Effect of tumor burden and growth rate on treatment outcomes of nivolumab in head and neck cancer.

BACKGROUND: Nivolumab improves overall survival (OS) in patients with platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). In one study, however, Kaplan-Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3-6 months, suggesting that patients with initial resistance to immunotherapy might have better outcomes with cytotoxic treatment. Here, we explored the conditions and candidates which are predictive of nivolumab outcomes in R/M HNSCC. METHODS: We retrospectively reviewed the clinical records of 27 consecutive R/M HNSCC patients treated with nivolumab from 2014 to 2018. Tumor size was evaluated by RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3log(D0/Dpre)/t, where D0 and Dpre are the sum of the diameters of the target lesions (SumTLs) at baseline and pre-baseline, and t is time, with 1t defined as 4 weeks. RESULTS: Twenty-five patients were enrolled. Survival was significantly worse in patients with disease progression within 3 months. Outcomes appeared poorer in patients with higher pre-treatment Gr and bigger SumTLs at baseline. We therefore explored the association between prognosis, Gr and SumTLs. Recursive partitioning analysis showed that the characteristics of patients with disease progression after 3 months were Gr < 0.76 and SumTLs < 31.0 mm. Further, Gr < 0.76 and SumTLs < 31.0 mm was associated with significantly longer PFS (p = 0.01) and OS (p < 0.01). CONCLUSIONS: These results suggest that Gr and SumTLs at baseline are significantly associated with OS and PFS in R/M HNSCC patients treated with nivolumab.

A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody.

BACKGROUND: An important unmet need for new treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based chemotherapy and anti-programmed cell death protein 1 (PD-1) antibody. Retrospective studies suggest that previous treatment with immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. Here, we conducted a phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab for patients in this setting. PATIENTS AND METHODS: This was a single-arm, multicenter, phase II trial. Key eligibility criteria were R/M-HNSCC, and previous treatment with both platinum-based chemotherapy and PD-1 antibody. Paclitaxel plus biweekly cetuximab consisted of weekly paclitaxel 100 mg/m2 (days 1, 8, 15) and biweekly cetuximab 500 mg/m2 (days 1, 15) with a cycle of 28 days until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (Common Terminology Criteria for Adverse Events version 5.0). RESULTS: Between August 2020 and August 2022, 35 patients were enrolled, of whom 33 were assessable for response. ORR was 69.6% (95% confidence interval 51.2% to 84.4%). With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.5 and 13.3 months, respectively. DCR was 93.7%. Twenty-three patients (65%) experienced grade 3 or 4 AEs, including neutropenia (34%), infection (14%), leukopenia (11%), mucositis (8%), and pneumonitis (8%). Eight patients discontinued study treatment due to treatment-related AEs, and no treatment-related death was observed. CONCLUSIONS: Paclitaxel plus biweekly cetuximab showed highly encouraging efficacy and manageable toxicities in R/M-HNSCC patients previously treated with both platinum-based chemotherapy and PD-1 antibody. This combination therapy warrants further investigation in this setting.

Fibroblast growth factor-23 as an early marker of CKD-mineral bone disorder in dogs: preliminary investigation.

OBJECTIVES: To examine the relationship between fibroblast growth factor-23 levels, chronic kidney disease severity and mineral metabolic disorders associated to chronic kidney disease in dogs. MATERIALS AND METHODS: Fifteen control and 75 chronic kidney disease dogs were retrospectively included. Serum fibroblast growth factor-23 concentration and other phosphate metabolite parameters were compared between controls and each International Renal Interest Society stage. Multiple regression analysis was performed to determine the predictors of fibroblast growth factor-23. RESULTS: Serum fibroblast growth factor-23 concentrations were significantly higher in dogs with IRIS stages 2, 3 and 4 chronic kidney disease than those in dogs in control group and with stage 1 and increased along with the severity of chronic kidney disease. Compared with control dogs, serum intact parathyroid hormone significantly increased from stage 2 and serum phosphorus concentrations increased in dogs with stage 4. In dogs with stage 2, fibroblast growth factor-23 levels significantly increased in those with hyperphosphatemia compared with those with normophosphatemia. While eight of 26 (30.8%) dogs with stage 2 developed hyperparathyroidism (intact parathyroid hormone>8.5 ng/L), 19 (73.1%) dogs with stage 2 had elevated fibroblast growth factor-23 levels above the reference range (>528 pg/mL). Log creatinine, log intact parathyroid hormone and log product of total calcium and phosphorus were independent predictors of log fibroblast growth factor-23. CLINICAL SIGNIFICANCE: This preliminary study suggests that canine fibroblast growth factor-23 might be involved in mineral metabolic disorders associated to chronic kidney disease in dogs, and this factor could be potentially used as an early marker for this condition.

Hyperfunctional parathyroid glands with 99mTc-MIBI scan: semiquantitative analysis correlated with histologic findings.

UNLABELLED: The purpose of this study was to correlate the semiquantitative analysis of 99mTc-methoxyisobutyl isonitrile (MIBI) scan with histologic findings of hyperfunctional parathyroid glands. METHODS: Early and delayed cervical images of MIBI scans were reviewed in 31 patients who eventually underwent parathyroidectomies because of biochemically suspected hyperparathyroidism ([HPT], primary, n = 13; secondary, n = 18). The sensitivity of a scan for localizing the diseased glands was determined by comparing scan findings with pathologic findings, which were considered the gold standard. The average ratio of parathyroid-to-thyroid (P/T) count was compared between glands with large and small areas of whole gland, chief cell, oxyphil cell or cellular components. The mean areas of whole gland, chief cells and oxyphil cells were also compared between glands detected by MIBI scan and those that the scan missed. RESULTS: There were 99 resected lesions, including 9 parathyroid adenomas and 61 hyperplastic parathyroids. The sensitivity for localizing the diseased glands in patients with primary HPT (91%) was higher than that in patients with secondary HPT (83%). Significantly greater average P/T counts ratio on both early and delayed images was observed in the diseased glands with greater areas of whole gland, chief cells, oxyphil cells or cellular components. Fifty-nine MIBI-positive glands had significantly greater average areas of whole gland (P < 0.001) and chief cell (P = 0.002) than did 11 MIBI-negative glands. CONCLUSION: The uptake of MIBI in hyperfunctional parathyroid is dependent on gland size and the amount of cellular components, chief cells and oxyphil cells. However, the amount of oxyphil cells does not clearly affect the results of MIBI parathyroid scintigraphy, because it is small in most hyperfunctional glands.

Endoscopic incision of persistent ureteral infoldings.

We report 2 cases of persistent ureteral infolding in a four-month-old infant and an eight-year-old boy, both presenting with hydronephrosis. Initial diagnostic evaluation showed multiple pleats in the upper ureter. Endoscopic incision of the pleats relieved hydronephrosis. The concept of persistent ureteral infolding seems to apply to these cases.

Intra-arterial chemotherapy using a reservoir for endocrine-refractory prostate cancer.

For local control in patients with endocrine-refractory prostate cancer, an intra-arterial chemotherapy regimen comprising methotrexate (MTX), Adriamycin (ADM), and cisplatin (CDDP) was evaluated. A total of 19 patients having a mean age of 66.4 +/- 8.8 years and a mean performance status (PS) of 1.3 +/- 1.0 were enrolled. Of these patients, 3 had proved to be resistant to initial endocrine therapy and the remaining 16 had relapsed from disease stabilization after endocrine therapy. The catheter tip was placed in the internal iliac artery in 16 cases, in the common iliac artery in 2 cases, and in the aorta in 1 case after occlusion of the contralateral feeding artery. The intraarterial chemotherapy was performed mainly using MTX (30 mg/m2), ADM (30 mg/m2), and CDDP (50 mg/m2) as one course and was repeated for a mean of 2.9 +/- 2.3 courses. Then, in an outpatient clinic, 5-fluorouracil (5-FU), ADM, or MTX was given intra-arterially as maintenance chemotherapy until re-relapse. As based on the criteria for evaluation of nonsurgical therapy in prostate cancer proposed by the Japanese Urological Association, the prostatic lesion showed a partial response (PR) in 9 cases and no change (NC) in 10 cases. As judged from the response of prostate-specific antigen (PSA), a complete response (CR) was obtained in 6 cases, a PR, in 3 cases; and NC and progressive disease (PD), in 2 cases each. Therefore, the overall response rate was 63%. Improvement in the symptoms was observed in 83% of patients. The duration of the response was 15.1 +/- 10.5 months for the PR cases and 7.4 +/- 5.7 months for the NC cases. Furthermore, the mean survival time observed in the PR group was 38.9 months, which was better than that seen in the NC (16.4 months) and PD (10.5 months) groups. These results suggest that intra-arterial chemotherapy may become an option for the treatment of locally advanced and endocrine-refractory prostate cancers. Using a reservoir, this chemotherapy can be easily given in an outpatient clinic.

Intra-arterial administration of methotrexate, adriamycin, and cisplatin as neoadjuvant chemotherapy for bladder cancer.

As neoadjuvant chemotherapy for advanced bladder cancer, the intra-arterial administration of methotrexate (MTX), Adriamycin (ADM), and cisplatin (CDDP; IA-MAC) was evaluated. A total of 48 patients with bladder cancer (greater than or equal to T2 or CIS) were selected and received 30.1 mg MTX, 34.5 mg ADM, and 89.1 mg CDDP as an average course. The mean tumor-regression rate after 2 or 3 weeks was 52.3%, and patients with grade 3 transitional-cell carcinoma showed the best results, achieving a 69.6% regression rate. In 30 cases (63%), downstaging was observed. Among the 46 patients who underwent subsequent surgical therapy, the bladder could be preserved in 26 cases by transurethral resection or segmental resection. According to the criteria of the Japanese Association of Cancer Therapy, a histological effect of GIII or better was obtained in 15 cases (29%). The histological effect correlated well with the tumor-regression rate. As compared with intravenous therapy with MTX, vinblastine, ADM, and CDDP (M-VAC), IA-MAC treatment was well tolerated due to its lower degree of bone marrow suppression, and it resulted in a longer disease-free interval and better survival. In addition, the period prior to surgical therapy was shortened in this study. These results suggest that IA-MAC chemotherapy can be useful as an arm of multidisciplinary treatment of advanced bladder tumors.

[A rapid determination of allantoin by high-performance liquid chromatography using tris(hydroxymethyl)aminomethane-HCl buffer as a mobile phase].

A rapid and simple method for the determination of allantoin in pharmaceuticals by reversed-phase ion-pair high-performance liquid chromatography using an ODS column was presented. In general, it is difficult to retain allantoin to the ODS column owing to its very low hydrophobicity. We solved these problems by the use of a Tris-HCl buffer (pH 7.5) containing tetra-n-hexyl-ammonium bromide (THAB) as an ion-pair reagent for the mobile phase. Comparatively low concentrations of Tris-HCl buffer (0.9 mM) and THAB (0.5 mM) gave a high capacity factor (k'). As a results of the examination of the chromatographic behavior, it is confirmed that the retention mechanism of allantoin to the ODS column on the present method was not the ion-pair mode, but the ion-exchange mode. Calibration curves for allantoin showed a good linearity in the range of 10 to 400 micrograms/ml (r = 0.9999). The reproducibility (R.S.D., n = 6) was invariably good (0.37%). The lowest concentration of allantoin for the determination was 200 ng per 20 microliters of injection. The present method was successfully applied to the determination of allantoin in commercial eyedrops with good recovery (99.4%). It was found that allantoin in pharmaceuticals could be determined by the present method in short time and without any complicated derivatization.

[A case of retrovesical tumor].

A 53-year-old man was admitted with complaint of left lower abdominal pain. Retrovesical tumor was suggested after digital examination and imaging diagnosis. At operation, the encapsulated tumor occupied the retrovesical space, but was not adhered to the adjacent organs such as prostate, seminal vesicles, bladder and rectum. The entire tumor was successfully resected. Histopathological report revealed a mature teratoma. He is alive without recurrence at 1 year after operation. This is the second case of retrovesical teratoma in the Japanese literature.

[Spontaneous peripelvic extravasation: reports of two cases].

Spontaneous peripelvic extravasation must be distinguished from spontaneous rupture of the renal pelvis in urological emergency. The literatures revealed 42 cases of peripelvic extravasation and 35 cases of rupture of the renal pelvis in Japan. Most of them were caused by urolithiasis and malignant tumors. We report 2 cases of spontaneous peripelvic extravasation caused by urolithiasis, which were successfully treated conservatively.

[A case of granulomatous orchitis in a hemodialysis patient].

A case of granulomatous orchitis in a 47-year-old patient is described. He had a history of recurrent pyelonephritis and subsequent chronic renal failure, and was under treatment with hemodialysis therapy. He presented with painful swelling of the right scrotal contents accompanied by fever. After the unsuccessful treatment with antibiotics, an exploration of the right scrotal contents revealed the testis replaced by a hard yellow mass. An orchiectomy was performed and granulomatous orchitis was diagnosed pathologically. The clinical and etiological aspects of this rare inflammatory disease of the testis are reviewed. It is important to recognize this disease, because this is often initially thought to be neoplastic. Although the cause of this disease is still controversial, it is supposed to be associated with sperm extravasation caused by urinary tract infection or trauma.

[A case of adrenal myelolipoma].

A case of myelolipoma of the right adrenal gland is reported. A 43-year-old female was admitted to our hospital, Department of 1st Internal Medicine, because of acute hepatitis. CT incidentally showed a well circumscribed mass, as an area of low density, arising from the right adrenal gland. Although sonography showed a markedly echogenic tumor, it was not visualized on the angiogram. Results, of hormonal examinations, were unremarkable except for low levels of ACTH. We confirmed a myelolipoma of the right adrenal gland, and performed right adrenalectomy. The tumor was 65 x 50 x 35 mm in size, 95 g in weight. Pathology disclosed an admixture of mature adipose tissue and hematopoietic elements resembling bone marrow.

[Clinical study of male sterility patients].

We report the results of a clinical study of the male sterility in our institute during the past 55 months. A total of 187 male patients consulted us with the complaint of sterility, and the semen of 173 patients was examined, sixty two cases were diagnosed as azoospermia, 34 as severe oligozoospermia, 17 as moderate oligozoospermia and 60 cases as normospermia. Based upon the results of semen examination, endocrinological examination and so on, 78 cases were diagnosed as idiopathic spermatogenetic dysfunction. Serum follicle stimulating hormone (FSH) levels in azoospermia patients were significantly higher than those of normal males statistically, and the serum FSH level was considered to correlate with the damage of spermatogenesis. We performed serial treatment using kallikrein and/or human chorionic gonadotropin, on 44 patients. Only patient, who was treated with a high dose kallikrein, succeeded in impregnating his spouse. Four of our patients with oligozoospermia had received chemotherapy for testicular cancer. Recently, with the progress of anticancer chemotherapy, curative cases have increased gradually. However, because of adverse reaction, oligozoospermia cases have also increased. Considering the quality of life, the management of the sterility may be very important.

[Evaluation of urinary cytology for upper urinary tract disease].

One hundred and seventy-two patients with upper urinary tract disease were examined by cytological study of ureteral urine which was taken by ureteral catheterization. Of 139 patients with benign disease or ureteral stricture due to non-urological cancer, only one case with renal cyst revealed positive findings (false positive rate: 0.7%). Two positive cases, which were a renal hemorrhage without followup and a uterine cervical cancer with squamous cancer cells in the ureteral urine, were excluded. Although 6 of 17 (35%) uroepithelial cancers in the upper urinary tract were registered as positive, this examination was little use for detecting stage pTa, grade 1 or papillary non-invasive tumors. However, 2 out of 12 (17%) renal pelvic or ureteral cancer patients with negative results of voided urine were cytologically detected by ureteral urine. Five out of 6 cases of these cancers demonstrated malignant cells in the renal pelvic urine sampled from surgical specimen. We have recently experienced aspiration cytology for upper urinary tract disease, using the percutaneous puncture method, and five of 7 upper urinary tract patients were cytologically diagnosed. This procedure could be valuable for detecting even patients with associated bladder cancer or failure of ureteral catheterization.

[Application of the nucleolar organizer regions to urinary cytology and its computer-assisted image analysis].

Quantification of argyrophilic nucleolar organizer regions (AgNORs) stained by the silver colloid method in urinary exfoliative cells from 36 benign urological diseases and 33 transitional cell carcinomas (TCC) of the urinary bladder was carried out. Also, AgNORs of these cells were measured by means of the computer-assisted image analysis system. There was a significant correlation between AgNORs numbers of cells from voided or wash-out smears and those from touch smears (p less than 0.01). The mean AgNOR numbers per nucleus showed a stepwise increase from non-infected benign urological diseases (mean +/- SD: 3.33 +/- 0.60) through infected urological diseases (3.88 +/- 0.58), grade 1 of TCC (5.23 +/- 1.39) and grade 2 of TCC (6.34 +/- 0.86), to grade 3 of TCC (8.09 +/- 1.19). The maximum number of AgNORs in each group indicated almost the same results. The estimation of the distribution of the maximum AgNOR number might be of great value for rapid and reliable detection of bladder cancers. Moreover, the computer-assisted image analysis of AgNORs could offer an objective index for the cytological assessment of urinary bladder diseases including TCC.

[Transurethral endoureteropyelotomy].

Transurethral endoureteropyelotomy was performed in a total of 37 patients with primary ureteropelvic junction obstruction or various ureteral strictures. Thirty-one (84%) of the 37 evaluable patients showed a radiographical improvement of hydronephrosis with a mean follow-up period of 15.8 +/- 10.5 months (range: 3-40). The clinical success rates were as follows: primary ureteropelvic junction obstruction, 11/12 92%); upper ureteral stricture, 6/7 (86%); lower ureteral stricture, 14/18 (78%). This endourological procedure required a mean operation time of 38.0 +/- 27.7 minutes and hospital stay of 7.3 +/- 4.9 days. No major complication has been identified. This retrograde procedure has a straight access to the strictured segment of ureteropelvic junction. It is safe and less invasive to the renal parenchym as it does not require percutaneous nephrostomy. Therefore, it might be clinically useful for the treatment of primary ureteropelvic junction obstruction and other ureteral strictures.

[Endoscopic and fluoroscopic pyeloureterotomy for ureteropelvic junction obstruction and ureteral stricture].

Endoscopic or fluoroscopic pyeloureterotomy was performed in a total of 32 patients (34 ureters) with ureteropelvic junction obstruction (UPJO) or ureteral stricture from March 1985. Cold incision was performed, using a flexible knife over a guidewire, endoscopically on 23 ureters and fluoroscopically on 11 ureters. The mean operation time was 98.9 +/- 48.3 minutes. Twenty-five (74%) of the 34 ureters showed relief of subjective symptoms, normalized urinalysis and radiographical improvement of hydronephrosis with a mean follow-up period of 11.7 +/- 10.0 months (range: 3-43). The clinical results by etiology were as follows: primary UPJO, 13/16 (81%); secondary UPJO, 4/4 (100%); ureteral stricture, 6/7 (85%); obliteration of ureteral implantation, 2/7 (29%). No major complication was noted with this endourological technique. This endourological technique might be clinically useful for the treatment of UPJO and ureteral strictures.

[Acute focal bacterial nephritis (acute lobar nephronia) report of two cases].

Acute focal bacterial nephritis (AFBN) is one of the acute renal infections, its entity can be distinguished from other renal infections by the findings of sonography and computed tomography. There is no evidence of liquefaction in focal masses of AFBN in contrast to renal abscess. We present two cases with AFBN. The first case was a 52-year-old man with diabetes mellitus and benign prostatic hypertrophy. The second case was a 24-year-old woman with bilateral vesico-ureteral refluxes. Although their initial symptoms mimicked those of acute pyelonephritis, the findings of sonography and computed tomography revealed renal masses. They were treated with anti-microbial agents, and showed rapid improvement on both clinical symptoms and renal masses.

[Endourological re-establishment by transluminal puncture for a complete obliteration of traumatic urethral disruption].

We performed transluminal re-canalization by needle puncture under fluoro-endoscopic control on a total of ten patients (membranous urethra, 8; bulbous urethra, 2) with complete obliteration after traumatic urethral disruption. The re-canalized tract was created by balloon dilation, internal urethrotomy or endoscopic resection of the scar tissue. The patient age ranged from 10 to 57 years (mean age; 37.9 +/- 15.3 years). A transluminal puncture was attempted in three patients by transperineal-transurethral approach and in seven by transurethral approach. In one of them, who sustained a complete membranous disruption 5 weeks ago, transluminal puncture failed because of the movable proximal urethra. The remaining nine patients voided without difficulty for the mean follow-up period of 18.1 +/- 14.3 months (range: 2-46). Three patients had mild stress urinary incontinence. A transluminal puncture is less invasive, safe and reliable for re-establishment of the true proximal part of the disrupted urethra. It can be recommended as a useful technique for endo-urological re-establishment for a completely obliterated urethra. Although this endoscopic re-establishment requires urethral sounding or internal urethrotomy for 6 months postoperatively, it may be an alternative to conventional surgical repair.