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.

Initial Safety Analysis of CapeOx for Elderly Patients With Advanced Gastric Cancer Patients: A Phase II Trial.

BACKGROUND: Safety of combination chemotherapy using platinum and fluorouracil has not been evaluated adequately for advanced gastric cancer (AGC) in elderly patients. PATIENTS AND METHODS: We initiated a phase II study to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapeOX) as first-line therapy for patients with AGC aged ≥70 years. Planned assessment of toxicity was made upon recruitment of the first 20 patients. RESULTS: In five out of 20 patients, unacceptable toxicity was observed, including three patients who were unable to complete the initial two courses due to adverse events. Among the other 15 patients, dose reduction due to toxicity were needed in 10 and treatment delay for adverse events also occurred in 12 patients during the first two courses. CONCLUSION: Early analyses of safety suggest that the CapeOX regimen was not tolerated without dose reduction for elderly patients with AGC in this study.

Nivolumab-induced Myositis and Myocarditis with Positive Anti-titin Antibody and Anti-voltage-gated Potassium Channel Kv1.4 Antibody.

Immune checkpoint inhibitors (ICIs) are complicated by immune-related adverse events (irAEs), such as myositis, myocarditis, and myasthenia gravis (MG). Anti-titin antibody and anti-voltage-gated potassium channel Kv1.4 antibody are anti-striated antibodies that are frequently detected in MG patients with myositis and/or myocarditis. However, the clinical relationship between positive anti-striated antibodies and irAEs of ICIs remains unknown. We herein report a case of nivolumab-induced myositis and myocarditis with positive anti-titin antibody and anti-voltage-gated potassium channel Kv1.4 antibody in a patient with non-small-cell lung cancer. We also review reported cases of positive anti-striated antibodies related to irAEs of ICIs.

Predictive and Prognostic Biomarker Identification in a Large Cohort of Androgen Receptor-Positive Salivary Duct Carcinoma Patients Scheduled for Combined Androgen Blockade.

Patients suffering from recurrent or metastatic (R/M) salivary duct carcinoma (SDC) are often treated with combined androgen blockade (CAB). However, CAB frequently fails, resulting in a worse prognosis. Therefore, biomarkers that can predict treatment failure are urgently needed. mRNA from 76 R/M androgen receptor (AR)-positive SDC patients treated with leuprorelin acetate combined with bicalutamide was extracted from pre-treatment tumor specimens. AR, Notch, MAPK, TGFß, estrogen receptor (ER), Hedgehog (HH), and PI3K signaling pathway activity scores (PAS) were determined based on the expression levels of target genes. Additionally, 5-alpha reductase type 1 (SRD5A1) expression was determined. These markers were related to clinical benefit (complete/partial response or stable disease ≥6 months) and progression-free and overall survival (PFS/OS). SRD5A1 expression had the highest general predictive value for clinical benefit and positive predictive value (PPV: 85.7%). AR PAS had the highest negative predictive value (NPV: 93.3%). The fitting of a multivariable model led to the identification of SRD5A1, TGFß, and Notch PAS as the most predictive combination. High AR, high Notch, high ER, low HH PAS, and high SRD5A1 expression were also of prognostic importance regarding PFS and SRD5A1 expression levels for OS. AR, Notch PAS, and SRD5A1 expression have the potential to predict the clinical benefit of CAB treatment in SDC patients. SRD5A1 expression can identify patients that will and AR PAS patients that will not experience clinical benefit (85.7% and 93.3% for PPV and NPV, respectively). The predictive potential of SRD5A1 expression forms a rational basis for including SRD5A1-inhibitors in SDC patients' treatment.

Multicentre, retrospective study of the efficacy and safety of nivolumab for recurrent and metastatic salivary gland carcinoma.

Although immune-checkpoint inhibitors (ICIs) are effective against various cancers, little is known regarding their role in salivary gland carcinoma (SGC) treatment. Therefore, we evaluated the efficacy and safety of nivolumab monotherapy in patients with recurrent and/or metastatic SGC. In this multicentre retrospective study, nivolumab (240 mg) was administered every 2 weeks. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were examined; the correlation between treatment outcomes and clinicopathological factors was analysed. Twenty-four patients were enrolled; the most common histopathology was salivary duct carcinoma. Eleven tumours were PD-L1-positive; no tumour was microsatellite instability-high. The ORR was 4.2%, and the median PFS and OS were 1.6 and 10.7 months, respectively. One patient continued nivolumab for 28 months without disease progression. One patient showed grade 4 increase in creatine phosphokinase levels and grade 3 myositis. Biomarker analysis revealed significantly increased OS in patients with performance status of 0; modified Glasgow prognostic score of 0; low neutrophil-to-lymphocyte ratio, lactate dehydrogenase, and C-reactive protein; and high lymphocyte-to-monocyte ratio and in patients who received systemic therapy following nivolumab. Although nivolumab's efficacy against SGC was limited, some patients achieved long-term disease control. Further studies are warranted on ICI use for SGC.

Carboplatin and Docetaxel in Patients With Salivary Gland Carcinoma: A Retrospective Study.

BACKGROUND/AIM: The aim of this study was to evaluate the efficacy and safety of carboplatin/docetaxel combination therapy in patients with locally advanced and/or recurrent/metastatic (LA/RM) salivary gland carcinoma (SGC). MATERIALS AND METHODS: This was a retrospective analysis of 24 patients that included six patients with AR-positive salivary duct carcinoma (SDC) after progressive disease treated with combined androgen blockade (CAB). Carboplatin (AUC5) and docetaxel (70 mg/m2) were administered for six courses every three weeks. RESULTS: The overall response rate was 42%, the median progression-free survival was 8.4 months, and the median overall survival was 26.4 months. Among the six patients with CAB-resistant SDC, two achieved a partial response and two long-term stable disease. Grade 3/4 neutropenia and anemia were observed in 20-30% of the patients; all adverse events were manageable. CONCLUSION: Carboplatin/docetaxel combination therapy may be a chemotherapeutic option for patients with LA/RM SGC, and a valuable second-line chemotherapy for CAB-resistant, AR-positive SDC.

Phase II Trial of Trastuzumab and Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2-Positive Salivary Duct Carcinoma.

PURPOSE: Clinical evidence demonstrating the effectiveness of systemic therapy for advanced salivary duct carcinoma (SDC) is lacking because of the disease's rarity. We assessed the efficacy and toxicity of trastuzumab plus docetaxel in patients with locally advanced and/or recurrent or metastatic human epidermal growth factor receptor 2-positive SDC. PATIENTS AND METHODS: This was a single-center, single-arm, open-label, phase II study in Japan. The patients received trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Docetaxel 70 mg/m2 was administrated every 3 weeks. The primary end point was the overall response rate; the secondary end points included the clinical benefit rate, progression-free survival, overall survival, and toxicity. This study is registered with the University Hospital Medical Information Network Clinical Trials Registry (Identification No. UMIN000009437). RESULTS: Fifty-seven eligible patients with SDC were enrolled. The overall response rate was 70.2% (95% CI, 56.6% to 81.6%), and the clinical benefit rate was 84.2% (95% CI, 72.1% to 92.5%). Median progression-free and overall survival times were 8.9 months (95% CI, 7.8 to 9.9 months) and 39.7 months (95% CI, not reached), respectively. The most frequent adverse event was anemia (52 patients [91%]), followed by a decreased WBC count (51 patients [89%]) and neutropenia (50 patients [88%]). The most frequently observed grade 4 adverse event was a decreased neutrophil count (34 patients [60%]). Grade 3 febrile neutropenia was reported in eight patients (14%). No grade 2 or greater adverse events of heart failure or left ventricular ejection fraction decline to less than 50% occurred. CONCLUSION: Our data show encouraging efficacy of trastuzumab plus docetaxel therapy in patients with human epidermal growth factor receptor 2-positive SDC, with a manageable toxicity profile.

Metastasis of Mammary Gland Malignant Phyllodes Tumor to the Mandibular Region: A Case Report and Review of the Literature.

Phyllodes tumor is a rare breast tumor described by Müller (1938) as a lesion comprising leaflike stromal fibrous components and narrow cysts. The frequency of distant metastasis from this entity is reportedly approximately 20%, and no effective therapy has been established, so the prognosis is poor. This report describes the case of a 60-year-old woman with a history of left lung resection who showed metastasis of a mammary gland malignant phyllodes tumor to the oral cavity. Intraoral examination showed an elastic, hard mass measuring 28 × 27 mm in the gingiva around the left mandibular second molar. Biopsy examination showed growth of giant cells and roughly circular cells showing positivity for S-100, p63, and vimentin on immunohistochemical staining. The authors diagnosed metastasis of the mammary gland malignant phyllodes tumor to the left mandible and performed cyber knife irradiation (44 Gy in 5 fractions) of the left mandible. The mass in the oral cavity disappeared after cyber knife irradiation, but the patient died of direct invasion to the spine.

Chemotherapy for anaplastic thyroid cancer using docetaxel and cisplatin: report of eight cases.

Anaplastic thyroid carcinoma has a dismal prognosis and lacks an established therapeutic strategy. We have recently conducted chemotherapy with docetaxel and cisplatin as part of multimodal treatment for eight patients with anaplastic thyroid carcinoma. Docetaxel (75 mg/m2) and cisplatin (75 mg/m2) were administered on day 1 every 4 weeks for six courses. This chemotherapy was used as induction therapy in one patient, as therapy for distant metastases in five patients and as postoperative adjuvant therapy in two patients. Three patients showed partial responses and three patients showed stable disease. After excluding the two patients receiving the treatment as adjuvant therapy the response rate was 50 %. Grade 3 or 4 leukocytopenia occurred in seven patients (88 %), but these adverse events were tolerable. Chemotherapy with docetaxel and cisplatin may thus be feasible for anaplastic thyroid carcinoma.

[A Case of a Metastatic Liver Tumor from a Thymic Carcinoma Detected During a Cesarean Section].

A 40-year-old pregnant woman who had previously been diagnosed with uterine myoma underwent cesarean section. During the operation, a tumor thought to be uterine myoma was found to be an extrauterine tumor arising from the upper abdomen. After the delivery of the fetus, a staging CT scan was performed, which revealed a huge, 18 cm, hepatic tumor in the left lateral segment, a mediastinal tumor with calcification, and multiple lung nodules. She underwent a left hepatic lobectomy and a wedge resection 8 days after the delivery. The initial pathological diagnosis was moderately differentiated neuroendocrine tumor (NET). However, as a primary hepatic NET is extremely rare, further immunohistochemical staining was performed. The tumor was positive for p63, CD5, c-kit, and bcl-2, indicating a diagnosis of thymic carcinoma with liver and lung metastases.

Chemotherapy for anaplastic thyroid cancer using docetaxel and cisplatin: report of eight cases.

Anaplastic thyroid carcinoma has a dismal prognosis and lacks an established therapeutic strategy. We have recently conducted chemotherapy with docetaxel and cisplatin as part of multimodal treatment for eight patients with anaplastic thyroid carcinoma. Docetaxel (75 mg/m²) and cisplatin (75 mg/m²) were administered on day 1 every 4 weeks for six courses. This chemotherapy was used as induction therapy in one patient, as therapy for distant metastases in five patients and as postoperative adjuvant therapy in two patients. Three patients showed partial responses and three patients showed stable disease. After excluding the two patients receiving the treatment as adjuvant therapy the response rate was 50 %. Grade 3 or 4 leukocytopenia occurred in seven patients (88 %), but these adverse events were tolerable. Chemotherapy with docetaxel and cisplatin may thus be feasible for anaplastic thyroid carcinoma.

Phase I/II study of docetaxel, cisplatin and S-1 in locally advanced, recurrent and metastatic head and neck squamous cell carcinoma.

The purpose of this study was to evaluate the maximum tolerated dose, dose-limiting toxicities and preliminary efficacy of chemotherapy with cisplatin, docetaxel and S-1 (TPS) to treat advanced head and neck squamous cell cancer. S-1 was administered orally twice daily on days 1-14 and docetaxel and cisplatin were injected intravenously on day 8, with one course lasting 4 weeks. The recommended dose obtained from a phase I study was set at docetaxel 60 mg/m(2), cisplatin 60 mg/m(2) and S-1 80 mg/m(2)/day. The phase II study revealed that the overall response rate was 81%, comprising 95% in untreated patients with localized advanced cancer and no distant metastases, 50% in untreated patients with distant metastases and 33% in previously treated patients with recurrence. The overall survival rate of untreated patients with localized advanced cancer and no distant metastases was 95% at 1 year and 64.33% at 2 years. In terms of grade 3 or higher hematotoxicity, neutropenia occurred in 100%, thrombocytotopenia in 4% and anemia in 4%. Febrile neutropenia occurred in 46%, with the rate rising to 57% in elderly patients ≥66 years. Grade 3 or higher non-hematotoxicity consisted of loss of appetite in 8%, diarrhea in 8%, hyponatremia in 13% and hypokalemia in 13%. This TPS therapy may be recommended for use as induction chemotherapy. For patients ≤65 years, the appropriate dose was docetaxel 60 mg/m(2), cisplatin 60 mg/m(2) and S-1 80 mg/m(2), whereas for those ≥66 years, it was docetaxel 60 mg/m(2), cisplatin 60 mg/m(2) and S-1 60 mg/m(2).

[Efficacy of CHOP+/-Rituximab-like therapy plus radiation therapy for patients with diffuse large B-cell lymphoma stage I].

Clinically, R-CHOP-like therapy plus radiation therapy is commonly performed for patients with limited stage diffuse large B-cell lymphoma. However, the efficacy and the safety of the management have not been evaluated properly. In particular, we have few definitive reports about patients with stage I DLBCL. This time we evaluated the effect of CHOP+/-R-like therapy plus radiation therapy, by analyzing 28 patients with stage I DLBCL, retrospectively. 15 patients were treated with the RCHOP-like therapy, and 13 received CHOP-like therapy combined with radiation therapy. A complete response was observed in all of the patients. With a median follow-up time of 14 months, 1-year progression-free survival (PFS) was 100%, and the 1-year overall survival (OS) was 100% for the patients receiving the R-CHOP-like therapy. With a median follow-up time of 68 months, 5-year PFS was 84. 6%, and 5-year OS was 100% for patients receiving the CHOP-like therapy. Since the followup time was not enough and the patient numbers were too few, the benefit of the addition of Rituximab to the CHOP therapy could not be clarified. We need to assess the safety and the efficacy of the combined modality therapy for patients with limited-stage DLBCL by a larger prospective study.

[A case of mediastinal cancer of unknown primary with elevation of serum concentrations of interleukin-6].

Interleukin-6(IL-6)is an inflammatory cytokine. It's produced by monocyte, lymphocyte, vascular endothelial cell, and fibroblast. Elevation of serum concentrations of IL-6 is reported a lot of kind of diseases, such as cancer, infection, inflammatory diseases. But it is production mechanism was still unknown. A 67-year-old man was referred to our hospital because of treatment against the large mediastinal cancer of unknown primary. He had complication with superior vena cave syndrome. After he was exposed to irradiation, the tumor size was reduced, his symptoms were improved and the serum IL-6 level was decreased.

[A pilot study of TS-1+CDDP therapy for highly advanced stage IV gastric cancer].

We performed a pilot study of combination chemotherapy with TS-1 and cisplatin for highly advanced gastric cancer. From June 2002, 12 patients with multiple liver metastases, carcinomatous lymphangitis or peritoneal dissemination, were enrolled in the study. TS-1 was administered at a daily dose on day 1-21 and an intermediate-dose of cisplatin (60 mg/m2) was administered on day 8. The combination was repeated in a 5-week cycle. The median administered cycles were three (one to eight). An objective response was obtained in 9 cases (75.0%) of primary sites and 6 cases of metastatic sites. No severe hematological toxicity occurred, and grade 3 stomatitis (in one case) and vomiting (in two cases) occurred as non-hematological toxicities. The improvement of clinical symptoms such as appetite loss and abdominal discomfort was obtained in 9 of 10 cases. The median survival time is 244 days. The TS-1/CDDP regimen had almost no survival benefits, but may induce relief of symptoms due to cancer and better quality of life.

Therapy-related myelodysplastic syndrome with trisomy 1q due to der(1;7) and megakaryoblastic proliferation developing during complete remission of therapy-related acute myeloid leukemia with t(8;21).

Therapy-related acute myeloid leukemia (t-AML) with t(8;21) and therapy-related myelodysplastic syndrome (t-MDS) with trisomy 1q due to der(1;7) developed in the same patient with T-cell lymphoma at intervals of six years. After the development of t-MDS with trisomy 1q, during complete remission of t-AML, the number of megakaryoblasts increased to maximally 74% of leukocytes in the blood. This is a very rare case of two separate therapy-related myeloid malignancies (early t-AML and late t-MDS) and is also a notable case of t-MDS with trisomy 1q due to der(1;7) accompanied by megakaryoblastic proliferation.

Irinotecan hydrochloride for the treatment of recurrent and refractory non-Hodgkin lymphoma: a single institution experience.

BACKGROUND: Irinotecan hydrochloride (CPT-11) has a broad range of antitumor activity and has demonstrated little cross-resistance with doxorubicin or vincristine. In the current study, the authors investigated the efficacy and adverse effects of irinotecan in the treatment of recurrent and refractory non-Hodgkin lymphoma, for which current therapies appear to be unsatisfactory. METHODS: Irinotecan was administered by intravenous infusion at a dose of 40 mg/m(2)/day for 3 days, and this regimen was repeated 2-3 times at weekly intervals, followed by 2 weeks off therapy. The subjects were 48 patients with recurrent or refractory non-Hodgkin lymphoma. The histologic classification (Working Formulation) was low grade in 8 patients, intermediate grade in 36 patients, high grade in 1 patient, and other (angiocentric lymphoma, Ki-1 lymphoma, and unidentified) in 3 patients. RESULTS: Forty-five patients were determined to be evaluable. Therapy resulted in a complete disease remission in 2 patients and a partial remission in 15 patients. The response rate was 37.8%. The median duration of response was 64 days and the median time to disease progression was 77 days. The median survival time was 422 days. Major adverse reactions included myelosuppression and gastrointestinal toxicity. Leukopenia, anemia, and thrombocytopenia of Grade 3 or 4 (according to the National Cancer Institute Common Toxicity Criteria) was observed in 63.0%, 30.4%, and 6.5% of the patients, respectively, and Grade 3 or 4 diarrhea occurred in 30.4% of patients. Treatment was withdrawn because of diarrhea in three patients. Because of myelosuppression and diarrhea, approximately 67% of the patients required changes to the regimen, including dose reduction, prolongation of the interval between treatments, and reducing the number of days of consecutive treatment. CONCLUSIONS: The results of the current study suggest the activity of irinotecan as salvage therapy for patients with recurrent and refractory non-Hodgkin lymphoma. However, the optimum dosing schedule remains to be determined.