (60 or 80 mg m2·day) on days 1-7, fixed doses of oxaliplatin (85 mg/m2) biweekly, and escalating doses of irinotecan (150, 165, or 180 mg/m2) once every 2 weeks. In the dose-escalation cohort, a 3 + 3 design was used to determine the maximum-tolerated dose (MTD) and explore the recommended dose (RD). A dose-expansion cohort was added to further evaluate the safety and efficacy of the combination. This trial was registered at UMIN-CTR (UMIN000012054). RESULTS: Approximately 47 patients were enrolled, of whom 45 were eligible for the analysis. The MTD was not determined, but the RD was determined to be dose level 1 based on a review of data from each level. Among the 45 patients, the ORR was 51.1% [95% confidence interval (CI), 35.8-66.3%]. The median progression-free survival and median overall survival was 6.9 months (95% CI, 5.1-8.8 months) and 15.8 months (95% CI, 9.8-20.8 months), respectively. Common adverse events included neutropenia, elevated liver enzyme levels, diarrhoea, and nausea. CONCLUSIONS: The S-IROX regimen showed promising efficacy with manageable toxicities in Japanese patients with APC. A randomised phase 2/3 trial comparing S-IROX, mFOLFIRINOX, and gemcitabine plus nab-paclitaxel is currently ongoing (jRCTs031190009).

Prosthetic hip infection due to Campylobacter jejuni.

A woman in her 60s with a left hip prosthesis was presented with left hip pain and fever. She had an elevated white blood cell count and inflammatory markers. Synovial fluid Gram stain demonstrated curved Gram-negative rods identified as Campylobacter jejuni The patient initially refused surgery and after 3 months underwent one-stage exchange after which she was treated with 12 weeks of levofloxacin. Her inflammatory markers normalised and she was clinically doing well at her 6-month follow-up. C. jejuni is a rare cause of prosthetic joint infection and should be included in the differential diagnosis when a patient has risk factors even without significant preceding gastrointestinal symptoms. Per most recent Infectious Diseases Society of America guidelines, treatment after one-stage revision includes 4-6 weeks of intravenous antimicrobials followed by possible oral suppression therapy, while the European guidelines recommend 12 weeks of orally bioavailable antibiotics.

Short-term effectiveness of COVID-19 vaccines in immunocompromised patients: A systematic literature review and meta-analysis.

OBJECTIVES: We aimed to assess the short-term effectiveness of COVID-19 vaccines among immunocompromised patients to prevent laboratory-confirmed symptomatic COVID-19 infection. METHODS: Systematic review and meta-analysis. We calculated the pooled diagnostic odds ratio [DOR] (95% CI) for COVID-19 infection between immunocompromised patients and healthy people or those with stable chronic medical conditions. VE was estimated as 100% x (1-DOR). We also investigated the rates of developing anti-SARS-CoV-2 spike protein IgG between the 2 groups. RESULTS: Twenty studies evaluating COVID-19 vaccine response, and four studies evaluating VE were included in the meta-analysis. The pooled DOR for symptomatic COVID-19 infection in immunocompromised patients was 0.296 (95% CI: 0.108-0.811) with an estimated VE of 70.4% (95% CI: 18.9%- 89.2%). When stratified by diagnosis, IgG antibody levels were much higher in the control group compared to immunocompromised patients with solid organ transplant (pOR 232.3; 95% Cl: 66.98-806.03), malignant diseases (pOR 42.0, 95% Cl: 11.68-151.03), and inflammatory rheumatic diseases (pOR 19.06; 95% Cl: 5.00-72.62). CONCLUSIONS: We found COVID-19 mRNA vaccines were effective against symptomatic COVID-19 among the immunocompromised patients but had lower VE compared to the controls. Further research is needed to understand the discordance between antibody production and protection against symptomatic COVID-19 infection.

Mistaken Identity: Many Diagnoses are Frequently Misattributed to Lyme Disease.

BACKGROUND: Prior studies have demonstrated that Lyme disease is frequently over-diagnosed. However, few studies describe which conditions are misdiagnosed as Lyme disease. METHODS: This retrospective observational cohort study evaluated patients who lacked evidence for Borrelia burgdorferi infection referred for Lyme disease to a Mid-Atlantic academic center from 2000-2013. The primary outcome is clinically described diagnoses contributing to symptoms. Secondary outcomes included symptom duration and determination whether diagnoses were new or attributed to existing medical conditions. RESULTS: Of 1261 referred patients, 1061 (84%) had no findings of active Lyme disease, with 690 (65%) receiving other diagnoses; resulting in 405 (59%) having newly diagnosed medical conditions, 134 (19%) attributed to pre-existing medical issues, and 151 (22%) with both new and pre-existing conditions. Among the 690 patients, the median symptom duration was 796 days, and a total of 139 discrete diagnoses were made. Infectious disease diagnoses comprised only 3.2%. Leading diagnoses were anxiety/depression 222 (21%), fibromyalgia 120 (11%), chronic fatigue syndrome 77 (7%), migraine disorder 74 (7%), osteoarthritis 62 (6%), and sleep disorder/apnea 48 (5%). Examples of less frequent but non-syndromic diseases newly diagnosed included multiple sclerosis (n = 11), malignancy (n = 8), Parkinson's disease (n = 8), sarcoidosis (n = 4), or amyotrophic lateral sclerosis (n = 4). CONCLUSIONS: Most patients with long-term symptoms have either new or pre-existing disorders accounting for their symptoms other than Lyme disease, suggesting overdiagnosis in this population. Patients referred for consideration of Lyme disease for chronic symptoms deserve careful assessment for diagnoses other than Borrelia burgdorferi infection.

Examination of risk factors for postoperative vestibular symptoms in patients with cholesteatoma.

BACKGROUND: In cholesteatoma, the prognosis of tympanoplasty has been well discussed in terms of hearing outcomes and residual or recurrent lesions. Postoperative dizziness and vertigo are major complications of tympanoplasty; however, few reports are available. AIMS/OBJECTIVES: We investigated each condition of cholesteatoma postoperative vestibular risk using the STAM system and staging published by EAONO/JOS, as well as findings on bony destruction. MATERIAL AND METHODS: From April 2010 to March 2021, 156 patients (166 ears) with cholesteatoma who underwent primary microscopic tympanoplasty at our hospital were registered. Subjective vestibular symptoms were recorded the day after surgery. RESULTS: Postoperative vestibular symptoms were observed in 13.9% of subjects. All of them were stage II and had both attic and mastoid lesions. Attic (p < .05) and mastoid (p < .01) lesions were risk factors. Multivariate analysis showed that significant differences were found in past histories of vestibular symptoms (p < .05) and exposure of the dura mater (p < .01). CONCLUSIONS AND SIGNIFICANCE: In the exposed dura group, the length of the prominence of the lateral semicircular canal to the middle cranial fossa dura was significantly shorter than that of the non-exposed group (p < .01). Narrow working space and downward operation may increase vestibular risk.

Adult Living-Donor Kidney Transplantation, Donor Age, and Donor-Recipient Age.

INTRODUCTION: Owing to organ shortage, the number of kidney transplantation (KT) involving older adult living donors is increasing. We aimed to investigate the effects of living-donor age and donor-recipient age differences on KT outcomes. METHODS: This single-center, retrospective cohort study involved 853 adult LDKTs performed between January 2008 and December 2018. Recipients were stratified into the following 5 groups based on donor age and donor-recipient age difference: donor age, 30 to 49 years and age difference, -10 to 15 years; donor age, 50 to 69 years and age difference, -10 to 15 years; donor age, 50 to 69 years and age difference, 15 to 40 years; donor age, 70 to 89 years and age difference, -10 to 15 years; and donor age, 70 to 89 years and age difference, 15 to 40 years (groups 1, 2, 3, 4, and 5, respectively). As a primary outcome, the risk of graft loss was investigated. The secondary outcomes were postoperative estimated glomerular filtration rates (eGFRs) and mortality rates of recipients. RESULTS: Group 4, representing KT between older adult donors and older adult recipients, had the highest graft loss risk and mortality. The eGFRs of the recipients from donors aged 70 to 89 years (groups 4 and 5) were significantly lower than those from donors in the other groups. Although the differences in the eGFR between groups 4 and 5 were not significant, the eGFR of group 4 was lower than that of group 5 at 6 months post-KT. CONCLUSION: LDKTs from older adult donors to older adult recipients resulted in the worst graft survival and mortality rates.

An autopsy case study of lymphocytic hypophysitis induced by nivolumab treatment for esophageal malignant melanoma.

Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death-1 antibodies are effective against malignant tumors. However, they induce unique adverse events known as immune-related adverse events. Hypophysitis is one of the most frequent immune-related adverse events of anti-cytotoxic T-lymphocyte antigen-4 therapies. However, there have been few reports describing the pathological findings of hypophysitis induced by anti-programmed death-1 antibodies. The present case is the first autopsy case of hypophysitis induced by nivolumab monotherapy, an anti-programmed death-1 antibody. Pathologically, lymphocytes infiltrated the anterior lobe of the pituitary gland, and the number of pituitary cells, especially adrenocorticotropic hormone-positive cells, decreased. However, necrosis and remarkable fibrosis were not observed. Immunohistologically, some pituitary cells expressed programmed death-ligand 1. Lymphocytes were predominantly CD8-positive T cells, and CD68-positive macrophages and CD20-positive B-cells were also observed. IgG and C4d were deposited on pituitary cells, but IgG4 (a subclass of nivolumab) was not detected. These findings indicate that type IVc and type II hypersensitivity mechanisms may occur in hypophysitis induced by anti-programmed death-1 antibodies and that the inflammatory mechanisms underlying hypophysitis induced by anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen-4 antibodies are different.

Stable Clostridioides difficile infection rates after the discontinuation of ultraviolet light for terminal disinfection at a tertiary care center, Iowa 2019-2020.

We compared the incidence of Clostridioides difficile infection before and after the discontinuation of Ultraviolet light used in addition to bleach in terminal disinfection of hospital rooms. We found no difference in C. difficile infection rates but found a decreased turn over time. The benefit of Ultraviolet light may be diminished in hospitals with a high thoroughness of manual cleaning.

Association of Remdesivir Treatment With Survival and Length of Hospital Stay Among US Veterans Hospitalized With COVID-19.

Importance: Randomized clinical trials have yielded conflicting results about the effects of remdesivir therapy on survival and length of hospital stay among people with COVID-19. Objective: To examine associations between remdesivir treatment and survival and length of hospital stay among people hospitalized with COVID-19 in routine care settings. Design, Setting, and Participants: This retrospective cohort study used data from the Veterans Health Administration (VHA) to identify adult patients in 123 VHA hospitals who had a first hospitalization with laboratory-confirmed COVID-19 from May 1 to October 8, 2020. Propensity score matching of patients initiating remdesivir treatment to control patients who had not initiated remdesivir treatment by the same hospital day was used to create the analytic cohort. Exposures: Remdesivir treatment. Main Outcomes and Measures: Time to death within 30 days of remdesivir treatment initiation (or corresponding hospital day for matched control individuals) and time to hospital discharge with time to death as a competing event. Associations between remdesivir treatment and these outcomes were assessed using Cox proportional hazards regression in the matched cohort. Results: The initial cohort included 5898 patients admitted to 123 hospitals, 2374 (40.3%) of whom received remdesivir treatment (2238 men [94.3%]; mean [SD] age, 67.8 [12.8] years) and 3524 (59.7%) of whom never received remdesivir treatment (3302 men [93.7%]; mean [SD] age, 67.0 [14.4] years). After propensity score matching, the analysis included 1172 remdesivir recipients and 1172 controls, for a final matched cohort of 2344 individuals. Remdesivir recipients and matched controls were similar with regard to age (mean [SD], 66.6 [14.2] years vs 67.5 [14.1] years), sex (1101 men [93.9%] vs 1101 men [93.9%]), dexamethasone use (559 [47.7%] vs 559 [47.7%]), admission to the intensive care unit (242 [20.7%] vs 234 [19.1%]), and mechanical ventilation use (69 [5.9%] vs 45 [3.8%]). Standardized differences were less than 10% for all measures. Remdesivir treatment was not associated with 30-day mortality (143 remdesivir recipients [12.2%] vs 124 controls [10.6%]; log rank P = .26; adjusted hazard ratio [HR], 1.06; 95% CI, 0.83-1.36). Results were similar for people receiving vs not receiving dexamethasone at remdesivir initiation (dexamethasone recipients: adjusted HR, 0.93; 95% CI, 0.64-1.35; nonrecipients: adjusted HR, 1.19; 95% CI, 0.84-1.69). Remdesivir recipients had a longer median time to hospital discharge compared with matched controls (6 days [interquartile range, 4-12 days] vs 3 days [interquartile range, 1-7 days]; P < .001). Conclusions and Relevance: In this cohort study of US veterans hospitalized with COVID-19, remdesivir treatment was not associated with improved survival but was associated with longer hospital stays. Routine use of remdesivir may be associated with increased use of hospital beds while not being associated with improvements in survival.

Prosthetic hip infection due to Salmonella enterica serovar Enteritidis.

Prosthetic joint infection (PJI) is a serious complication of prosthetic joint implantation with a prevalence of about 1-2 % of all prosthetic joint surgeries. While Staphylococcus spp. are the most common organisms isolated, Salmonella spp. are a rare cause of PJI (estimated prevalence < 0.3 %). We present a case of a 62-year-old patient with a history of previous joint trauma complicated by osteonecrosis, infection and chronic alcohol abuse with late hematogenous prosthetic hip infection due to Salmonella enterica serovar Enteritidis. PJI due to Salmonella spp. should be considered in the differential diagnosis when a patient has risk factors such as malignancy, hemoglobinopathies, diabetes mellitus, human immunodeficiency virus/acquired immunodeficiency syndrome, alcohol dependency or immunosuppressed state, even without significant preceding gastrointestinal symptoms. Our patient had a few of these risk factors and required surgical debridement in addition to antimicrobials for treatment of his PJI.

Palliative care consultation in patients with Staphylococcus aureus bacteremia.

BACKGROUND: Palliative care consultation has shown benefits across a wide spectrum of diseases, but the utility in patients with Staphylococcus aureus bacteremia remains unclear despite its high mortality. AIM: To examine the frequency of palliative care consultation and factors associated with palliative care consult in Staphylococcus aureus bacteremia patients in the United States. DESIGN: A population-based retrospective analysis using the Nationwide Inpatient Sample database in 2014, compiled by the Healthcare Costs and Utilization Project of the Agency for Healthcare Research and Quality. SETTING/SUBJECTS: All inpatients with a discharge diagnosis of Staphylococcus aureus bacteremia (ICD-9-CM codes; 038.11 and 038.12). MEASUREMENTS: Palliative care consultation was identified using ICD-9-CM code V66.7. Patients' baseline characteristics and outcomes were compared between those with and without palliative care consult. RESULTS: A total of 111,320 Staphylococcus aureus bacteremia admissions were identified in 2014. Palliative care consult was observed in 8140 admissions (7.3%). Palliative care consultation was associated with advanced age, white race, comorbidities, higher income, teaching/urban hospitals, Midwest region, Methicillin-resistant Staphylococcus aureus bacteremia and the lack of echocardiogram. Palliative care consult was also associated with shorter but more expensive hospitalizations. Crude mortality was 53% (4314/8140) among admissions with palliative care consult and 8% (8357/10,3180) among those without palliative care consult (p < 0.001). CONCLUSIONS: Palliative care consultation was infrequent during the management of Staphylococcus aureus bacteremia, and a substantial number of patients died during their hospitalizations without palliative care consult. Given the reported benefit in other medical conditions, palliative care consultation may have a role in Staphylococcus aureus bacteremia. Selecting patients who may benefit the most should be explored.

Effect of UGT1A1, CYP3A and CES Activities on the Pharmacokinetics of Irinotecan and its Metabolites in Patients with UGT1A1 Gene Polymorphisms.

BACKGROUND AND OBJECTIVES: Irinotecan (CPT-11) is metabolized to an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase (CES). SN-38 is then converted to the inactive metabolite SN-38 glucuronide (SN-38G) by glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms in UGT1A1 have been associated with altered SN-38 pharmacokinetics, which increase the risk of toxicity in patients. CPT-11 is also converted to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC) by cytochrome P450 3A (CYP3A), and this route also affects the plasma concentration of SN-38. We evaluated the activities of UGT1A1, CYP3A, and CES and the factors affecting the pharmacokinetics of plasma SN-38 in patients with UGT1A1 gene polymorphisms. METHODS: Three male patients aged 56, 65, and 49 years were recruited for the analysis. All patients had pancreatic cancer, received FOLFIRINOX, and had UGT1A1*6/*6 (patients 1 and 3) or *6/*28 (patient 2) genetic polymorphisms. The rate constants for evaluating the enzyme activity were determined from the measured plasma concentration of CPT-11 and its metabolites using a two-compartment model by WinNonlin. RESULTS: The area under the plasma concentration-time curve (AUC) of SN-38 was patient 1 > patient 2 > patient 3. The rate constants obtained from the model analysis indicated the respective enzyme activities of UGT1A1 (k57), CYP3A (k13 + k19), and CES (k15). The order of values for UGT1A1 activity was patient 2 > patient 3 > patient 1. Since UGT1A1 activity was low in patient 1 with a high AUC of SN-38, it can be said that the increase in plasma concentration was due to a decrease in UGT1A1 activity. Conversely, the order of values for CYP3A and CES activities was patient 3 > patient 1 > patient 2 and patient 2 > patient 1 > patient 3, respectively. Patient 3 had the lowest AUC of SN-38, caused by a lower level of CES activity and increased CYP3A activity. CONCLUSION: In this study, we indicated that the plasma AUC of SN-38 and AUC ratio of SN-38G/SN-38 may depend on changes in the activities of CYP3A, CES, and UGT1A1. Using pharmacokinetic analysis, it is possible to directly evaluate enzyme activity and consider what kind of enzyme variation causes the increase in the AUC of SN-38.

Biomarker Analyses in Patients With Advanced Solid Tumors Treated With the LAT1 Inhibitor JPH203.

BACKGROUND/AIM: Amino acids are among the most important nutrients for supplying energy and building protein blocks in cancers. L-type amino acid transporter (LAT) 1 is known to play a critical role in cancer growth. We have completed the first-in-human phase I study using the LAT1-specific inhibitor JPH203. PATIENTS AND METHODS: We evaluated plasma free amino acids (PFAAs), body mass index (BMI), and efficacy of JPH203 in patients enrolled in the phase I study. RESULTS: LAT1-substrate PFAAs and branched chain amino acids (BCAAs) were higher in patients with biliary tract cancer (BTC) than in those with other cancers. High inhibition of uptake of LAT1-substrate PFAAs was associated with survival. BMI of more than the median was associated with disease control and survival. BCAAs tended to be associated with BMI. CONCLUSION: BCAAs and BMI are useful predictors of the efficacy of JPH203, which shows promising activity against BTC.