Influence of preoperative body mass index on prognosis for patients with upper urinary tract urothelial carcinoma treated with radical nephroureterectomy.

PURPOSE: The impact of body mass index (BMI) on patients with upper urinary tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU) is controversial. Increasing evidence suggests an age-dependent relationship between obesity and outcomes for some solid organ tumors. Herein, we aimed to assess the prognostic value of preoperative BMI in UTUC patients treated with RNU in Taiwan. METHODS: This was a retrospective single-center study of 468 UTUC patients undergoing RNU during January 2010-December 2017, with preoperative BMI classification and subgroup analysis based on ages of < or ≥ 70 years. All UTUC patients underwent RNU and bladder cuff excision. Overall survival (OS), cancer-specific survival, and disease-free survival (DFS) were analyzed. Fisher's exact test, Mann-Whitney U test, Kaplan-Meier method, and Cox regression model were used for data analysis. RESULTS: The median follow-up duration was 36 months. Patients with higher versus lower BMI (cutoff: 25 kg/m2) showed no differences in OS; older patients had poor OS (hazard ratio [HR] 1.74; 95% confidence interval [CI] 1.24-2.40; p < 0.001). Older age was an independent predictor of poor OS in multivariate Cox regression analysis (p = 0.001). Younger patients with higher BMI (p = 0.02) had better DFS than older patients with no BMI-related survival differences. Higher BMI was an independent predictor of favorable DFS in younger patients in multivariate Cox regression analysis (HR, 0.53; 95% CI 0.28-0.99; p = 0.043). CONCLUSION: Younger UTUC patients with higher BMI were independently associated with a favorable DFS.

Prostate health index density predicts aggressive pathological outcomes after radical prostatectomy in Taiwanese patients.

BACKGROUND: There are models to predict pathological outcomes based on established clinical and prostate-specific antigen (PSA)-derived parameters; however, they are not satisfactory. p2PSA and its derived biomarkers have shown promise for the diagnosis and prognosis of prostate cancer (PCa). The aim of this study was to investigate whether p2PSA-derived biomarkers can assist in the prediction of aggressive pathological outcomes after radical prostatectomy (RP). METHODS: We prospectively enrolled patients who were diagnosed with PCa and treated with RP between February 2017 and December 2018. Preoperative blood samples were analyzed for tPSA, free PSA (fPSA), percentage of fPSA (%fPSA), [-2]proPSA (p2PSA), and percentage of p2PSA (%p2PSA). Prostate health index (PHI) was calculated as (p2PSA/fPSA) × âˆštPSA. Prostate volume was determined by transrectal ultrasound using the ellipsoid formula, and PHI density was calculated as PHI/prostate volume. The areas under the receiver operating characteristic curve were estimated for various PSA/p2PSA derivatives. Aggressive pathological outcomes measured after RP were defined as pathological T3 or a Gleason score (GS) >6 as determined in RP specimens. RESULTS: One hundred and forty-four patients were included for analysis. Postoperative GS was >6 in 86.1% of the patients, and pT stage was T3a or more in 54.2%. Among all PSA- and p2PSA-derived biomarkers, PHI density was the best biomarker to predict aggressive pathological outcomes after RP. The odds ratio of having an aggressive pathological outcome of RP was 8.796 (p = 0.001). In multivariate analysis, adding %fPSA to base model did not improve the accuracy (area under curve), but adding PHI and PHI density to base model improved the accuracy by 2% and 16%, respectively, in predicting pT3 stage or GS ≥ 7. The risk of pT3 stage or GS ≥ 7 was 20.8% for PHI density <1.125, and 64.6% for PHI density >1.125 (sensitivity: 74.6% and specificity: 88.9%). CONCLUSION: PHI density may further aid in predicting aggressive pathological outcomes after RP. This biomarker may be useful in preoperative counseling and may have potential in decision making when choosing between definitive treatment and active surveillance of newly diagnosed PCa.

Is intravesical prostatic protrusion a risk factor for hydronephrosis and renal insufficiency in benign prostate hyperplasia patients?

BACKGROUND: Some patients with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms hesitate to undergo surgical treatment until acute urinary retention (AUR) occurs. Some of these patients have been found to have hydronephrosis or even renal insufficiency. This study aimed to analyze the risk factors for hydronephrosis in patients with AUR who needed to receive transurethral resection of the prostate (TURP). METHODS: We retrospectively analyzed 91 patients from January 2014 to June 2015, who had BPH and received TURP for AUR. Patients with urolithiasis, prostate cancer, bladder cancer, gross hematuria, previous bladder radiation therapy, or urinary tract surgery were excluded. Parameters of intravesical prostatic protrusion (IPP), serum prostatic specific antigen (PSA), total prostate volume (PV), age, body mass index (BMI), hypertension (HTN), diabetes mellitus (DM), coronary artery disease (CAD), and serum creatinine (Cr) were compared between the hydronephrosis and non-hydronephrosis groups. RESULTS: There were significant differences in IPP (p < 0.001) and Serum Cr (p < 0.001) between the hydronephrosis and non-hydronephrosis groups. For IPP, the cut-off values of the highest risk of hydronephrosis was 1.95 cm. There were no significant differences in age, BMI, DM, HTN, CAD, total PV, and PSA between the two groups. IPP was not correlated with total PV (p = 0.423). Most of the patients with hydronephrosis had renal function improvement after TURP. CONCLUSION: IPP was a significant risk factor for hydronephrosis in BPH patients. If the patients' IPP exceeded 1.95 cm, they had a higher risk of having hydronephrosis when AUR occurred. Hydronephrosis is a risk factor for renal insufficiency, and Serum Cr levels decreased significantly in the patients of our study.

Clinical analysis of 48-h emergency department visit post outpatient extracorporeal shock wave lithotripsy for urolithiasis.

BACKGROUND: Patients suffering from renal or ureteral stones can undergo significant discomfort, even when timely diagnosed and treated. The aim of this study was to assess the risk factors and safety of outpatient Extracorporeal Shock Wave Lithotripsy (ESWL) in the management of patients with renal or ureteral stones. METHODS: In this study, our cohort consisted of 844 outpatients who underwent outpatient ESWL treated between February 2012 and November 2014 at Taipei Veterans General Hospital. Patients who visited the emergency room (ER) within 48 h after Outpatient ESWL were included in this article. This article analyzes the stone size, stone shape (long to short axis ratio), stone location, previous medical management, urinalysis data, complications and treatment received in the emergency department. RESULTS: Among the 844 initial consecutive patients who underwent outpatient ESWL a total of 1095 times, there were 22 (2%) patients who sought help at our emergency room within 48 h after the outpatient ESWL. Of those 22 patients, the mean age was 54.3 ± 12.6 years, and the BMI was 25.9 ± 3.2. The most common complication complaint was flank pain (55.2%). Other complications included hematuria (13.8%), fever (17.2%), nausea with vomiting (6.9%), acute urinary retention (3.4%) and chest tightness with cold sweating (3.4%). In 22 patients who went back to the ER, 7 patients were admitted to the ward and 1 patient again returned to the ER. All patients received medical treatment without ESWL or surgical management. The meaningful risk factor of ER-visiting rate following outpatient ESWL within 48 h was stone location, and the renal stones showed statistic significant (p = 0.047) when compared to ureteral stones. CONCLUSION: Our study indicated that renal stone contributed to a significantly higher risk of ER-visiting rate to patients than did ureteral stone, following outpatient ESWL within 48 h. This study confirmed that Outpatient ESWL is a safe treatment for renal or ureteral stones, while inpatient ESWL is not absolutely necessary.

Clinical efficacy of transrectal ultrasound-guided prostate biopsy in men younger than 50 years old with an elevated prostate-specific antigen concentration (>4.0 ng/mL).

BACKGROUND: Prostate cancer (PCa) is not commonly found in men younger than 50 years of age. However, serum prostate-specific antigen (PSA) concentration has been examined more frequently at a younger age in Asia partially due to an increased awareness of prostate cancer. The purpose of our study was to investigate the efficacy and complication of PSA-triggered transrectal ultrasonography-guided prostate (TRUSP) biopsies. We retrospectively reviewed TRUSP biopsies in young men with elevated PSA concentration in Taipei Veterans General Hospital. METHODS: We reviewed the cases of patients younger than 50 years of age with elevated PSA concentration (>4.0 ng/mL), who received 12 cores TRUSP biopsies at TPEVGH from January 2008-December 2013. The age, family history, digital rectal examination (DRE) results, PSA concentration, free/total PSA ratio, total prostate volume, PSA density, lower urinary tract symptoms and complications after the procedure were reviewed. The pathologic findings of TRUSP biopsy and clinical follow-up were reviewed and analyzed according to the Epstein criteria. RESULTS: A total of 77 patients were included and were divided into 2 groups: 1) the younger group consisted of 20 patients <40 years of age; and 2) the elder group had 57 patients who were 40-50 years of age. The overall detection rate of PCa was 11.69% (9/77), and all of the PCa cases were diagnosed in the elder group (group detection rate: 15.8%). There was a significant difference in the severity of lower urinary tract symptoms (LUTS) between these 2 groups. All PCa patients were clinically significant according to the Epstein criteria. Two patients experienced fever (2.60%) after TRUSP biopsy. CONCLUSION: From our patient cohort, it appears that no benefit was apparent for patients younger than 40 years old who received TRUSP biopsy, even with elevated PSA. However, PCa detected in men between 40 and 50 years of age were all clinically significant. Overall, our results supported current major practice guidelines which recommend an initial PSA checkup at 40 years of age.

Prostate cancer in young adults-Seventeen-year clinical experience of a single center.

BACKGROUND: In the general population, prostate adenocarcinoma affects predominately older men. If fact, most current guidelines suggest that males over the age of 50 years should undergo prostate cancer screening. However, the clinical behavior and prognosis of prostate cancer in young adults is not well defined. The aim of this study was to evaluate the clinical behavior, pathological characteristics, and prognosis of prostate cancer in young adults. METHODS: We retrospectively reviewed the records of young patients (age, ≤50 years) in our hospital with prostate adenocarcinoma between 1997 and 2013. We compared data including initial presentation, cancer cell type, Gleason score, disease stage, prostate-specific antigen (PSA) level, prostate volume, treatment, and survival between patients both younger and older than 50 years. Data were analyzed using the Kaplan-Meier method to assess survival. RESULTS: Twenty-six patients were enrolled in our study, accounting for 0.55% of all patients with a diagnosis of prostate cancer at our facility. All 26 patients had a pathology diagnosis of adenocarcinoma, with a mean age on diagnosis of 46.8±2.8 years (range, 39-50 years). On initial presentation, patients older than 50 years more frequently displayed lower urinary tract symptoms (LUTS) than younger patients (62.3% vs. 30.4%, p=0.008). There was no statistical difference in histological grade, disease stage, PSA level, overall survival, and biochemical-free survival between the two groups. CONCLUSION: The result of our investigation indicated that prostate adenocarcinoma patients younger than 50 years had similar histological grade, disease stage, PSA level, overall survival, and biochemical-free survival as the older population. However, patients younger than 50 years with prostate cancer less frequently showed initial symptoms of LUTS.

Does extended prostate needle biopsy improve the concordance of Gleason scores between biopsy and prostatectomy in the Taiwanese population?

BACKGROUND: Discordance between the Gleason scores of prostate needle biopsies and radical prostatectomy specimens has been reported by several investigators. We conducted this study to determine if increasing the number of prostate needle biopsies in patients with prostate cancer improves the accuracy of Gleason scores in the Taiwanese population. METHODS: Between March 2000 and September 2009, 281 patients underwent radical prostatectomy at Taipei Veterans General Hospital. All of these patients had prostate cancer that was diagnosed and graded either by extended needle biopsy (121 patients, ≥ 10 cores/patient, range: 10-13, median: 12) or by traditional sextant transrectal biopsy (160 patients, <10 cores/patient, range: 6-9, median: 6). We analyzed the patients' Gleason scores of their biopsies and radical prostatectomy specimens. RESULTS: The concordance rate, defined as similarity between the Gleason score of a patient's biopsy and prostatectomy specimens, was 57.9% in the extended biopsy group and 45.6% in the nonextended biopsy group (χ(2) test: p = 0.042). The primary Gleason pattern was accurately predicted by extended needle biopsy in 81% of cases (98/121 cases), higher than the 70% accuracy rate of the nonextended biopsies (112/160 cases, p = 0.036). Undergrading was found in 43/121 cases (32%) and 63/160 cases (39.4%) (p = 0.511). However, overgrading was found in 8/121 cases (6.6%) and in 24/160 cases (15.0%) (p = 0.028) by extended and nonextended biopsies, respectively. Forty-seven (16.7%) of those patients who fit the criteria of active surveillance were upgraded to a Gleason score >7 after radical prostatectomy. CONCLUSION: The addition of an extended transrectal needle biopsy increases the accuracy of the Gleason score for predicting the final prostate cancer grade in the Taiwanese population.

Correlation between pretreatment serum biochemical markers and treatment outcome for prostatic cancer with bony metastasis.

BACKGROUND: This study was undertaken to evaluate whether or not pretreatment serum biochemical markers are prognostic factors for prostatic cancer with bony metastasis in patients on hormonal treatment. METHODS: Between 1983 and 1998, 127 patients with prostatic cancer and bony metastasis were included for evaluation. Serum prostate-specific antigen, alkaline phosphatase, calcium (Ca), lactic dehydrogenase, inorganic phosphate, gamma-glutamine transpeptidase, uric acid, albumin (Alb), iron, cholesterol (Cho), triglyceride, alanine aminotransferase, aspartate aminotransferase, and hemoglobin (Hb) were checked before treatment. The patients were divided into 2 groups according to their response (group 1, good response; group 2, poor response). RESULTS: There were 54 patients in group 1 and 73 patients in group 2. Pretreatment levels of serum Ca, Alb, Cho and Hb were higher in group 1 than in group 2, while the other parameters were lower in group 1 than in group 2; only pretreatment levels of serum Ca, Alb and Hb were significantly different between groups (p < 0.05). When stratified by tumor grading, patients in group 1 still had significantly higher pretreatment levels of Ca, Alb and Hb than those in group 2. CONCLUSION: Higher pretreatment serum levels of Ca, Alb and Hb are good prognostic factors for patients with metastatic prostatic cancer on hormonal treatment, irrespective of tumor grading.

Pan-urethral wart treated with 5-fluorouracil intraurethral instillation.

We evaluated whether or not intraurethral instillation of 5-fluorouracil (5-FU) solution can rapidly, safely, and effectively eradicate intraurethral condyloma acuminata in a human immunodeficiency virus (HIV) carrier. A 43-year-old man presented with the major complaint of difficult micturition and blood dribbling from the urethral meatus for more than 6 months. He was an HIV carrier for more than 10 years and had undergone diathermy for perianal warts. Physical examination showed cauliflower lesions over the orifice of the urethra and frenulum base of the penile prepuce. Urinalysis disclosed pyuria and microscopic hematuria. Cystourethroscopy on the following day showed extensive wart lesions extending from the urethra to the bladder neck. Biopsy of the lesions was compatible with condyloma acuminata. 5-FU solution (500 mg in normal saline 50 mL) urethral instillation with massage at the ventral side of the penile shaft for 20 minutes was given once a week for 7 doses. The urine routine was normal. Management was then prescribed once a month until the lesions became invisible under urethroscopy. After 18 doses of 5-FU solution urethral instillation, no visible wart lesions were noted. He has been asymptomatic with no voiding difficulty for more than 1 year.

Correlation between serum prostate specific antigen and prostate volume in Taiwanese men with biopsy proven benign prostatic hyperplasia.

PURPOSE: We studied the correlation between serum prostate specific antigen and the volume of different zones of the prostate in Taiwanese men with biopsy proven benign prostatic hyperplasia. MATERIALS AND METHODS: A total of 233 patients with a mean age of 71.4 years (range 42 to 89), serum prostate specific antigen less than 10 ng/ml and pathologically confirmed benign prostatic hyperplasia were enrolled in this study. Total prostate and transitional zone volumes were measured with transrectal ultrasonography. Peripheral zone volume was determined by subtracting transitional zone volume from total prostate volume. Correlations between patient age, total serum prostate specific antigen and the volume of each prostate zone were analyzed with the Pearson correlation coefficient. A linear regression model was used to determine the relationship between prostate specific antigen and prostate volume. The prostate specific antigen-prostate volume relationship in our patients was compared with published data on white and Japanese men. RESULTS: Age did not significantly correlate with serum prostate specific antigen and prostate volume. Serum prostate specific antigen significantly correlated with the volume of each prostate zone. After log transformation the Pearson correlation coefficient between total prostate specific antigen and the volume of the whole prostate gland, the transitional zone and the peripheral zone were 0.369, 0.377 and 0.272, respectively (p <0.001). Taiwanese men had lower prostate volume per unit prostate specific antigen comparing with white men, while the prostate specific antigen-total prostate volume relationship between Taiwanese and Japanese men was similar. CONCLUSIONS: In Taiwanese men with biopsy proven benign prostatic hyperplasia the volume of each prostate zone has significantly correlates with serum prostate specific antigen. The prostate specific antigen-total prostate volume relationship in Taiwanese men is different from that in white men. However, the prostate specific antigen-total prostate volume relationship between Taiwanese and Japanese men is similar.

Transurethral prostatic resection for acute urinary retention in patients with prostate cancer.

BACKGROUND: Few studies have focused on clinical findings in prostate cancer patients receiving transurethral resection of the prostate (TURP) for acute urinary retention (AUR). We compared the clinical findings (preoperative characteristics, operative morbidities, and pathology results) of patients with diagnosed prostate cancer undergoing palliative TURP for AUR with those of patients undergoing TURP for AUR who were diagnosed with prostate cancer postoperatively. METHODS: The charts of 25 patients with prostate cancer undergoing TURP for AUR between 1986 and 2003 were retrospectively reviewed. Fourteen patients underwent palliative TURP (group A) and the other 11 patients with newly diagnosed prostate cancer received TURP (group B). The data, including preoperative characteristics, operative morbidities, and pathology results were analyzed. RESULTS: There were no significant differences between the 2 groups in parameters such as age at diagnosis and operation, operative time, hospitalization, and catheter duration. However, the Gleason score was higher in group A (7.6 +/- 1.7) than in group B (5.4 +/- 1.8) (p < 0.005). The mean resected weight was lower in group A (19.9 g) than in group B (39.5 g). Group A was more likely to receive recatheterization (33.3% vs 0%, p = 0.058) and repeat operation (28.6%), although the difference was not statistically significant. There were no complications such as transurethral resection syndrome or perioperative death in either group. CONCLUSION: TURP can be performed safely for relief of AUR in patients with prostate cancer, no matter if the cancer was diagnosed before or after surgery. The higher Gleason score and more advanced cancer stage, as found in group A, may correlate to high recatheterization and reoperation rates due to preexisting tumor progression.

Lymphangioma of male exogenital organs.

Lymphangioma manifesting in the genitourinary tract is an uncommon disease. Cystic lymphangioma is a congenital lymphatic hamartoma known as lymphatic malformation. Herein we report 2 cases of lymphangioma of male exogenital organs. After complete excision of the tumor and subsequent follow-up for 6 months, both of them were free of recurrence. Ultrasonography and computed tomography scans are very useful in the differential diagnosis of this cystic disease.

Long-term efficacy and safety of sildenafil for patients with erectile dysfunction.

BACKGROUND: To investigate the long-term efficacy and safety of sildenafil for patients with erectile dysfunction (ED). METHODS: Between March 1999 and February 2001, a total of 3168 patients visited Taipei Veterans General Hospital for prescription of sildenafil. The follow-up period was 1-3 years. A questionnaire was designed for evaluation of efficacy and safety of sildenafil via telephone survey. RESULTS: Of the 3168 patients, 1414 were interviewed by telephone. Data from telephone questionnaires were successfully obtained in 1074 cases. Achievement of the first penile erection after sildenafil was reported in 58.8% of our patients. The distribution of the first doses was 0.6%, 8.5%, 81.9% and 90% for 12.5 mg, 25 mg, 50 mg and 100 mg, respectively. After administration of sildenafil, 72.1% men had successful intercourses "sometimes" or "always achieving vaginal penetration", and 72.3% had "slight difficulty" or "no difficulty" in maintaining of sexual intercourses. The "sometimes/most times/always" satisfaction accounted 63.9% and 62.8%, respectively for patients and partners. The global assessment of penile erection was improved in 58.6% of the patients. The sexual confidence of the patients was moderate, high and very high in 72.4% of the patients. Of the 434 patients who failed first penile erections, 400 (92.2%) were related to improper administration of sildenafil. Discontinuation of sildenafil in the last 3 months before telephone survey was found in 852 patients (80.2%). The causes of discontinuation were loss of efficacy in 51.6% of patients, lack of sexual desire in 8.8%, and chronic diseases in 8.2%. Spontaneous erection without sildenafil was claimed in 21.5% of the patients (most times in 9.5% and always in 12.0%). The rate of adverse events after taking sildenafil were 16.6%, and the most common adverse event was facial flushing (9.2%). CONCLUSIONS: The results of this study demonstrated that the efficacy of sildenafil was similar to the previous clinical trials. The adverse events after sildenafil were mild and tolerable. Recovery of complete or partial spontaneous erection was noted in some patients (21.5% in our study) after long-term usage of sildenafil.

Chyluria--experience of Taipei Veterans General Hospital.

BACKGROUND: Chyluria is caused by rupturing of lymphatic varices into the pyelocaliceal system. Although Chyluria is rare in western countries, it is not uncommon in Asia. We would like to present the experience of diagnosis, evaluation and treatment of chyluria in Taipei Veterans General Hospital. METHODS: From 1973 to 1999, a total of 30 patients with chyluria were reviewed. All had the chief complaint of milky white urine passage. They were investigated by multiple workup modalities including computed tomography, intravenous urography, lymphangiography, and cystoscopy. Fifteen cases received 1% silver nitrate instillation and 4 cases underwent nephrolysis either as primary or salvage treatment. RESULTS: Lymphangiography was performed in 24 of the 30 cases and responsible causes of chyluria were noted in 21. They were followed up for at least 12 months in 9 patients treated by intrarenal pelvic instillation of silver nitrate and 3 by nephrolysis, respectively. Recurrence was found in 1 patient (11.1%) receiving silver nitrate only and no significant adverse effect was noted. CONCLUSIONS: Lymphangiography is the most powerful diagnostic tool. Intrarenal silver nitrate instillation is a safe and effective management of chyluria.

Antiandrogen-associated hepatotoxicity in the management of advanced prostate cancer.

BACKGROUND: Antiandrogens available for patients with advanced prostate cancer are reported to cause hepatotoxicity. The aim of this study is to investigate the antiandrogen-associated hepatotoxicity in patients with advanced prostate cancer. METHODS: By retrospective charts review, 229 patients (47-89 years old) with advanced prostate cancer treated by total androgen blockade (TAB) with bilateral orchiectomy or LHRH (luteinizing hormone-releasing hormone) analogues plus antiandrogen, or antiandrogen-radiotherapy were enrolled in this study. There were 124 patients taking flutamide 750 mg daily and 105 patients taking cyproterone acetate (CPA) 150 mg daily. Hepatotoxicity defined by the International Consensus Meeting in 1990 and Food and Drug Administration, USA was used to evaluate the hepatotoxicity (including serious hepatotoxicity). RESULTS: There was a higher occurrence of hepatotoxicity in patients taking flutamide (15.3%) than taking CPA (9.5%) (p = 0.034). The occurrence of serious hepatotoxicity of flutamide and CPA was 4.8% (6/124) and 3.8% (4/105), respectively. The mean latency period of hepatotoxicity for CPA was 4.8 +/- 2.0 months for flutamide and 5.8 +/- 1.9 months for CPA, respectively. The 2 groups made no significant difference of liver enzyme (mean maximal alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) = 284.2 +/- 99.3/300.6 +/- 58.5 U/L versus 341.8 +/- 67.1/301.6 +/- 80.5 U/L). All of the 19 patients (100%) and 9 of 10 patients (90%) with flutamide and CPA-induced hepatotoxicity got self-resolution after discontinuation of the antiandrogens. The average time of self-resolution is 4.5 +/- 3.1 months and 6.3 +/- 4.7 months for flutamide and CPA, respectively. Five patients of flutamide-induced and 2 patients of CPA-induced hepatotoxicity got resolution after changing to other antiandrogen. CONCLUSIONS: Flutamide and CPA appear to cause hepatotoxic effects in some patients. Discontinuation of the antiandrogens seems to be the resolution of hepatotoxicity. A change to other antiandrogen may be the alternative strategy to the antiandrogen-induced hepatotoxicity. The results of this study suggest that all patients received flutamide and CPA should be monitored carefully for signs and symptoms referable to hepatic injury to prevent the development of serious hepatic dysfunction.