Immune Checkpoint Inhibitors for Nasopharyngeal Carcinoma in a Real-world Setting in Japan.

BACKGROUND/AIM: The advent of immune checkpoint inhibitor (ICI) treatment has transformed the treatment of recurrent or metastatic head and neck cancer; however, nasopharyngeal carcinoma (NPC) has not been included in major phase III trials. The clinical outcomes of ICI for NPC in real-world practice remain to be fully elucidated. PATIENTS AND METHODS: We retrospectively reviewed 23 patients with recurrent or metastatic NPC treated with nivolumab or pembrolizumab at 6 institutions from April 2017 to July 2021 and investigated the correlation of clinicopathological factors and immune-related adverse events with the effects of ICI therapy and the prognosis. RESULTS: The objective response rate was 39.1% and the disease control rate was 78.3%. The median progression-free survival was 16.8 months and overall survival has not been reached. As with other treatment procedures, the efficacy and the prognosis tended to be better in EBER-positive cases than in EBER-negative cases. The rate of significant immune-related adverse events that necessitated discontinuation of treatment was only 4.3%. CONCLUSION: ICI monotherapy (e.g., nivolumab and pembrolizumab) was effective and tolerable for NPC in a real-world setting.

Retrospective Study of Cisplatin/Carboplatin, 5-Fluorouracil Plus Cetuximab (EXTREME) for Advanced-stage Salivary Gland Cancer.

BACKGROUND/AIM: Surgery remains the standard treatment for salivary gland carcinoma (SGC). Our study investigated the association between epidermal growth factor receptor (EGFR) status in recurrent/metastatic SGC and the effectiveness of treatment with cisplatin/carboplatin and 5-fluorouracil plus cetuximab (EXTREME). PATIENTS AND METHODS: We retrospectively collected 19 SGCs from patients treated with the EXTREME regimen. After analyzing EGFR expression and gene copy number gain, we evaluated the correlation between EGFR status and clinicopathological factors and prognosis. RESULTS: EGFR overexpression was detected in 77.8% cases, but not statistically associated with clinicopathological factors or prognosis. EGFR gene copy number gain was detected in 16.7% cases, and statistically positively correlated with lymph node metastasis (p=0.0291). The best overall response was partial response in two cases, stable disease in 15, and progressive disease in one case. The EXTREME regimen was discontinued in all cases. CONCLUSION: Our results suggest that SGCs are positive for EGFR protein expression but the response rate to the EXTREME regimen was unremarkable.

Treatment Efficacy of PD-1 Inhibitor Therapy in Patients With Recurrent and/or Metastatic Salivary Gland Carcinoma.

BACKGROUND/AIM: The efficacy of programmed cell death 1 (PD-1) inhibitor therapy for patients with recurrent and/or metastatic salivary gland carcinoma (R/M SGC) remains unclear. PATIENTS AND METHODS: We retrospectively analyzed 36 patients with R/M SGC treated with PD-1 inhibitor. The expression of programmed cell death ligand 1 (PD-L1) and mismatch repair (MMR) proteins was also analyzed. RESULTS: The objective response rate (ORR) was 11.1%. The histopathological subtypes of patients who achieved complete response or partial response were salivary duct carcinoma (SDC) in three patients and poorly differentiated carcinoma in one patient, all of whom showed a positive PD-L1 expression. The expression of MMR proteins was not associated with the efficacy of PD-1 inhibitors. CONCLUSION: Although the efficacy of PD-1 inhibitor therapy in R/M SGC is limited, certain patients may respond and achieve long-term disease control. There is a potential therapeutic effect in SDC patients with positive PD-L1 expression.

PD-L1 expression, tumor-infiltrating lymphocytes, mismatch repair deficiency, EGFR alteration and HPV infection in sinonasal squamous cell carcinoma.

The antitumor efficacies of immune checkpoint inhibitors (ICIs) and the usefulness of potential predictive markers such as programmed death-ligand 1 (PD-L1) expression, density of tumor-infiltrating lymphocytes (TILs) and microsatellite instability (MSI) in sinonasal squamous cell carcinoma (SNSCC) have not been fully elucidated. We retrospectively analyzed 131 SNSCCs with immunohistochemistry for PD-L1 expression, TIL subpopulations and loss of mismatch repair (MMR) proteins as a surrogate for MSI-high. We also comprehensively evaluated the mutual relationships among these immuno-markers, high-risk human papillomavirus (HPV) infection, epidermal growth factor receptor (EGFR) gene status, and KRAS mutation. PD-L1 expression (tumor proportion score ≥ 1%) was detected in 60 (45.8%) SNSCC cases and was significantly associated with worse overall survival (OS) (p = 0.0240). High density of cluster of differentiation 8 (CD8)-positive TILs was significantly associated with better progression-free survival (PFS) (p = 0.0368), and high density of forkhead box protein P3-positive TILs was significantly associated with better PFS and OS (p = 0.0007 and 0.0143, respectively). With respect to the combination of CD8 + TIL and PD-L1 expression, the high-CD8/PD-L1-negative group showed the most favorable prognosis, whereas the low-CD8/PD-L1-positive group showed the worst prognosis. MMR loss was detected in 3 (2.3%) of the 131 cases. HPV infection (6.1%), EGFR mutation (14.5%), EGFR copy number gain (26%), and MMR loss were essentially mutually exclusive; patients in these molecular groups showed significant differences in prognosis but not in the degree of PD-L1 expression or TILs. Among the nine ICI-treated patients, three (33.3%) were responders, and the EGFR-wild type cases (n = 7) showed better clinical responses to an ICI compared to the EGFR-mutant cases (n = 2). Among the patients with residual/recurrent EGFR-wild type tumors (n = 43), ICI treatment significantly improved OS (p = 0.0281). The results suggest that the evaluation of immuno-markers and molecular subclassification may be helpful for prognostic prediction and selecting an individualized therapeutic strategy for patients with SNSCC.

Therapeutic effect of Nivolumab for advanced / recurrent temporal bone squamous cell carcinoma.

OBJECTIVE: The immune checkpoint inhibitor Nivolumab was approved for the treatment of platinum-refractory head and neck squamous cell carcinoma (SCC), expanding the treatment options for recurrent or advanced head and neck SCC. However, since temporal bone squamous cell carcinoma (TB-SCC) is very rare cancer, the effectiveness of Nivolumab remains unclear. We investigated the effects of Nivolumab for TB-SCC. METHOD: Chart information was collected for all patients who underwent the first administration of Nivolumab for recurrent or residual TB-SCC in our hospital between September 2017 and December 2019. Tumor staging followed the modified Pittsburgh classification. Changes in the tumor burden and survival outcome were examined. RESULTS: We examined 9 patients with recurrent or residual TB-SCC who started administration of Nivolumab. In these cases, recurrent or residual SCC was observed after chemotherapy and/or chemoradiotherapy including platinum. The duration of Nivolumab was 2-54 weeks (median 20.0 weeks). The evaluation of the therapeutic effect according to the RECIST method showed partial response in 1 case, stable disease in 2 cases, progressive disease in 4 cases, and size unevaluated in 2 case. Although the number of cases was small, comparing with 5 cases without Nivolumab, these cases showed longer overall survival (1-year OS 33.3% vs 20.0%). CONCLUSION: We used Nivolumab as palliative chemotherapy in 9 patients with recurrent/residual TB-SCC, and we were able to obtain a certain therapeutic effect on TB-SCC as well as other head and neck SCC.

Small Cell Carcinoma in the Head and Neck.

OBJECTIVES: Small cell carcinomas in extrapulmonary sites (ESmCCs) are very rare. ESmCCs originating in the head and neck account for approximately 10% of all ESmCCs, and there are few reports about this disease. ESmCCs have an aggressive natural history characterized by widespread metastasis. The aim of this study was to investigate the characteristics and outcomes of patients with ESmCCs of the head and neck. METHODS: The outcomes of 21 patients with ESmCCs of the head and neck treated between January 2001 and December 2015 at the authors' hospital and associated facilities were reviewed. RESULTS: There were 18 men and 3 women, and the median age was 74 years (range, 53-91 years). The tumor site was the larynx in 6 patients; the paranasal sinus in 5; the hypopharynx in 3; the oropharynx in 2; the nasopharynx in 2; and the oral cavity, salivary gland, and primary unknown in 1 patient each. The extent of the disease was staged as follows: stage I or II, 3 cases; stage III, 4 cases; stage IVA, 9 cases; stage IVB, 1 case; and stage IVC, 4 cases. The median observation time was 17 months (range, 1-103 months). Four patients (19%) had distant metastasis at initial treatment, and 13 patients (62%) developed distant metastasis within 3 years. Treatments were administered, including radical surgery (9 patients), radiation therapy (5 patients), chemoradiotherapy (7 patients), and chemotherapy (6 patients). The 1- and 3-year overall survival rates of patients were 56% and 37%, respectively. More than half of the patients died of distant metastasis. CONCLUSIONS: ESmCCs of the head and neck have a poor prognosis, similar to those of carcinomas in many other sites. Control of distant metastasis would contribute to improving the prognosis of ESmCCs of the head and neck. Further studies are required for better understanding these disease entities and their response to treatment modalities.

Evaluation of the Effects of Chronic Kidney Disease and Hemodialysis on the Inner Ear Using Multifrequency Tympanometry.

OBJECTIVES: To evaluate the effects of chronic kidney disease (CKD) and hemodialysis (HD) on the inner ear using the G width (the width between the bimodal peaks of the conductance (G) tympanogram at 2,000 Hz), which reflects the inner ear pressure and/or the existence of endolymphatic hydrops. MATERIALS AND METHODS: We selected five patients (10 ears) from the patients with CKD who were hospitalized for creation of arteriovenous fistula prior to initiation of HD (non-HD group), and we selected seven patients (14 ears) from the patients with CKD who were undergoing HD (the HD group). As a control group, we selected 80 healthy individuals (160 ears); these were mainly the medical staff of the hospital. We measured the G width of the control group and that of patients with CKD using multifrequency tympanometry. RESULTS: The mean G widths of the HD (measured just before an HD session), non-HD, and control groups were 210.7, 128.4, and 97.0 daPa, respectively. The G width of the HD group was significantly greater than that of the control and non-HD groups (p<0.01 and p<0.01, respectively; Tukey-Kramer test after one-way analysis of variance). The non-HD group also had a greater G width than the control, but it was not significant (p=0.20; Tukey-Kramer). No significant changes were observed in the G widths of the HD group, just before and after a single HD session (p=0.423; paired t-test). CONCLUSION: The greater G width observed in hemodialyzed CKD patients suggests either an increased inner ear pressure or the existence of endolymphatic hydrops in these patients, which is probably related to their otologic symptoms.

Diagnosis and following up of Ménière's disease using multifrequency tympanometry-Cutoff values and temporal changes in measurements.

OBJECTIVE: This study aimed to verify cutoff values for G width (the width of bimodal peaks for the waveform obtained when measuring conductance at 2000Hz) in Japanese individuals diagnosed with Ménière's disease (MD) using multifrequency tympanometry (MFT) and to determine the relationship between the G width and ability to hear low-pitched sounds using measurements over time. METHODS: The study included 51 patients with clinically diagnosed MD, who had not undergone endolymphatic sac surgery, but had no other known ear disease (57 ears in patients aged 22-80 years were affected, and 45 ears in patients aged 18-83 years were unaffected; mean age: 53.3±16.9 years). We also enlisted 80 healthy controls with no prior history of ear disease (160 ears, aged 22-76 years, mean age: 40.8±15.7 years). MFT was used to measure the bimodal peak width of the waveform obtained when measuring conductance at resonance frequency of 2000Hz. For patients who had G width measured several times over multiple outpatient visits, we used initial test data to analyze cutoff values. In nine cases with four or more measurements over time, we evaluated a possible correlation between G width and the sum of the hearing threshold for three low-pitched frequencies (125Hz, 250Hz, and 500Hz). We used Student's t-test to determine significance. RESULTS: The both ears in the MD patients had a G width wider than the distribution in the control group. There was a significant difference between G width in the control group and in affected ears with MD (p=0.00026) and there was also a significant difference between G width in the control group and in unaffected ears of MD patients (p=0.0056). The cutoff value set with a specificity of 95% was 200daPa, with a sensitivity of 35.1% and specificity of 95.6%. The cutoff value set with a sensitivity of 50% was 140daPa, with sensitivity of 50.9% and specificity of 78.8%. There was no significant difference between resonance frequency of ears in the control group and ears with MD (p=0.41). In nine cases with four or more measurements over time, a case showed a statistically significant positive correlation between the G width and hearing ability threshold for low-pitched sounds (125Hz, 250Hz, and 500Hz) (p=0.03), while an another case showed a tendency toward a positive correlation, which was not statistically significant (p=0.08). Further, there were cases that did not show significant differences in the present study, but might have shown a negative correlation if the number of measurements had been increased. CONCLUSION: Measurement of G width using MFT may have accuracy as the traditional endolymphatic hydrops test. MFT is non-invasive, causes little discomfort for patients, requires little time to perform, and can be performed by paramedics. MFT was shown to be useful in screening for MD and it is effective in diagnosing MD to measure the change over time of G width using MFT.

Syndrome of inappropriate antidiuretic hormone secretion in a case of olfactory neuroblastoma without anti-diuretic hormone immunoreactivity: A case report and review of the literature.

Olfactory neuroblastoma (ONB) is a relatively rare nasal or paranasal malignant tumor. This tumor is rarely accompanied by paraneoplastic syndromes such as syndrome of inappropriate antidiuretic hormone secretion (SIADH). Here, we report a 31-year-old female with histologically confirmed ONB who had been diagnosed with SIADH three years prior. She was treated with surgery followed by concurrent chemoradiotherapy. SIADH resolved immediately after surgical tumor resection. Immunohistochemically, both biopsy and resected specimens from the nasal cavity had been negative for ADH. Although extremely rare, ONB may be associated with SIADH, and the possibility of this cancer should be taken into account during the follow-up of idiopathic SIADH.

Primary combined small cell carcinoma and squamous cell carcinoma of the oropharynx with special reference to EGFR status of small cell carcinoma component: Case report and review of the literature.

Combined small cell carcinoma (SCC) and squamous cell carcinoma (SqCC) of the oropharynx is extremely rare and shows an aggressive clinical course. There are only 5 reported cases of combined SCC and SqCC in the English language literature. Here, we report a 59-year-old male presenting with a right tonsillar mass. The mass was biopsied, and the histological findings showed a proliferation of small-sized tumor cells with scant cytoplasm. Immunohistochemically, the tumor cells were positive for neuroendocrine markers (synaptophysin, chromogranin A, and CD56). Our first diagnosis was tonsillar small cell carcinoma. We treated the patient with concurrent chemoradiotherapy together with cisplatin followed by surgery. The resected tonsillar specimen showed a residual tumor composed of SCC and SqCC, and lymph nodes showed metastatic tumor cells of the SCC component. Immunohistochemically, the SCC component was positive for all neuroendocrine markers and p16; on the other hand, the SqCC component was positive for p40, p63, p16, and EGFR. Fluorescence in situ hybridization revealed that neither component showed any EGFR gene copy number gain. The patient was treated with adjuvant chemotherapy consisting of irinotecan and cisplatin. Liver and bone metastases developed, resulting in the death of the patient. We discuss the present case and review similar cases. Most cases of combined SCC and SqCC occur regardless of p16 status, and a therapeutic strategy has yet to be determined. Further examination of this kind of combined tumor is necessary.

Inflammatory pseudotumor in head and neck.

BACKGROUND: Inflammatory pseudotumor (IPT) is a tumefactive lesion characterized by fibroblastic proliferations and a prominent inflammatory component. It behaves as a locally benign or aggressive lesion, clinically and radiologically mimicking a neoplastic process. Numerous entities can be diagnosed as IPT, from reactive lesions to true neoplasms. The diagnosis of IPT requires further elaboration, and IPT should be distinguished from other similar entities such as inflammatory myofibroblastic tumor and IgG4-related sclerosing disease. CASE SUMMARY: We report two cases of IPT arising from the head and neck region. One occurred at the orbit and the other at the parapharyngeal space. Histologically, they showed aggregates of myofibroblasts and inflammatory cells. Immunohistochemically, the number of IgG4-positive cells was less than 40% of the number of IgG positive cells, and the myofibroblastic cells were negative for anaplastic lymphoma kinase. The diagnosis was IPT/not otherwise specified. One patient was treated by systemic administration of corticosteroid and had good response. The other, who was treated by local administration of corticosteroid, partially responded and is currently stable with limited disease. DISCUSSION: IPT has been reported to occur in various anatomical sites, most commonly in the lungs. The incidence in the head and neck area is extremely rare. Treatment of IPT is controversial and may involve corticosteroids or surgical resection, or both. Other chemotherapeutic agents and radiotherapy may be considered in steroid-resistant patients. The pathological subtype, safety of resection, and safety of corticosteroid use must be included in the decision-making process for treatment.

Surgical management of malignant tumors of the trachea: report of two cases and review of literature.

Malignant neoplasms occurring from the trachea are extremely rare. Therefore, their clinical characteristics and surgical results have not been thoroughly discussed. These tumors are often misdiagnosed and treated as bronchial asthma or chronic obstructive pulmonary disease. It is critically important to probe the cause-effect relationship between the medical presentations and the clinical diagnosis. In this report, two cases of tracheal malignancy suffering from dyspnea due to obstruction of the proximal trachea are described, and a review of the literature is presented.

A case of laryngeal carcinoma in a young adult with dyskeratosis congenita.

Dyskeratosis congenita (DC) is an inherited disorder that is characterized by the triad of skin pigmentation, nail dystrophy, and mucosal leukoplakia. Individuals with DC suffer from premature mortality because of bone marrow failure, pulmonary disease, or malignant transformation within the areas of mucosal leukoplakia, caused by telomerase dysfunction. We present a case of a 31-year-old Japanese man with DC who developed laryngeal cancer (supraglottic T4aN0M0). To avoid the serious risks of accelerating the DC-associated complications by DNA-damaging therapies, he was treated with a total laryngectomy plus right modified neck dissection (levels IB, IIA, III, and IV). A contralateral nodal metastasis appeared 4 months after initial surgery and was salvaged by a left radical neck dissection. Our strategy to spare DNA-damaging therapies has proven effective so far. This is the first reported case of laryngeal cancer in a patient with DC in the English-language medical literature.

Cell-type-specific excitatory and inhibitory circuits involving primary afferents in the substantia gelatinosa of the rat spinal dorsal horn in vitro.

The substantia gelatinosa (SG) of the spinal dorsal horn shows significant morphological heterogeneity and receives primary afferent input predominantly from A delta- and C-fibres. Despite numerous anatomical and physiological studies, correlation between morphology and functional connectivity, particularly in terms of inhibitory inputs, remains elusive. To compare excitatory and inhibitory synaptic inputs on individual SG neurones with morphology, we performed whole-cell recordings with Neurobiotin-filled-pipettes in horizontal slices from adult rat spinal cord with attached dorsal roots. Based on dendritic arborization patterns, four major cell types were confirmed: islet, central, radial and vertical cells. Dorsal root stimulation revealed that each class was associated with characteristic synaptic inputs. Islet and central cells had monosynaptic excitatory inputs exclusively from C-afferents. Islet cells received primary-afferent-evoked inhibitory inputs only from A delta-fibres, while those of central cells were mediated by both A delta- and C-fibres. In contrast, radial and vertical cells had monosynaptic excitatory inputs from both A delta- and C-fibres and inhibitory inputs mediated by both fibre types. We further characterized the neurochemical nature of these inhibitory synaptic inputs. The majority of islet, central and vertical cells exhibited GABAergic inhibitory inputs, while almost all radial cells also possessed glycinergic inputs. The present study demonstrates that SG neurones have distinct patterns of excitatory and inhibitory inputs that are related to their morphology. The neurotransmitters responsible for inhibitory inputs to individual SG neurones are also characteristic for different morphological classes. These results make it possible to identify primary afferent circuits associated with particular types of SG neurone.

[Mediastinal dissection for patients with differentiated thyroid carcinoma: sternotomy vs VATS (video-assisted thoracoscopic surgery)].

We here present two cases of differentiated thyroid carcinoma with mediastinal lymph nodes metastases below level 106 according to the classification of the Guidelines for the Clinical and Pathologic Studies for Carcinoma of the Esophagus (9 th edition) edited by the Japanese Society for Esophageal Diseases. For Case 1, we adopted a conventional anterior approach with resection of the right half of the manubrium and sternum to the level of the second intercostal space and medial half of the right clavicule. Case 2 underwent a combined cervical approach and video-assisted thoracoscopic surgery (VATS). In Case 1, the lymph nodes around the subclavian vein, 105R, 106pre and 106recR were successfully dissected under clear view. However, through this case, the difficulty in the dissection of 106tbR was recognized, because it is quite challenging to gain an adequate surgical view in this small compartment by this approach. Conversely, in Case 2, in which mediastinal lymph nodes extended to level 107, the lymph nodes were relatively easily dissected by VATS under excellent surgical views of 106tbR and 107. Although VATS is associated with difficulty in en bloc resection, requirements of a thoracotomy, changes of body position and an intubation tube during the surgery, this approach is of great use for the dissection of 106tbR and 107.

Direct inhibition of substantia gelatinosa neurones in the rat spinal cord by activation of dopamine D2-like receptors.

Dopaminergic innervation of the spinal cord is largely derived from the brain. To understand the cellular mechanisms of antinociception mediated by descending dopaminergic pathways, we examined the actions of dopamine (DA) on nociceptive transmission by using behavioural studies and whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurones in the spinal cord. Intrathecal administration of DA increased the mechanical nociceptive threshold and this effect was mimicked by a D2-like receptor agonist, quinpirole, but not by a D1-like receptor agonist, SKF 38393. In current-clamp mode of patch-clamp recordings, bath application of DA hyperpolarized the membrane potential of SG neurones and suppressed action potentials evoked by electrical stimulation of a dorsal root. In voltage-clamp mode, DA induced an outward current that was resistant to TTX, was blocked by the addition of Cs+ or GDP-beta-S in the pipette solution, and was inhibited in the presence of Ba+. The DA-induced current reversed its polarity at a potential close to the equilibrium potential of the K+ channel calculated from the Nernst equation. The DA-induced outward current was mimicked by quinpirole, but not by SKF 38393. The DA-induced outward current was suppressed by a D2-like receptor antagonist, sulpiride, but not by a D1-like receptor antagonist, SCH 23390. In contrast, DA did not cause any significant change in amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs). These results indicate that DA mainly acts on postsynaptic SG neurones to induce an outward current via G-protein-mediated activation of K+ channels through D2-like receptors. This may be a possible mechanism for antinociception by the descending dopaminergic pathway.