Soichiro Takase

Biomarker immunoprofile in salivary duct carcinomas: clinicopathological and prognostic implications with evaluation of the revised classification

Salivary duct carcinoma (SDC) is an uncommon, aggressive malignant neoplasm histologically resembling high-grade mammary ductal carcinoma. SDC can arise de novo or ex pleomorphic adenoma. To clarify the correlation of biomarker immunoprofile with clinicopathological findings and clinical outcome of SDC, we conducted immunohistochemistry for EGFR, HER2, HER3, AR, CK5/6, p53, and Ki-67, along with HER2 fluorescence in situ hybridization in 151 SDCs. SDCs ex pleomorphic adenoma more commonly overexpressed EGFR, HER2, HER3, and Ki-67 than de novo SDCs (P = 0.015, < 0.001, 0.045, and 0.02, respectively). In multivariate analysis, AR− and CK5/6+ were associated with shorter progression-free survival (P = 0.027 and 0.004, respectively). Moreover, patients with p53-extreme negative/positive demonstrated poorer overall survival (P = 0.007). On assessing the revised classification by the combination of biomarker expression, the percentages of each subtype were as follows: ‘apocrine A’ (AR+/HER2−/Ki-67-low) (24%), ‘apocrine B’ (AR+/HER2−/Ki-67-high) (18%), ‘apocrine HER2’ (AR+/HER2+) (35%), ‘HER2-enriched’ (AR−/HER2+) (12%), and ‘double negative’ (AR−/HER2−) (11%). ‘Double negative’ was further subclassified into ‘basal-like’ (EGFR and/or CK5/6+) (7%) and ‘unclassified’ (3%). Consequently, patients with ‘apocrine A’ showed a better progression-free survival than those with any other subtypes. Our revised immunoprofiling classification was valuable for predicting the survival and might be useful in personalized therapy for patients with SDC.

Impact of hematological inflammatory markers on clinical outcome in patients with salivary duct carcinoma: a multi-institutional study in Japan

The prognostic role of modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with salivary duct carcinoma (SDC) remains unclear. We conducted a multi-institutional retrospective cohort study of 140 SDC patients. The survival impact of these hematological markers was evaluated using multivariate proportional hazard models.High mGPS (≥1) was significantly associated with worse survival (3-year overall survival (OS): 16.7% vs 66.1%, p-value=0.003; 3-year progression-free survival (PFS): 0.0% vs 27.9%, p-value<0.001). Additionally, high C-reactive protein (CRP) (≥0.39 mg/dl) was significantly associated with worse survival (3-year OS: 32.1% vs 68.2%, p-value=0.001; 3-year PFS: 7.1% vs 31.1%, p-value<0.001). These associations were consistent with multivariate analysis adjusted for established prognostic factors. Although we also found significant association of high NLR (≥2.5) with OS (HR 1.80; 95% confidence interval, 1.05-3.08) in multivariate analysis, this association were inconsistent with the results of PFS. In addition, we found no significant associations of PLR with survival. In conclusion, we found that mGPS, CRP and NLR were identified as prognostic factors associated with survival in SDC patients.

The efficiency and adverse events of radiotherapy with cetuximab for Japanese head and neck cancer patients

OBJECTIVES Radiotherapy with cisplatin (Chemoradiotherapy, CRT) has long been one of the standard treatments for head and neck squamous cell cancer (HNSCC). Approval of cetuximab for the treatment of HNSCC has made radiotherapy with cetuximab (Bioradiotherapy, BRT) a new treatment option for HNSCC. Reports of BRT in the Japanese written in English up to now is only the phase II study, though it includes only 22 patients. Also on the nature of the clinical Phase II trial, sampling bias of cases may exist. Here we report the treatment completion rate, response rate and frequency of adverse events of BRT in Japanese patients with HNSCC in English for the first time. In association with this, we examine the issues related to BRT in Japanese patients. PATIENTS AND METHODS The subjects consisted of patients with HNSCC who underwent BRT as the first curative treatment (45 cases). Their treatment completion rate, response rate and frequency of adverse events were examined. RESULTS Of the 45patients, 42 were male and 3 were female. The mean age of the patients was 64 (range from 40 to 86). Adverse events of Grade3 or more were 12 cases (27%) of dermatitis, 31 cases (69%) of mucositis/stomatitis, 6 cases (13%) of interstitial pneumonia. The complication rate of pulmonary emphysema in those who developed interstitial pneumonia and those who did not were 83% and 21%, respectively. The BRT completion rate was 78%, and the response rate was 84%. CONCLUSION BRT is sufficiently tolerable and have high response rate even for the Japanese, but we should recognize that BRT is not a minimally invasive and easily manageable treatment.

Prognostic and histogenetic roles of gene alteration and the expression of key potentially actionable targets in salivary duct carcinomas

The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: TP53, 68%; PIK3CA, 18%; H-RAS, 16%; BRAF, 4%; and AKT1, 1.5%. PIK3CA/H-RAS/BRAF mutations were more common in de novo SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. TP53 mutations were frequently detected in cases with the aberrant p53 expression, and TP53 missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of EGFR amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring TP53 truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC.

Chemoradiotherapy with generic cisplatin formulations for head and neck cancers

The use of generic drugs has been increasing. However, studies of the safety of generic cisplatin (CDDP) for the treatment of head and neck cancer (HNC) have not been reported. This study investigated the treatment completion rates and incidence of CDDP-related adverse events in patients with advanced HNC treated with concurrent chemoradiotherapy (CRT) using generic CDDP. This study included 72 patients who received concurrent CRT using generic CDDP. The number of courses of CDDP was 3 in 45 patients, 2 in 19 patients, and 1 in 8 patients. During 154 courses of 80 mg/m2 generic CDDP, grade 3/4 leukopenia in 21 (14%), neutropenia in 18 (12%), and hypochromia in 8 (5%) cases were reported. Grade 2 elevated serum creatinine occurred in 4 cases (3%), but no grade 3/4 elevated serum creatinine was reported. These results suggest that CRT using generic CDDP is well tolerated in patients with HNC.

The high expression of FOXA1 is correlated with a favourable prognosis in salivary duct carcinomas: a study of 142 cases

Salivary duct carcinoma (SDC) is an uncommon, aggressive tumour that, histologically, resembles high‐grade mammary ductal carcinoma, and is characterised by the expression of androgen receptor (AR). The androgen signalling pathway, a potential therapeutic target, can be regulated by FOXA1. This study aimed to evaluate the clinicopathological implications of FOXA1 in SDC.

Usefulness of thoracic duct clipping in thoracoscopic surgery for chylous fistula occurring after neck dissection

Chylous fistula is a rare complication after neck dissection. No methods of treatment have been established and conservative treatment is problematic in many cases. The present case report concerns a 79-year-old man in whom we performed total pharyngolaryngectomy, bilateral neck dissection, and free jejunum transfer for stage II hypopharyngeal cancer. On day 5 following surgery, chylous fistula was observed in the left neck. As no improvement was seen with conservative therapy comprising a low-fat diet and octreotide, we performed thoracoscopic thoracic duct clipping on day 28 following surgery. Directly after clipping, chylous leakage stopped. Oral food ingestion was resumed the following day and the patient was discharged within a week. In view of its low invasiveness and few complications, thoracoscopic thoracic duct clipping may offer a good therapeutic option for chylous fistula.