Effects of rehabilitation treatments jointly considered by physiatrists and rehabilitation therapists in patients with severe burn injury.

Rehabilitation treatments for patients with severe burn injury (SBI) are difficult owing to the lack of knowledge, skills, and experience among clinicians and physical and occupational therapists, resulting in serious patient disability. This study retrospectively evaluated the effectiveness of rehabilitation treatments jointly considered by physiatrists and rehabilitation therapists (Physiatrist and Registered therapist Operating rehabilitation: PROr) for patients with SBI admitted to our hospital's burn intensive care unit (BICU). Eligible patients were classified into the PROr and standard rehabilitation (SR) groups. Contents of the rehabilitation program in the BICU, the functional ambulation categories (FAC), and the Barthel index at the first rehabilitation, BICU discharge, and hospital discharge were collected. Of the 184 patients with severe burns admitted to the BICU, 29 (PROr group, n = 16; SR group, n = 13) met the eligibility criteria. The PROr group received more types of exercise interventions for a longer time than the SR group. No significant differences in the FAC and Barthel index scores at the first time of rehabilitation were found between the two groups; however, the scores of FAC and Barthel index at BICU and hospital discharges were higher in the PROr group than in the SR group. The PROr program may help in the functional improvement of patients with SBI.

Identification of Optimal Tissue-Marking Dye Color for Pathological Evaluation in Fluorescence Imaging Using IRDye800CW.

PURPOSE: Fluorescence-guided surgery using a tumor-specific antibody-dye conjugate is useful in various cancer types. Fluorescence imaging is a valuable tool both intraoperatively and postoperatively for ex vivo imaging. The color of inks used for tumor specimens during ex vivo specimen processing in pathology is an important consideration for fluorescence imaging since the absorption/emission of the dyes may interfere with the fluorescent dye. This study assesses suitable ink colors for use specifically with IRDye800CW fluorescence imaging. PROCEDURES: Eight tissue-marking inks or dyes (TMDs) commonly used for pathological evaluation were assessed. Agarose tissue-mimicking phantoms containing Panitumumab-IRDye800CW were used as an initial model. Mean fluorescence intensity was measured at 800 nm using both Pearl Trilogy as a closed-field fluorescence imaging system and pde-neo II as an open-field fluorescence imaging system before and after TMD application. An in vivo mouse xenograft model using the human head and neck squamous cell carcinoma FaDu cell line was then used in conjunction with TMDs. RESULTS: The retained IRDye800CW fluorescence on Pearl Trilogy was as follows: yellow at 91.0 ± 4.5%, red at 90.6 ± 2.7%, orange at 88.2 ± 2.2%, violet at 56.6 ± 1.1%, lime at 40.9 ± 1.8%, green at 19.3 ± 2.8%, black at 13.3 ± 0.6%, and blue at 8.1 ± 0.2%. The retained IRDye800CW fluorescence on pde-neo II was as follows: yellow at 86.5 ± 6.4%, red at 77.0 ± 6.2%, orange at 76.9 ± 2.8%, lime at 72.5 ± 9.5%, violet at 59.7 ± 0.4%, green at 30.1 ± 6.9%, black at 17.0 ± 2.7%, and blue at 6.7 ± 1.7%. The retained IRDye800CW fluorescence in yellow and blue TMDs was 42.1 ± 14.9% and 0.2 ± 0.2%, respectively in the mouse experiment (p = 0.039). CONCLUSION: Yellow, red, and orange TMDs should be used, and blue and black TMDs should be avoided for evaluating tumor specimens through fluorescence imaging using IRDye800CW.

Prognostic value and clinicopathological roles of the tumor immune microenvironment in salivary duct carcinoma.

Salivary duct carcinoma (SDC) is an aggressive type of salivary gland carcinoma. Recently, immunotherapies targeting immune checkpoints, including PD1, PD-L1, CTLA4, and LAG3, have had a considerable prognostic impact on various malignant tumors. The implementation of such immune checkpoint inhibitor (ICI) therapies has also been attempted in cases of salivary gland carcinoma. The tumor immune microenvironment (TIME) is implicated in tumorigenesis and tumor progression and is closely associated with the response to ICI therapies. However, the TIME in SDC has not been fully explored. We examined the immunohistochemical expression of CD8, FOXP3, PD1, PD-L1, CTLA4, LAG3, and mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (TILs), and microsatellite instability (MSI) status in 175 cases of SDC. The associations between these TIME-related markers and the clinicopathological factors and prognosis were evaluated. An elevated expression of CD8, FOXP3, PD1, CTLA4, and LAG3 was associated with more aggressive histological features and an advanced N and/or M classification, elevated Ki-67 index, and poor prognosis. Furthermore, cases with a high PD-L1 expression exhibited more aggressive histological features and adverse clinical outcomes than those with a low expression. Alternatively, there was no significant correlation between TILs and clinicopathological factors. No SDC cases with an MSI-high status or MMR deficiency were found. The coexistence of both an immunostimulatory and immunosuppressive TIME in aggressive SDC might play a role in the presence of T-cell exhaustion. The contribution of multiple immune escape pathways, including regulatory T cells and immune checkpoints, may provide a rationale for ICI therapy, including combined PD1/CTLA4 blockade therapy.

Effects of Pembrolizumab in Recurrent/Metastatic Squamous Cell Head and Neck Carcinoma: A Multicenter Retrospective Study.

BACKGROUND/AIM: Pembrolizumab exhibits anticancer efficacy in platinum-sensitive or platinum-unfit patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). However, no large-scale retrospective real-world data are available. This retrospective study aimed to examine the efficacy and safety of pembrolizumab in multiple facilities. PATIENTS AND METHODS: Data of 167 patients with R/M SCCHN treated with pembrolizumab between December 2019 and February 2022 were analyzed. The endpoint was overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs). OS and PFS were analyzed comparatively with and without irAEs, and complete response (CR) or partial response (PR), and stable disease (SD) or progressive disease (PD) were compared. RESULTS: One hundred thirty-five patients received pembrolizumab alone, whereas the others received pembrolizumab with chemotherapy. For the pembrolizumab only group, the median OS and PFS were 22.7 and 5.1 months, respectively. There were significant differences in OS and PFS between CR or PR and SD or PD (p<0.01, p<0.01, respectively). For pembrolizumab with chemotherapy, the OS was not reached and median PFS was 7.0 months. There was a significant difference in PFS between CR or PR and SD or PD (p<0.01). There was a significant difference in PFS between patients with and without irAEs (p=0.02). CONCLUSION: The real-world therapeutic effect of pembrolizumab for R/M SCCHN was comparable to that observed in the KEYNOTE048 trial. In addition, irAEs and best overall response were considered as prognostic factors.

Macroscopic and multiple metastases in sentinel lymph node biopsy are respectively associated with poor prognosis in early oral cancer.

BACKGROUND: A multicenter, randomized controlled phase III trial was conducted on sentinel lymph node biopsy (SLNB) and elective neck dissection for T1 (depth of invasion ≥ 4 mm)-T2N0M0 oral cavity squamous cell carcinoma. This study identified factors associated with poor prognosis in patients who underwent SLNB based on a subgroup analysis of this trial. METHODS: We analyzed 418 sentinel lymph nodes (SLNs) from 132 patients who underwent SLNB. The metastatic SLNs were classified into three categories based on size-isolated tumor cells: < 0.2 mm, micrometastasis: ≥ 0.2 mm and < 2 mm, and macrometastasis: ≥ 2 mm. Three groups were formed based on the number of metastatic SLNs: no metastasis, 1 metastatic node, and ≥ 2 metastatic nodes. The size and number of metastatic SLNs on survival were evaluated using Cox proportional hazard models. RESULTS: Patients with macrometastasis and ≥ 2 metastatic SLNs had worse overall survival (OS) and disease-free survival (DFS) after adjustment for potential confounders (HR for OS: macrometastasis, 4.85; 95% CI 1.34-17.60; ≥ 2 metastatic SLN, 3.63; 95% CI 1.02-12.89; HR for DFS: macrometastasis, 2.94; 95% CI 1.16-7.44; ≥ 2 metastatic SLN, 2.97; 95% CI 1.18-7.51). CONCLUSIONS: In patients who underwent SLNB, a poorer prognosis was associated with macrometastasis or having ≥ 2 metastatic SLNs.

Predicting risk factors for hypothyroidism after definitive radiotherapy for early glottic carcinomas.

Hypothyroidism may occur after definitive radiotherapy in rare cases of early glottic carcinoma. However, to the best of our knowledge, no study to date has examined the risk factors for hypothyroidism specifically after definitive radiotherapy in patients with early glottic carcinoma. The present study determined risk factors for hypothyroidism after definitive radiotherapy in patients with early glottic carcinoma. This was a retrospective study that included 73 patients with T1 or T2, N0 glottic squamous cell carcinoma who underwent radiotherapy between June 3, 2009 and December 25, 2020. Demographic and clinical characteristics, including age, sex, tumor stage and pretreatment thyroid volume, were examined to elucidate the clinical risk factors for hypothyroidism. Field size, total prescribed dose and thyroid receiving dose were evaluated as dosimetric risk factors for hypothyroidism. Irradiated underlying thyroid volumes of more than 5, 10, 20, 30, 40, 50, 60 and 65 Gy (V5Gy, V10Gy, V20Gy, V30Gy, V40Gy, V50Gy, V60Gy and V65Gy) and mean thyroid dose were included as thyroid receiving doses. The median follow-up duration was 61 months (range, 7-150 months). Hypothyroidism was present in 15 (21%) of the 73 patients, including 12 and 3 patients with grade 1 and 2 hypothyroidism, respectively. Among the demographic and clinical factors, sex and pretreatment thyroid volume were significantly associated with hypothyroidism (P=0.007 and P<0.001, respectively). Among the dosimetric factors, the presence of hypothyroidism was significantly associated with V5Gy (P=0.012), V10Gy (P=0.015), V20Gy (P=0.020), V30Gy (P=0.024), V40Gy (P=0.028), V50Gy (P=0.028), V60Gy (P=0.027) and mean thyroid dose (P=0.023). In conclusion, sex, pretreatment thyroid volume and thyroid receiving dose were associated with hypothyroidism after definitive radiotherapy in patients with early glottic carcinoma. Particularly, the receiving dose to the thyroid gland should be reduced in female patients and in those with small thyroid volumes who are at higher risk for hypothyroidism following radiotherapy.

Identification of novel prognostic and predictive biomarkers in salivary duct carcinoma via comprehensive molecular profiling.

Molecular targets and predictive biomarkers for prognosis in salivary duct carcinoma (SDC) have not been fully identified. We conducted comprehensive molecular profiling to discover novel biomarkers for SDC. A total of 67 SDC samples were examined with DNA sequencing of 464 genes and transcriptome analysis in combination with the clinicopathological characteristics of the individuals. Prognostic biomarkers associated with response to combined androgen blockade (CAB) treatment were explored using mRNA expression data from 27 cases. Oncogenic mutations in receptor tyrosine kinase (RTK) genes or genes in the MAPK pathway were identified in 55 cases (82.1%). Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway were identified in 38 cases (56.7%). Interestingly, patient prognosis could be predicted using mRNA expression profiles, but not genetic mutation profiles. The risk score generated from the expression data of a four-gene set that includes the ADAMTS1, DSC1, RNF39, and IGLL5 genes was a significant prognostic marker for overall survival in the cohort (HR = 5.99, 95% confidence interval (CI) = 2.73-13.1, p = 7.8 × 10-6). Another risk score constructed from the expression of CD3E and LDB3 was a strong prognostic marker for progression-free survival for CAB treatment (p = 0.03). Mutations in RTK genes, MAPK pathway genes, and PI3K/AKT pathway genes likely represent key mutations in SDC tumorigenesis. The gene expression profiles identified in this study may be useful for stratifying patients who are good candidates for CAB treatment and may benefit from additional systemic therapies.

Nivolumab for Platinum-refractory and -sensitive Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: Nivolumab has antitumor efficacy in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) who relapse within 6 months after platinum-based therapy; however, the efficacy of nivolumab for platinum-sensitive R/M HNSCC has not been shown. Therefore, this study compared the efficacy and safety of nivolumab for platinum-refractory and platinum-sensitive R/M HNSCC. PATIENTS AND METHODS: This was a retrospective study of patients who received nivolumab for R/M HNSCC who had been previously treated with platinum-based anticancer drugs. Patients were divided into a platinum-sensitive and a platinum-refractory group, and progression-free survival (PFS), overall survival (OS), the overall response rate (ORR) [complete response (CR) + partial response (PR)], the disease control rate (DCR) (CR + PR + stable disease), and the incidence of immune-related adverse events (irAEs) were compared between the two groups. RESULTS: We included 88 patients with squamous cell carcinoma: 60 with platinum-refractory disease and 28 with platinum-sensitive disease. The median PFS in the platinum-refractory and platinum-sensitive groups were 2.7 months and 5.3 months, respectively (p=0.03), and the median OS were 8.8 months and 17.1 months, respectively (p=0.06). There were no significant differences in the ORR, DCR, or incidence of irAEs between the two groups (p>0.99, p=0.11, and p>0.99, respectively). CONCLUSION: Nivolumab is a safe and effective treatment for platinum-sensitive R/M HNSCC.

Survival benefit of HER2-targeted or androgen deprivation therapy in salivary duct carcinoma.

Background: The efficacy and safety of human epidermal growth factor receptor 2 (HER2)-targeted therapy and androgen deprivation therapy (ADT) for locally advanced or recurrent or metastatic (LA/RM) salivary duct carcinoma (SDC) have been reported in prospective studies. However, the survival benefit of these therapies to conventional therapy remains controversial, and whether HER2-targeted therapy or ADT should be chosen in HER2- and androgen receptor (AR)-positive SDC patients remains unknown. Methods: Overall, 323 LA/RM SDC patients treated at seven institutions between August 1992 and June 2020 were retrospectively enrolled. The primary aim was to analyze the effect of HER2-targeted therapy and ADT on overall survival from the diagnosis of LA/RM disease to death from any cause (OS1). The secondary indicators included the overall response rate (ORR), clinical benefit rate (CBR), overall survival from therapy initiation for LA/RM disease (OS2), progression-free survival (PFS), time to second progression (PFS2), duration of response (DoR), and duration of clinical benefit (DoCB) of HER2-targeted therapy or ADT as first-line therapy for HER2-positive/AR-positive SDC. Results: Patients treated with HER2-targeted therapy or ADT had longer OS1 than those treated without these therapies (Median OS1: historical control, 21.6 months; HER2-targeted therapy, 50.6 months; ADT, 32.8 months; HER2-targeted therapy followed by ADT, 42.4 months; and ADT followed by HER2-targeted therapy, 45.2 months, p < 0.001). Among HER2-positive/AR-positive SDC patients, although HER2-targeted therapy had better ORR, CBR, and PFS than those of ADT as first-line therapy, we found no significant differences between HER2-targeted therapy and ADT regarding OS2, PFS2, DoR, and DoCB. Conclusion: Patients treated with HER2-targeted therapy and ADT showed longer survival in LA/RM SDC. HER2-targeted therapy can be recommended prior to ADT for HER2-positive/AR-positive SDC. It is warranted to establish a biomarker that could predict the efficacy of clinical benefit or better response in ADT.

The clinical outcome of the patients with horizontal semicircular canal variants of benign paroxysmal positional vertigo.

BACKGROUND: Gufoni maneuver is known to be effective for horizontal canal benign positional vertigo (HC-BPPV), but there are some intractable patients that the treatment procedure does not work. OBJECTIVE: The clinical outcomes of patients with HC-BPPV were investigated. We also investigated the characteristics of intractable patients which needed long time to the remission. METHODS: Sixty-six patients with HC-BPPV receiving Gufoni maneuver at Tokyo Medical University Hachioji Medical Center were investigated. The patients were classified into geotropic DCPN group and apogeotropic DCPN group. The clinical outcomes in 2 groups were examined. RESULTS: There were 48 patients with geotropic DCPN and 18 patients with apogeotropic DCPN. There were significant differences between the geotropic HC-BPPV and apogeotropic HC BPPV in the period to remission. There were 7 intractable patients and the average ages of these intractable patients were higher than other patients. CONCLUSION: The patients with geotropic DCPN and the patients with the nystagmus conversion from apogeotropic to geotropic DCPN have tendency to easy to resolve, but in patients with apogeotropic type without nystagmus transformation have long time to resolve. The elderly patients whose nystagmus remains apogeotropic without nystagmus conversion have tendencies to become intractable.

Postoperative Complications and Swallowing Function after Jejunal and Skin Flap Reconstruction for Hypopharyngeal Carcinoma-A Multicenter Retrospective Study.

This study compared the incidence of perioperative complications and swallowing function between free jejunal flap reconstruction and cutaneous free tissue flap construction. We included 223 patients who underwent hypopharyngeal reconstruction using free flap. At discharge, +the free jejunal flap was associated with a Functional Oral Intake Scale (FOIS) score of 1-6 in 132 cases (70%) and a score of 7 in 56 cases (30%). Regarding the cutaneous free tissue flaps, FOIS scores of 1-6 were observed in 18 cases (51%), and a score of 7 was noted in 17 cases (49%). Donor site complications occurred in 12% of the patients who underwent free jejunal flap procedures and in none of the patients who underwent cutaneous free tissue flap procedures. We found that the free jejunal flap had a regular dietary intake rate in 56 patients (30%), whereas cutaneous free tissue flaps had a regular dietary intake rate in 17 patients (49%). Cutaneous free tissue flaps had a significantly higher regular dietary intake rate at discharge and a significantly lower incidence of donor site complications than free jejunal flaps. In conclusion, free-flap reconstruction may be a better method than free jejunal flap reconstruction for the treatment of hypopharyngeal cancer.

Tracheobronchial chondritis as an immune-related adverse event occurring during the administration of nivolumab for recurrent hypopharyngeal squamous cell carcinoma.

Tracheobronchial chondritis is a rare immune-related adverse event (irAE) associated with immune checkpoint inhibitors. We report a case wherein tracheobronchial chondritis occurred while administering nivolumab for recurrent hypopharyngeal squamous cell carcinoma (SCC) in a man diagnosed with T2N3bM0 stage IVB hypopharyngeal SCC. After treatment with cisplatin and radiotherapy followed by left and right neck dissection, local recurrence was observed in the hypopharynx. Because of the difficulty of salvage surgery, we administered 240 mg/body of nivolumab. After 9 cycles of nivolumab, the patient was judged to have complete response. After 10 cycles, he had cough and sputum, for which prompting us to perform imaging tests. Computed tomography (CT) showed edematous thickening around the trachea and bilateral bronchi and elevated amounts of adjacent subcutaneous fat tissue. Positron emission tomography-CT showed diffuse fluorodeoxyglucose uptake in the trachea and bilateral bronchi, bronchial endoscopy showed redness and swelling throughout the bronchi, and biopsy showed partial mucosal erosion, inflammatory cell (lymphocyte) infiltration, interstitial edema, and desmoplasia. The patient was diagnosed with tracheobronchial chondritis as an irAE resulting from administering anti-programmed death-1 monoclonal antibody. After four-day prednisolone treatment, his cough and sputum disappeared; after two weeks, tracheobronchial chondritis no longer appeared on CT.

Comparison of Dosage of Nivolumab in Efficacy and Safety for Recurrent Metastatic Squamous Cell Carcinoma.

BACKGROUND/AIM: There are no real-world comparative data of nivolumab doses of 3 mg/kg and 240 mg/body for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). We investigated the efficacy and safety of nivolumab in treating recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) at different doses using real-world data. PATIENTS AND METHODS: R/M SCCHN patients who received nivolumab were divided into the 3 mg/kg and 240 mg/body groups and retrospectively examined for efficacy and safety. RESULTS: A total of 199 patients (3 mg/kg and 240 mg/body, 88 and 111 patients, respectively) were included. The 3 mg/kg vs. 240 mg/body groups had similar overall response rates (15% vs. 25, p=0.15), disease control rates (46% vs. 57%, p=0.15), overall survival (9.5 months vs. 10.9 months), and progression-free survival (3.7 months vs. 3.8 months, p=0.95). The incidence of immune-related adverse events was also similar in both groups. CONCLUSION: In R/M SCCHN patients, nivolumab showed similar efficacy and safety at doses of 3 mg/kg and 240 mg/body.

Minocycline-induced black thyroid with black pigmentation of the thyroid cartilage, cricoid cartilage, and trachea found during reconstructive surgery for hypopharyngeal cancer.

Black thyroid is characterized by a rare pigment change observed almost exclusively in patients taking minocycline. We present the case of a 72-year-old man diagnosed with T3N3bM0 stage IVB hypopharyngeal squamous cell carcinoma who had been taking minocycline for approximately 18 months as a treatment for prurigo chronica multiformis. Initial treatment consisted of total pharyngolaryngoesophagectomy, bilateral neck dissection, total thyroidectomy, pharyngeal reconstruction using a free jejunal autograft, and creation of a permanent tracheostoma. During surgery, black discoloration of the thyroid and trachea was observed. Postoperative histological findings confirmed the black discoloration, with deposits of dark-brown, melanin-like granules observed in the thyroid, trachea, thyroid cartilage, and cricoid cartilage. Therefore, the black discoloration of the thyroid associated with the use of minocycline can extend to the thyroid cartilage, cricoid cartilage, and trachea. This information is important for surgeons to recognize in order to prevent unnecessary resection due to misdiagnosis.

Nivolumab for recurrent/metastatic hypopharyngeal squamous cell carcinoma in a liver transplant recipient.

Nivolumab administration to patients with organ transplantation history requires careful management. Herein, we report the case of a living-donor liver-transplant recipient, a 52-year-old man, with recurrent and metastatic hypopharyngeal cancer treated with nivolumab. He was diagnosed with T2N2bM0 stage IVA hypopharyngeal squamous cell carcinoma. While using oral immunosuppressants (cyclosporine and mycophenolate mofetil), the patient underwent right neck dissection followed by radiotherapy as an initial treatment. Three months after radiotherapy, positron emission tomography scans revealed multiple bone metastases. We administered two courses of the EXTREME regimen, comprising cisplatin, 5-fluorouracil, and cetuximab, as the first-line treatment for distal metastasis, but the patient presented with progressive disease. The patient was administered nivolumab as the second-line treatment. The programmed death-ligand 1 (PD-L1) expression level in a biopsy specimen of the primary hypopharyngeal tumor and resected specimen of the cervical lymph node metastasis was 40% and 10%, respectively. PD-L1 expression was not detected in hepatocytes of the liver biopsy sample obtained before nivolumab introduction. The patient received four courses of nivolumab 240 mg. Although liver dysfunction was alleviated by adjusting the dose of the hepatoprotective agent and cyclosporine, the progressive disease status persisted after completing nivolumab courses. The patient died of hypopharyngeal cancer progression.

Effect of Concomitant Lafutidine on Adjuvant S-1 for Head and Neck Cancer: A Comparative Study.

BACKGROUND/AIM: This study evaluated the utility of the histamine H2-receptor antagonist lafutidine in patients taking oral fluorouracil (S-1) for head and neck squamous cell carcinoma (HNSCC), by comparing patients with and without concomitant lafutidine. PATIENTS AND METHODS: Study subjects comprised 63 patients who received adjuvant S-1 following curative resection of HNSCC at our institutions between August 1, 2013 and December 31, 2019. The primary endpoint was the completion rate of S-1 therapy. RESULTS: For the lafutidine-treated group, the median completion rate was significantly greater (94.4% vs. 24.6%, p=0.01), and progression-free and overall survival were both significantly prolonged compared to the non-lafutidine group. In terms of adverse events, the incidence of diarrhoea was significantly reduced (p<0.00189) in the lafutidine-treated group. CONCLUSION: Taking lafutidine during S-1 treatment appeared to reduce gastrointestinal disturbance and increased the S-1 completion rate, improving both progression-free and overall survival as a result.

Laryngeal Cancer With Lung Metastases Showing Long-Term Complete Response and Delayed Immune-Related Adverse Event After Nivolumab Discontinuation.

We report a case of laryngeal cancer with multiple lung metastases that maintained a complete response (CR) for 18 months after discontinuing nivolumab treatment, with colitis developing 5 months after drug discontinuation. A 65-year-old man was diagnosed with T3N2cM0 stage IVA right supraglottic squamous cell carcinoma that progressed after 1 course of TPF (cisplatin, docetaxel, and 5-fluorouracil) as induction chemotherapy. He underwent total laryngectomy, bilateral neck dissection, pharyngeal reconstruction with anterolateral thigh flap, and creation of a permanent tracheostoma; extranodal extension was detected in the right cervical lymph node metastasis, and the patient underwent adjuvant radiotherapy. Multiple lung metastases occurred during radiotherapy, and the patient was deemed platinum refractory; nivolumab treatment was thus initiated. The tumor proportion score for programmed death-ligand 1-evaluated via antibody testing of the laryngeal tumor-was <1. The patient received 240 mg/body nivolumab every 2 weeks; a computed tomography performed after course 16 of nivolumab treatment confirmed a CR. He exhibited grade 2 thyroid dysfunction, grade 1 interstitial pneumonia, and grade 2 colitis after 6, 7, and 14 months of receiving nivolumab, respectively; treatment was discontinued as despite maintaining a CR, interstitial pneumonia occurred twice. Colitis appeared 5 months after nivolumab discontinuation; nevertheless, a CR was maintained after 18 months.

Predicting the efficacy of chemoradiotherapy for locally advanced human papilloma virus-related oropharyngeal squamous cell carcinoma using one course of TPF chemotherapy.

PURPOSE: The standard induction chemotherapy for head and neck cancer is TPF [cisplatin (CDDP), docetaxel (DOC), and 5-fluorouracil (5-FU)]. We assessed whether one course of TPF could predict the efficacy of chemoradiotherapy for human papilloma virus (HPV)-related oropharyngeal squamous cell carcinoma. METHODS: We retrospectively reviewed 51 patients with stage III-IV HPV-related oropharyngeal squamous cell carcinoma who received one course of TPF with CDDP 60 mg/m2, DOC 60 mg/m2, and 5-FU 600 mg/m2. We recommended chemoradiotherapy for patients with complete or partial response (CR/PR), and surgery for those with stable or progressive disease (SD/PD). The endpoints were TPF-related adverse events and efficacy, chemoradiotherapy efficacy, and 2-year survival. RESULTS: Neutropenia was the most common grade ≥ 3 adverse event (88%). No grade 5 adverse events occurred. TPF achieved CR in 4% of patients (2/51), PR in 73% (37/51), SD in 20% (10/51), and PD in 4% (2/51). Concurrent cetuximab and radiotherapy (bio-radiotherapy, BRT) were administered to 61% of patients (31/51), concurrent CDDP and radiotherapy (CDDP-RT) to 16% (8/51), RT alone to 2% (1/51), and surgery was performed for 22% (11/51). CR was achieved in 85% of the chemoradiotherapy group, and the rate tended to increase with TPF efficacy. CR was achieved in 84% (26/31) of patients receiving BRT, 88% (7/8) receiving CDDP-RT, and 100% (1/1) receiving RT. The 2-year survival rates were 92% overall, and 97% and 79% in the chemoradiotherapy and surgery groups, respectively. CONCLUSIONS: When facing difficulty in deciding between chemoradiotherapy and surgery, one course of TPF may be an effective option.

The Role of the EZH2 and H3K27me3 Expression as a Predictor of Clinical Outcomes in Salivary Duct Carcinoma Patients: A Large-Series Study With Emphasis on the Relevance to the Combined Androgen Blockade and HER2-Targeted Therapy.

OBJECTIVE: Salivary duct carcinoma (SDC) is a highly aggressive and uncommon tumor arising not only de novo but also in pleomorphic adenoma. Androgen receptor (AR)- and HER2-targeted therapy have recently been introduced for SDC as promising treatment options; however, no predictive biomarkers have yet been established. EZH2 and H3K27me3 are closely linked to the development and progression of various cancers, and EZH2 is also expected to be a desirable therapeutic target. We therefore explored the clinicopathological and prognostic implications of EZH2 and H3K27me3 in a large cohort of SDC patients, focusing on their impact on the therapeutic efficacy of AR- or HER2-targeted therapy. MATERIALS AND METHODS: The EZH2 and H3K27me3 immunohistochemical expression and EZH2 Y646 gain-of-function mutation status were examined in 226 SDCs, and the relationship with the clinicopathological factors as well as clinical outcomes were evaluated within the three groups depending on the treatment: AR-targeted (combined androgen blockade with leuprorelin acetate and bicalutamide; 89 cases), HER2-targeted (trastuzumab and docetaxel; 42 cases), and conventional therapy (112 cases). RESULTS: EZH2 and H3K27me3 were variably immunoreactive in most SDCs. A positive correlation was found between the expression of EZH2 and H3K27me3. The EZH2 expression in the SDC component was significantly higher than that in the pre-existing pleomorphic adenoma component. EZH2 Y646 was not identified in any cases. EZH2-high cases more frequently had an advanced clinical stage and aggressive histological features than EZH2-low cases. An EZH2-high status in patients treated with AR-targeted therapy was associated with a significantly shorter progression-free and overall survival as well as a lower objective response rate and clinical benefit rate. In addition, a H3K27me3-high status in patients treated with AR-targeted therapy was related to a shorter overall survival. Conversely, there was no association between the EZH2 and H3K27me3 expression and the clinical outcomes in the conventional or HER2-targeted therapy groups. CONCLUSIONS: A high expression of EZH2 and H3K27me3 in SDC might be a predictor of a poor efficacy of AR-targeted therapy. Our data provide new insights into the role of EZH2 and H3K27me3 in therapeutic strategies for SDC.

Real-World, Long-Term Outcomes of Nivolumab Therapy for Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck and Impact of the Magnitude of Best Overall Response: A Retrospective Multicenter Study of 88 Patients.

No real-world, long-term outcomes of immunotherapy with nivolumab for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have yet been reported. Furthermore, the prognostic impact of the best overall response (BOR) of this therapy remains unclear. We conducted a multi-institutional cohort study of the long-term efficacy and safety of this therapy and investigated prognostic factors associated with survival. Further, we evaluated the relationship between BOR and survival. Median follow-up time was 25.9 months. Median overall survival (OS) was 9.6 months, and two-year survival rate was 25.0%. Median progression-free survival (PFS) was 3.7 months, and two-year PFS rate was 19.6%. BOR was assessed as complete response (CR) in 6%, partial response (PR) in 13%, stable disease (SD) in 30%, and progressive disease (PD) in 52% of the patients. Overall response rate was 18%, and disease control rate was 48%. For immune-related adverse events (irAEs), 38 irAEs were detected in 29 patients. On multivariate analysis, the development of irAEs was significantly associated with better OS and PFS. Better BOR was significantly associated with longer OS and PFS. These findings demonstrate the long-term efficacy and safety of nivolumab therapy for R/M SCCHN in a real-world setting. The magnitude of BOR and the development of irAEs might be useful surrogate markers of survival.