Clinical impact of a dose-escalation strategy for lenvatinib in differentiated thyroid cancer.

BACKGROUND:  Treatment options for patients with differentiated thyroid cancer (DTC) who experience disease progression on lenvatinib treatment are limited. Although dose escalation of treatment with tyrosine kinase inhibitors at disease progression has been reported across cancer types, clinical significance in patients with DTC has not been investigated. METHODS: We retrospectively reviewed patients with DTC who experienced disease progression on lenvatinib treatment from September 2011 to June 2022. We compared subjects who received dose-escalation treatment with standard treatment of termination at the time of initial disease progression. The escalated dose was decided by referencing to the previous effective and tolerated dose. RESULTS: Thirty-three patients were identified, 15 with dose escalation and 18 with lenvatinib termination. In both groups, the starting dose of lenvatinib was 24 mg/day, and the median dose at initial disease progression was 10 mg/day. In the former, the median dose escalation was 6 mg/day (range: 4-12). Objective response rate, clinical benefit rate by escalation, and median treatment duration of the dose-escalation phase were 13.3%, 73.3%, and 9.9 months (95% confidence interval [CI] 5.71-27.6), respectively. Median overall survival from initial disease progression was significantly longer in the dose-escalation group (median OS: 20.4 months [95% CI 7.0-NA] vs. 3.9 months [95% CI 1.7-7.9], log-rank p-value; 0.0004, hazard ratio; 0.22 [95% CI 0.09-0.55]). There were no grade 5 adverse events, and one patient discontinued due to a grade 3 lung abscess. CONCLUSION: The dose-escalation strategy appears to be a safe and effective treatment option after disease progression in patients treated with lenvatinib for DTC.

Potential efficacy of local therapy for progressive lesions after nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: In recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), local therapy (LT) such as surgery or radiotherapy can be treatment options for improved survival or quality of life. To date, however, few reports have addressed the efficacy of LT for sites of disease progression after immune checkpoint inhibitors, including other cancers. METHODS: We conducted a retrospective analysis of patients with R/M SCCHN originating from the oral cavity, oropharynx, hypopharynx, and larynx and treated with nivolumab. We extracted patients undergoing salvage LT or palliative radiotherapy (RT) to the selected progressive lesion at any time after initiation of nivolumab. RESULTS: Twenty-four patients received LT. Salvage LT was performed in 9 (37.5%) patients, including surgery and definitive RT in 5 and 4 patients, respectively. Palliative RT was performed in 15 (62.5%) patients. LT was provided in 10 (41.7%) patients for oligoprogressive disease. Twelve (50.0%) patients received subsequent systemic therapy immediately after LT. Classification based on patient treatment divided the population into four subgroups with different prognoses (salvage LT followed by subsequent systemic therapy [n = 3], salvage LT alone [n = 6], palliative RT followed by subsequent systemic therapy [n = 9], and palliative RT alone [n = 6]). Median OS in this order was 24.5, 9.0, 7.3, and 2.4 months (p = 0.001). All patients in the salvage LT followed by subsequent systemic therapy group continued nivolumab. CONCLUSION: In R/M SCCHN patients who have received nivolumab, salvage LT for the selected progressive lesion with continuation of nivolumab potentially provides an excellent survival prognosis.

Biweekly administration of cetuximab in Japanese patients with recurrent or metastatic head and neck cancer.

BACKGROUND: Cetuximab (Cmab) plays an important role in the treatment for recurrent or metastatic head and neck cancer (R/M HNC). To date, however, no safety data on biweekly administration of cetuximab at a dose of 500 mg/m2 (biweekly Cmab) for Japanese HNC patients have been available. METHODS: We retrospectively reviewed the clinical records of five R/M HNC patients who received biweekly Cmab in our institute between January 2016 and September 2021 and compared the safety profile between two phases of weekly 250 mg/m2 and biweekly 500 mg/m2 Cmab in the identical patients. RESULTS: All patients initially received Cmab in combination with chemotherapy. Chemotherapy consisted of paclitaxel plus carboplatin in two patients, cisplatin + 5-FU in one patient, and paclitaxel in two patients. Three patients switched treatment schedule from weekly Cmab to biweekly Cmab, while two patients received biweekly Cmab after completion of chemotherapy. The main reason for switching to biweekly Cmab was an unacceptably long commuting time to the hospital. The median duration of Cmab was 217 days (49-321) during weekly Cmab with or without chemotherapy and 42 days (28-175) during biweekly Cmab. Median dose of biweekly Cmab was 4 (3-12). During biweekly Cmab, worsened (Grade ≥ 2) toxicities were observed in two patients: one with grade 2 dry skin and the second with grade 2 skin infection. None developed grade ≥ 3 adverse events or discontinued treatment due to Cmab-related adverse events. CONCLUSION: Biweekly Cmab was well tolerated and did not demonstrate severe toxicities related to Cmab for R/M HNC.

[Endovascular Treatment for Contained Rupture of a Mycotic Abdominal Aneurysm].

We present a 76-year-old male patient on chronic dialysis for over 10 years with contained rupture of a mycotic abdominal aortic aneurysm, which was successfully treated by thoracic endovascular aortic repair(TEVAR) and computed tomography(CT) guided percutaneous drainage. Endovascular repair of mycotic aortic aneurysm is nowadays feasible and can be a suitable alternative especially in frail patients.

Physiologically Based Pharmacokinetic Modeling of Bosentan Identifies the Saturable Hepatic Uptake As a Major Contributor to Its Nonlinear Pharmacokinetics.

Bosentan is a substrate of hepatic uptake transporter organic anion-transporting polypeptides (OATPs), and undergoes extensive hepatic metabolism by cytochrome P450 (P450), namely, CYP3A4 and CYP2C9. Several clinical investigations have reported a nonlinear relationship between bosentan doses and its systemic exposure, which likely involves the saturation of OATP-mediated uptake, P450-mediated metabolism, or both in the liver. Yet, the underlying causes for the nonlinear bosentan pharmacokinetics are not fully delineated. To address this, we performed physiologically based pharmacokinetic (PBPK) modeling analyses for bosentan after its intravenous administration at different doses. As a bottom-up approach, PBPK modeling analyses were performed using in vitro kinetic parameters, other relevant parameters, and scaling factors. As top-down approaches, three different types of PBPK models that incorporate the saturation of hepatic uptake, metabolism, or both were compared. The prediction from the bottom-up approach (models 1 and 2) yielded blood bosentan concentration-time profiles and their systemic clearance values that were not in good agreement with the clinically observed data. From top-down approaches (models 3, 4, 5-1, and 5-2), the prediction accuracy was best only with the incorporation of the saturable hepatic uptake for bosentan. Taken together, the PBPK models for bosentan were successfully established, and the comparison of different PBPK models identified the saturation of the hepatic uptake process as a major contributing factor for the nonlinear pharmacokinetics of bosentan.

Interval to Recurrence Affects Survival in Recurrent Head and Neck Squamous Cell Carcinoma.

Background/Aim: Approximately half of head and neck squamous cell carcinoma (HNSCC) cases recur, with most recurrences occurring within the first two years after treatment. Although it has been suggested that the interval to recurrence after radical treatment is associated with prognosis in patients with HNSCC, further investigation is needed. Patients and Methods: Patients diagnosed with HNSCC at Kyushu University Hospital were retrospectively analyzed (n=500). Early recurrence (ER) was defined as disease recurrence within six months of radical treatment, whereas late recurrence (LR) was defined as recurrence after more than six months. Continuous variables were assessed using the Mann-Whitney U-test and categorical variables were assessed using Fisher's exact test. Results: A total of 234 patients experienced recurrence, with 110 and 124 patients experiencing ER (recurrence within two to six months) and LR (recurrence after six months), respectively. Multivariate analyses identified two independent risk factors for poor prognosis: ER [hazard ratio (HR)=3.200, 95% confidence interval (CI)=1.570-6.521, p=0.001] and absence of radiotherapy (HR=0.374, 95%CI=0.191-0.733, p=0.004). In patients with recurrent HNSCC, a short interval to recurrence is a risk factor for poor prognosis and survival. This study demonstrated the prognostic value of ER in these patients. Conclusion: The selection of treatment for patients with recurrent head and neck squamous cell carcinoma should consider the timing of recurrence, the initial treatment regimen, and the strategy for changing salvage therapy depending on the recurrence status.

Progression-Free Survival and Treatment-Free Interval in Head and Neck Cancer with Long-Term Response to Nivolumab: Timing of Active Discontinuation.

The optimal timing for actively discontinuing immune checkpoint inhibitor therapy in long-term responders with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains unresolved. We conducted a retrospective study of 246 patients with R/M HNSCC treated with nivolumab to determine the optimal timing to actively discontinue nivolumab therapy. We examined the point at which progression-free survival (PFS) plateaued in all cases. We compared the prognosis of 19 (7.7%) ongoing cases and 227 (92.3%) discontinued cases and analyzed treatment duration and treatment-free interval (TFI). The 6-year overall survival was 11.8% (median, 12.1), and the 6-year PFS was 15.3% (median, 3.0). The PFS curve remained stable for 3 years. The median duration of nivolumab treatment was 2.9 months (range 0.03-81.9): Ongoing group, 41.8 (5.6-81.9); Decision group, 36.8 (4.0-70.1); Toxicity group, 30.6 (2.8-64.8); and progressive disease group, 2.0 (0.03-42.9). TFI in the Decision group was 15.1 months (0.6-61.6) and 30.6 months (2.8-64.8) in the Toxicity group. Long-term responses in R/M HNSCC patients treated with nivolumab are rare but gradually increasing. For this patient group, our best estimate of the optimal time to end treatment is 3 years, as the PFS in this study reached a plateau at that timepoint.

Clinicopathological Review of Head and Neck Squamous Cell Carcinomas After Neoadjuvant Chemotherapy.

BACKGROUND/AIM: The benefit of neoadjuvant chemotherapy (NAC) in the treatment of head and neck squamous cell carcinoma (HNSCC) remains unclear. PATIENTS AND METHODS: We retrospectively collected 30 patients with HNSCC who had undergone radical resection after NAC. We pathologically evaluated the therapeutic response to NAC, and classified the residual tumor patterns. In addition, we compared the maximum horizontal diameter on pathology with imaging. RESULTS: The residual patterns were categorized as follows: 10 cases of shrunken type, 11 cases of mixed type, and seven cases of fragmented type. The majority of underestimation cases - those cases in which the maximum horizontal diameter measured on post-NAC imaging was less than the pathological size after resection - were multifocal residual lesions, with a tendency for more frequent "positive" or "close" surgical margins. CONCLUSION: The strategy of performing NAC to reduce resection volume is not appropriate, and resection margins should be based on the assessment before NAC.

Induction chemotherapy with paclitaxel, carboplatin, and cetuximab (PCE) followed by chemoradiotherapy for unresectable locoregional recurrence after curative surgery in patients with squamous cell carcinoma of the head and neck.

Background: The significance of induction chemotherapy (IC) in the treatment of squamous cell carcinoma of the head and neck (SCCHN) with unresectable locoregional recurrence after curative surgery has not been clarified. The aim of this study was to evaluate the efficacy of IC followed by chemoradiotherapy (CRT) in these patients. Methods: Among patients with unresectable locoregional recurrent SCCHN who had not undergone prior irradiation and were eligible for cisplatin, we conducted a retrospective analysis of patients who received CRT following IC with paclitaxel, carboplatin, or cetuximab (IC-PCE group) and those who received CRT without prior IC (CRT group) between June 2013 and August 2021. Result: Forty-two patients were included. The CRT group and IC-PCE group consisted of 15 and 27 patients, respectively. Primary site was the oral cavity (n=25), oropharynx (n=3), hypopharynx (n=13) and larynx (n=1). Objective response rate (ORR) with IC-PCE was 55.6%; 24 patients (88.9%) subsequently received CRT. ORR after completion of CRT was significantly better in the IC-PCE group (95.8% in the IC-PCE group vs. 66.7% in the CRT group, p=0.024). Progression-free survival (PFS) of the total population on median follow-up of 2.4 years (range: 0.8-7.3) tended to be better in the IC-PCE group (2-year PFS: 55.6% in the IC-PCE group vs. 33.3% in the CRT group, log-rank p=0.176), especially in oral cancer (2-year PFS: 37.5% in the IC-PCE group vs. 0% in the CRT group, log-rank p=0.015). Conclusion: Therapeutic strategies including IC-PCE in patients with unresectable locoregional recurrent SCCHN after curative surgery may contribute to improved prognosis, especially in oral cancer.

Efficacy of anti-PD-1 monotherapy for recurrent or metastatic olfactory neuroblastoma.

Background: Olfactory neuroblastoma (ONB) is a rare malignant tumor of the head and neck. Due to its rarity, standard systemic therapy for this condition has yet to be established. In particular, the use of immune checkpoint inhibitors (ICIs) for the recurrent or metastatic (R/M) ONB population remains unclear. Methods: We retrospectively evaluated 11 patients with R/M ONB who received any systemic chemotherapy at two Japanese institutions (National Cancer Center Hospital East and Kyushu Medical Center) between January 2002 and March 2022 and analyzed outcomes by use of anti-PD-1 antibody (nivolumab or pembrolizumab) monotherapy. Results: Of the 11 patients, 6 received ICI (ICI-containing treatment group) and the remaining 5 were treated with systemic therapy but not including ICI (ICI-non-containing treatment group). Overall survival (OS) was significantly longer in the ICI-containing group (median OS: not reached vs. 6.4 months, log-rank p-value: 0.035). The fraction of ICI systemic therapy in the entire treatment period of this group reached 85.9%. Four patients (66.7%) in the ICI-containing treatment group experienced immune-related adverse events (irAE), with grades of 1/2. No irAE of grade 3 or more was seen, and no patient required interruption or discontinuation of treatment due to toxicity. Conclusion: ICI monotherapy appears to be effective and to contribute to prolonged survival in R/M ONB.

[Evaluation of 2 ports video-assisted thoracoscopic surgery (VATS) using endo-close for primary spontaneous pneumothorax].

We aimed to assess the perioperative outcomes of 2 ports video-assisted thoracoscopic surgery(VATS) using Endo-Close (2 ports VATS) in patient for the primary spontaneous pneumothorax(PSP) compared to conventional 3 ports VATS in our hospital. 31 consecutive patients(11;2 ports VATS and 20;3 ports VATS) since 2009 were enrolled in this study. Endo-Close is a device that for pulling the anchoring thread by puncture 1.5 cm incision at the level of the 7th intercostal space( ICS) at the median axillary line( MAL) for camera port, a 1.5 cm incision at the level of the 4th ICS at the anterior axillary line for working port, and 2 mm puncture at the level of the 5th ICS at the MAL using the Endo-Close were placed for this procedure. Compared with 3 ports VATS, equivalent results were obtained by the present procedure;operation time(58.6±18.3 minutes vs 63.0±15.1 minutes, NS), duration of drainage after operation(1.0±0 days vs 1.3±0.5 days, NS), postoperative hospital stay(3.0±1.5 days vs 3.7±1.4 days, NS) significantly.Blood loss was minimal in both cases. In conclusion, 2 port VATS using Endo-Close proved to be feasible method in surgical treatment for PSP.

Subsequent chemotherapy with paclitaxel plus cetuximab-based chemotherapy following immune checkpoint inhibitor in recurrent or metastatic squamous cell carcinoma of the head and neck.

Background: Immune checkpoint inhibitors (ICIs) are essential in treating recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). However, the overall response rate (ORR) is limited to 10-20%, and subsequent chemotherapy is critical to maximizing the subjects' prognosis. Methods: We retrospectively reviewed 59 patients with R/M SCCHN treated with paclitaxel+cetuximab (PE)-based chemotherapy (PCE, paclitaxel+carboplatin+cetuximab; or PTX+Cmab, paclitaxel+cetuximab) following disease progression after either pembrolizumab or nivolumab monotherapy. Results: Of 59 patients, 15 were treated with pembrolizumab, with an ORR of 13.3%, and the remaining 44 with nivolumab, with an ORR of 11.4%. All patients in the pembrolizumab cohort had platinum-sensitive disease. Following ICI treatment, 19 patients were treated with PCE and the remaining 40 with PTX+Cmab. PE-based chemotherapy induced favorable and prompt tumor shrinkage even in cases where ICI was not effective, with a median change in the summed dimensions of target lesions of -43.4%, resulting in an ORR of 62.7%. Median time to response was 1.8 months. The patients in the pembrolizumab cohort appeared to have a numerically higher response rate than those receiving nivolumab (80.0% vs. 56.8%). For the 59 patients, progression-free survival and overall survival, calculated from the initiation of PE-based chemotherapy, were 4.6 months and 17.1 months, respectively. Grade ≥3 adverse events occurred in 40.7%, and no treatment-related death was observed. Conclusion: PE-based chemotherapy following ICI is encouraging for its robust antitumor efficacy in R/M SCCHN.

Proton pump inhibitors and antibiotics adversely effect the efficacy of nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Several reports have shown that the use of proton pump inhibitors (PPIs) and antibiotics (Abx) can reduce the efficacy of immune checkpoint inhibitors in various cancers. To date, however, the association of immune checkpoint inhibitors with PPI and/or Abx in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M SCCHN) has not been reported. METHODS: We retrospectively reviewed patients with platinum-refractory R/M SCCHN treated with nivolumab from May 2017 and March 2020 in our institute. Primary sites included the oral cavity, oropharynx, hypopharynx and larynx. The relationship between prognostic parameters, such as overall survival (OS), progression-free survival (PFS), PFS2 and PFS3, and clinical factors, including PPI or Abx use, was examined, and the creation of prognostic classification was also attempted. RESULTS: Of 110 patients identified, 56 patients received PPI and 24 patients received Abx within 30 days before or after the initiation of nivolumab. With a median follow-up of 17.2 months (range: 13.8-25.0), median PFS, PFS2, PFS3 and OS were 3.2, 8.1, 14.0 and 17.2 months, respectively. In univariate analysis, the use of PPI and of Abx was significantly associated with poor prognosis in all parameters (PFS, PFS2, PFS3 and OS). Median OS (hazard ratio; 95%confidence interval, p-value) by these covariates were 13.6 versus 23.8 months (1.70; 1.01-2.87, p = 0.046) for PPI and 10.0 versus 20.1 months (1.85; 1.00-3.41, p = 0.048) for Abx, respectively. Furthermore, these factors showed mutually independent adverse associations on multivariate analysis. CONCLUSION: The use of PPI and Abx attenuated the efficacy of nivolumab in R/M SCCHN. Further prospective evaluation is warranted.

Weekly paclitaxel, carboplatin and cetuximab (PCE) combination followed by nivolumab for recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

OBJECTIVES: Cetuximab-based chemotherapy is a standard 1st-line treatment for recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). However, few studies have reported survival data for a treatment sequence consisting of a PCE regimen (paclitaxel + carboplatin + cetuximab) followed by an immune checkpoint inhibitor. MATERIALS AND METHODS: We retrospectively assessed 37 patients with R/M SCCHN from the oral cavity, oropharynx, hypopharynx, and larynx who received PCE as 1st-line treatment followed by nivolumab as 2nd-line at the National Cancer Center Hospital East between December 2016 and July 2021. For comparison, we also analyzed 14 patients who did not receive nivolumab after PCE. RESULTS: Of the 37 patients who received nivolumab, overall response rate (ORR) by PCE was 48.6%, and median time to response and median progression-free survival (PFS) were 2.1 months (range: 0.8-4.8) and 4.4 months, respectively. In the nivolumab phase, ORR was 10.8%. 23 patients received 3rd-line therapy. Median PFS2, PFS3, and overall survival (OS) were 6.8, 11.6, and 19.5 months, respectively. Subgroup analysis by PD-L1 expression showed no significant difference in OS. Analysis of the comparison group revealed a trend toward improved OS in those who received nivolumab compared to those who did not (HR 0.47, 95%CI [0.19-1.13], p = 0.084). CONCLUSION: PCE followed by nivolumab shows a favorable survival outcome, representing the potential for rapid tumor response with PCE and extension of OS by the addition of nivolumab regardless of combined positive score.

Combination chemotherapy with taxane and platinum in patients with salivary gland carcinoma: a retrospective study of docetaxel plus cisplatin and paclitaxel plus carboplatin.

Background: Despite advances in precision medicine, most patients with recurrent or metastatic salivary gland carcinoma still need conventional chemotherapies, such as the combination of taxane and platinum. However, evidence for these standardized regimens is limited. Methods: We retrospectively reviewed patients with salivary gland carcinoma treated with a taxane and platinum, which contained docetaxel at a dose of 60 mg/m2 plus cisplatin at a dose of 70 mg/m2 on day 1, or paclitaxel at a dose of 100 mg/m2 plus carboplatin at a dose of area under the plasma concentration-time curve = 2.5 on days 1 and 8 (both on 21-day cycles), between January 2000 and September 2021. Result: Forty patients with ten adenoid cystic carcinomas and thirty other pathologies were identified. Of these, 29 patients were treated with docetaxel plus cisplatin and 11 with paclitaxel plus carboplatin. For the total population, the objective response rate (ORR) and median progression-free survival (mPFS) were 37.5% and 5.4 months (95% confidence interval: 3.6-7.4 months), respectively. On subgroup analysis, docetaxel plus cisplatin provided favorable efficacy compared with paclitaxel plus carboplatin (ORR: 46.5% vs. 20.0%, mPFS: 7.2 vs. 2.8 months), and the findings were well retained in patients with adenoid cystic carcinoma (ORR: 60.0% vs. 0%, mPFS: 17.7 vs. 2.8 months). Grade 3/4 neutropenia was relatively frequent in the docetaxel plus cisplatin (59% vs.27%), although febrile neutropenia was uncommon (3%) in the cohort. No treatment-related death was seen in any case. Conclusion: The combination of taxane and platinum is generally effective and well-tolerated for recurrent or metastatic salivary gland carcinoma. In contrast, paclitaxel plus carboplatin appears unfavorable in terms of efficacy in certain patients, such as those with adenoid cystic carcinoma.

Identification and functional characterization of uric acid transporter Urat1 (Slc22a12) in rats.

Uric acid transporter URAT1 contributes significantly to reabsorption of uric acid in humans to maintain a constant serum uric acid (SUA) level. Since alteration of SUA level is associated with various diseases, it is important to clarify the mechanism of change in SUA. However, although expression of mRNA of an ortholog of URAT1 (rUrat1) in rats has been reported, functional analysis and localization have not been done. Therefore, rat rUrat1 was functionally analyzed using gene expression systems and isolated brush-border membrane vesicles (BBMVs) prepared from rat kidney, and its localization in kidney was examined immunohistochemically. Uric acid transport by rUrat1 was chloride (Cl-) susceptible with a Km of 1773µM. It was inhibited by benzbromarone and trans-stimulated by lactate and pyrazinecarboxylic acid (PZA). Cl- gradient-susceptible uric acid transport by BBMVs showed similar characteristics to those of uric acid transport by rUrat1. Moreover, rUrat1 was localized at the apical membrane in proximal tubular epithelial cells in rat kidney. Accordingly, rUrat1 is considered to be involved in uric acid reabsorption in rats in the same manner as URAT1 in humans. Therefore, rUrat1 may be a useful model to study issues related to the role of human URAT1.

[Pleuroperitoneal communication with liver cirrhosis and chronic kidney disease needed hemodialysis successfully treated by video-assisted thoracoscopic surgery; report of a case].

A 59-year-old man treated with hemodialysis for liver cirhhosis and chronic kidney disease developed right pleural effusion and ascites. Ascites always decreased after thoracocentesis for pleural effusion. In spite of repeated treatment with chest tube drainage, massive pleural effusion reappeared. Under the diagnosis of pleuroperitoneal communication, surgical repair of the diaphragm by video assisted thoracoscopic surgery (VATS) were performed. Bulla and pin hole were found and they were resected and sutured. Surgery was safely and successfully accomplished though the patient had Child-Pugh B liver cirhhosis. Pleural effusion disappeared after surgery.

Nivolumab for recurrent or metastatic head and neck cancer patients with non-squamous cell carcinoma and/or a primary subsite excluded from CheckMate141, a retrospective study.

OBJECTIVES: In CheckMate 141, nivolumab significantly improved overall survival (OS) in patients with platinum-refractory recurrent or metastatic squamous cell carcinomas (R/M SCC) of the head and neck. However, reports on nivolumab for patients with non-SCC and/or a primary subsite excluded from CheckMate 141 are limited. MATERIALS AND METHODS: We conducted a retrospective analysis of R/M head and neck cancer patients who received nivolumab. The study subject excluded patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx. RESULTS: A total of 59 patients were included, consisting of 40 males and 19 females with a median age of 61 years. Half of the patients had non-SCC histology. The main primary site included the sinonasal cavity (n = 18), salivary gland (n = 15), and nasopharynx (n = 13). Three (6.0%) patients achieved a complete response and 5 (10.0%) a partial response, giving an overall response rate (ORR) of 16.6%. Median time-to-treatment failure (TTF) and OS were 3.7 and 16.2 months, respectively. Salivary gland and nasopharyngeal cancer achieved relatively higher ORR (25.0 and 36.4%, respectively). On analysis by primary site, nasopharyngeal cancer showed a significantly better TTF and OS than the other primary sites. On analysis by histological findings, no significant difference in TTF and OS was observed between non-SCC and SCC. CONCLUSION: Nivolumab for cancers involving the salivary gland/nasopharynx and non-SCC histology showed comparable efficacy to that in CheckMate 141. This result indicates that nivolumab may be effective even for patients not included in CheckMate 141.

Induction chemotherapy with paclitaxel, carboplatin and cetuximab for locoregionally advanced nasopharyngeal carcinoma: A single-center, retrospective study.

Background: The addition of induction chemotherapy (IC) before chemoradiotherapy (CRT) has improved survival over CRT alone in locoregionally advanced nasopharyngeal cancer (LA-NPC). Nevertheless, this population would benefit from further development of a novel IC regimen with satisfactory efficacy and a more favorable safety profile. Methods: We retrospectively assessed 29 LA-NPC patients who received the combination of paclitaxel (PTX), carboplatin (CBDCA), and cetuximab (Cmab) (PCE) as IC (IC-PCE) at the National Cancer Center Hospital East between March 2017 and April 2021. IC-PCE consisted of CBDCA area under the plasma concentration-time curve (AUC) = 1.5, PTX 80 mg/m2, and Cmab with an initial dose of 400 mg/m2 followed by 250 mg/m2 administered weekly for a maximum of eight weeks. Results: Patient characteristics were as follows: median age, 59 years (range 24-75); 0, 1 performance status (PS), 25, 4 patients; and clinical stage III/IVA/IVB, 6/10/13. The median number of PCE cycles was 8(1-8). After IC-PCE, 26 patients received concurrent cisplatin and radiotherapy (CDDP-RT), one received concurrent carboplatin/5-fluorouracil and radiotherapy (CBDCA/5-FU-RT), and two received RT alone. The % completion of CDDP-RT was 88.5%. The response rate was 75.9% by IC and 100% at completion of CRT. The 3-year recurrence-free survival, locoregional failure-free survival, distant recurrence-free survival, and overall survival were 75.9%, 79.3%, 84.3%, and 96.3%, respectively. The incidence of adverse events of grade 3/4 was 34.5% during IC and 44.8% during CRT. Conclusion: IC-PCE is feasible and effective for LA-NPC and may be a treatment option for this disease.

Functional characterization of apical transporters expressed in rat proximal tubular cells (PTCs) in primary culture.

Since in vitro cell culture models often show altered apical transporter expression, they are not necessarily suitable for the analysis of renal transport processes. Therefore, we aimed here to investigate the usefulness of primary-cultured rat proximal tubular cells (PTCs) for this purpose. After isolation of renal cortical cells from rat kidneys, PTCs were enriched and the gene expression and function of apical transporters were analyzed by means of microarray, RT-PCR and uptake experiments. RT-PCR confirmed that the major apical transporters were expressed in rat PTCs. Na(+)-dependent uptake of α-methyl-d-glucopyranoside (αMG), ergothioneine and carnitine by the PTCs suggests functional expression of Sglts, Octn1 and Octn2, respectively. Inhibition of pH-dependent glycylsarcosine uptake by low concentration of cephalexin, which is a ß-lactam antibiotics recognized by Pepts, indicates a predominant role of high affinity type Pept2, but not low affinity type Pept1, in the PTCs. Moreover, the permeability ratio of [(14)C]αMG (apical to basolateral/basolateral to apical) across PTCs was 4.3, suggesting that Sglt-mediated reabsorptive transport is characterized. In conclusion, our results indicate that rat PTCs in primary culture are found to be a promising in vitro model to evaluate reabsorption processes mediated at least by Sglts, Pept2, Octn1 and Octn2.