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.

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 combination of cisplatin-eluting gelatin microspheres and flavopiridol enhances anti-tumour effects in a rabbit VX2 liver tumour model.

The aim of this study was to investigate whether the combination of cisplatin-eluting gelatin microspheres (GMSs) and flavopiridol enhances anti-tumour effects in a rabbit VX2 liver tumour model. Tumour-bearing rabbits (n = 21) were divided into five groups and infused from the proper hepatic artery. Group 1 (n = 5) received cisplatin-eluting GMSs (1 mg kg(-1)) and flavopiridol (3 mg kg(-1)), group 2 (n = 5) cisplatin-eluting GMSs alone (1 mg kg(-1)), Group 3 (n = 5) flavopiridol (3 mg kg(-1)), Group 4 (n = 3) GMSs alone (1 mg kg(-1)), and Group 5 (n = 3) was the control group receiving physiological saline (1 ml kg(-1)). On days 0 and 7 after procedures the liver tumour volume was measured using a horizontal open MRI system and the relative tumour volume growth rates for 7 days after treatment were calculated. On T(1) weighted images, the tumours were visualised as circular, low-intensity areas just below the liver surface. After treatment, the signals remained similar. The relative tumour volume growth rate for 7 days after treatment was 54.2+/-22.4% in Group 1, 134.1+/-40.1% in Group 2,166.7+/-48.1% in Group 3, 341.8+/-8.6% in Group 4 and 583.1+/-46.9% in Group 5; the growth rate was significantly lower in Group 1 than the other groups (p<0.05). We concluded that in our rabbit model of liver tumours the combination of cisplatin-eluting GMSs and flavopiridol was effective.

Studies on the constituents from the aerial part of Baccharis dracunculifolia DC.

Ten new glycosides, named dracunculifosides A-J, were isolated along with sixteen known glycosides from the aerial part of Baccharis dracunculifolia DC. (Compositae). The structures of these glycosides were determined on the basis of spectral and chemical evidence. These new glycosides consisted of beta-D-glucopyranose or beta-D-apiofuranosyl-(1-->6)-beta-D-glucopyranose, and most possess an (E)-caffeoyl group.

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.

[Bacillus Calmette-Guerin intravesical instillation treatment for carcinoma in situ of the bladder. Gifu BCG Instillation Therapy Research Group].

We performed a retrospective long-term study to evaluate the efficacy of intravesical instillation of Tokyo 172 strain Bacillus Calmette-Guerin (BCG) on carcinoma in situ (CIS) of the bladder. Between 1989 and 1998, 42 patients with CIS of bladder underwent intravesical instillation of BCG. In the follow-up period from 6 to 116 months (mean: 37.3 months), the efficacy rate of intravesical BCG instillation for CIS of the bladder was 81.0%. Two patients died from the bladder cancer. The non-recurrence rate in patients with grade 2 carcinoma (19 cases) was not significantly different from that in those with grade 3 carcinoma (23 cases). However, the recurrence rate in patients with secondary CIS (15 cases) was significantly higher than in those with primary CIS (27 cases). The recurrence of CIS was observed in 7 of 42 cases. In 6 of 7 patients, CIS recurred within one year after treatment. Total cystectomy was performed in 10 of 42 patients, and pathological findings of muscle layer invasion were detected in 8 patients. Although side effects occurred in 33 patients (77.5%), no clinically significant side effects were observed. Our results suggest that intravesical BCG therapy may be useful for the treatment of CIS of the bladder.

[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.

Peripheral nerve intraneural ganglion cyst: MR findings in three cases.

We present MR findings of three cases of surgically proved intraneural ganglion cysts involving the common peroneal nerve (two patients) and ulnar nerve (one patient). The lesions were located along the course of the involved nerve and situated close to a joint. MRI demonstrated the cystic nature and extent of the lesions with clear definition of the anatomic relationship of the lesions to the surrounding structures.

A sensitive detection method for peptide using 4-fluoro-7-nitrobenzo-2-oxa-1,3-diazole and its application to measure prolyl endopeptidase activity.

A measuring method sensitive to prolyl endopeptidase (EC 3.4.21.26, PEP) activity using native peptides (Arg-vasopressin or substance P) as substrates was established. The investigation of three different derivatization reagents, which had been developed for an amino acid analysis, demonstrated that 4-fluoro-7-nitrobenzo-2-oxa-1,3-diazole (NBDF) was the most suitable for the detection of Arg-Gly-NH2, which was released from Arg-vasopressin by PEP. Arg-Gly-NH2 was reacted with NBDF at 65 degrees C for 5 min at pH 7.6 and the reaction mixture was analysed by HPLC on a reverse-phase column by monitoring the fluorescence intensity. The detection limit was 1 picomol per injection and the linear standard calibration curve could be constructed in the range of 1 to 100 picomol per injection with a 3.0% relative standard deviation. This sensitive detection method for peptide was applied to the measurement of PEP activity using Arg-vasopressin as a substrate and 1 x 10(-3) unit of PEP activity was detectable. This method was also applicable to the measurement of PEP activity using substance P as a substrate by detecting the derivative of its fragment peptide (Arg-Pro-Lys-Pro).

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.

[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 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.

Vascularized toe-to-finger joint transplantation. 11 patients followed for 4 years.

Since 1983, we have transplanted 11 free vascularized joints in 8 men and 3 women, mean age 32 years. The causes of joint involvement were trauma in 9 cases and infection in 2. One MP and 10 PIP joints of the second toe were transplanted to 3 MP and 8 PIP joints of the fingers. After a mean postoperative follow-up period of 4 years, the mean postoperative range of motion was 31 degrees compared with 16 degrees preoperatively. Radiographs showed destruction of 4 PIP joints, probably caused by vascular failure in 2 joints and infection in 2. In spite of no evidence of arthrosis, some of the joints had gradually undergone a loss of extension. Although there are some problems that should be overcome, we advocate a free vascularized toe-joint transplantation for severe finger-joint destruction without extensive surrounding soft-tissue damage.

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 case report of relapsed stage D2 prostate cancer successfully treated with intraarterial chemotherapy].

A 70-year-old Japanese male was first diagnosed as poorly differentiated adenocarcinoma of the prostate with bone metastasis in 1983. He received chemoendocrine therapy with both DESD and HCFU following subcapsular orchiectomy since 1983. As a result of the treatment, the prostate cancer was stabilized. At the end of 1988, the serum levels of PA were elevated. Diagnostic imaging revealed a local recurrence in the prostate. The pathological analysis of the prostate revealed undifferentiated adenocarcinoma. Intraarterial chemotherapy with a reservoir system was carried out. Doses of CDDP, ADM and MTX were 75 mg, 30 mg and 50 mg, respectively. Eight weeks after intraarterial chemotherapy, the regression rate was 60%, and serum PA titer improved to within normal limits. In this case, as the initial clue for suspecting recurrence, periodic detection of PA was useful, and the intraarterial chemotherapy was considered useful for the control of the locally recurrent prostate carcinoma.

[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.