Hiroshi Wataya

Prognosis of Bronchial artery embolization in the management of hemoptysis

Background: Bronchial artery embolization (BAE) is a well-accepted and widely used treatment modality for the management of massive and recurrent hemoptysis. However, few reports have previously investigated the long-term results. Objectives: To investigate the prognosis of patients with hemoptysis who had undergone BAE. Methods: Twenty-two patients with hemoptysis underwent BAE. The underlying diseases included bronchiectasis in 9, aspergillosis in 3, chronic bronchitis in 2, idiopathic bronchial bleeding in 4, and other diseases in 4. The follow-up period ranged from 25 to 88 months (median 47 months). Results: After the initial BAE, 11 of 22 (50%) patients had re-bleeding (5 patients with hemoptysis and 6 patients with minor hemosputa). Among them, 1 patient suffered from recurrent massive hemoptysis and died from airway obstruction within 1 month after BAE. In addition, 10 of these 11 (90.9%) patients experienced recurrent airway bleeding within 3 years after BAE. Recurrent cases of hemoptysis were seen in 6 of 22 patients (27.3%) within 3 years and no case recurred later than 3 years after BAE. A recurrence of hemoptysis was frequently seen in patients with either bronchiectasis or pulmonary-bronchial artery (P-B) shunt. Although BAE is an effective treatment for the immediate control of hemoptysis, 5 of the patients experienced recurrent bleeding in the long-term follow-up. Conclusions: It is important to follow-up such patients until 3 years after initial BAE, especially when either ectatic changes of the bronchi on a CT scan or a P-B shunt on angiographic findings are detected.

A Phase II Trial of Gefitinib Monotherapy in Chemotherapy-Naïve Patients of 75 Years or Older with Advanced Non-small Cell Lung Cancer

Background: Gefitinib has shown modest activity in patients with recurrent non-small cell lung cancer (NSCLC) after platinum-based chemotherapy. However, the activity of gefitinib as first-line chemotherapy remains unclear, especially unknown in elderly patients. A multicenter phase II trial was conducted to evaluate the efficacy and tolerability of gefitinib for elderly patients with chemotherapy-naïve NSCLC. Methods: Elderly chemotherapy-naïve patients with advanced NSCLC, ECOG PS of 0–2, and adequate organ functions received 250 mg/day of gefitinib. The primary objective of this study was to determine the objective response rate (RR). Secondary endpoints were tolerability, disease-related symptom using lung cancer subscale (LCS) in FACT-L, progression free survival (PFS) and overall survival (OS). We investigated mutation status of the epidermal growth factor receptor (EGFR) gene in cases with available tumor samples. Results: Fifty patients were enrolled, of whom 49 were eligible. Median age (range) was 80 (75–90) years. Thirty-two patients were female (65%) and 40 patients had adenocarcinoma (82%). The objective RR was 25% (CI 95%, 13–39). Median survival time was 10 months (CI 95%, 7–20) and 1-year survival rate was 50%. The most frequent adverse events were skin disorders (76%). Fifteen patients (30%) experienced toxicities ≥grade 3. There were four patients with possible interstitial lung disease including two treatment-related deaths. Symptom improvement rate using LCS was 49% at 4 weeks of gefitinib therapy. Tumor samples from 17 patients were analyzed for EGFR mutation status. EGFR mutations were detected in tumor tissues from 7 patients, of which 5 had partial responses (71%). Conclusions: Gefitinib monotherapy is effective and relatively well tolerated in chemotherapy-naïve elderly patients with advanced NSCLC. Gefitinib has potential as a first-line therapeutic option in elderly patients with advanced NSCLC.

Diagnostic value of bone‐turnover metabolites in the diagnosis of bone metastases in patients with lung carcinoma

Several biochemical markers of bone formation and bone resorption have been developed recently. The authors evaluated the usefulness of new biomarkers, such as urinary deoxypyridinoline (D‐PYD), serum pyridinoline cross‐linked C‐telopeptides of Type I collagen (1CTP), and urinary pyridinoline cross‐linked N‐telopeptides of Type I collagen (NTx), in the assessment of bone metastases in patients with lung carcinoma.

Second-line chemotherapy with weekly cisplatin and irinotecan in patients with refractory lung cancer.

Cisplatin and irinotecan are reported to act synergistically. The authors have conducted a phase II trial combining cisplatin and irinotecan in patients with refractory lung cancer to evaluate the activity and safety of the regimen. Twenty-one patients, who had not responded to prior platinum-based chemotherapy, were entered into the study. Both cisplatin (30 mg/m2) and irinotecan (60 mg/m2) were administrated on days 1, 8, and 15, and the regimen was repeated every 28 days. There were six partial responses, and the response rate was 29% (95% confidence interval, 11.3%-52.2%). The median survival time of all patients was 32 weeks, and 1-year and 2-year survival rates were 43% and 11%, respectively. Major toxicities were hematologic; leukopenia of grades 3 and 4 developed in 43% patients, anemia developed in 38%, and thrombocytopenia developed in 19%. One notable nonhematologic toxicity was diarrhea; which was grade 3 in 38%. The weekly chemotherapy combining cisplatin and irinotecan was active against lung cancer, which is refractory to platinum-based chemotherapy. However, skips of drug administration or dose reduction were necessary in 76% patients during two courses of planned administration, though the ratio of actual dose to scheduled dose was 81%. Dose modification would be necessary to yield better results by this weekly chemotherapy.

Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor–naïve patients with non–small cell lung cancer harboring EGFR mutations

The T790M secondary mutation of the epidermal growth factor receptor (EGFR) gene accounts for 50% to 60% of cases of resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. The prevalence of T790M in EGFR mutation-positive patients who acquire resistance to the irreversible, second-generation EGFR-TKI afatinib has remained unclear, however. We here determined the frequency of T790M acquisition at diagnosis of progressive disease in patients with EGFR-mutated non-small cell lung cancer (NSCLC) treated with afatinib as first-line EGFR-TKI. Among 56 enrolled patients, 37 individuals underwent molecular analysis at rebiopsy. Of these 37 patients, 16 individuals (43.2%) had acquired T790M, including 11/21 patients (52.4%) with an exon 19 deletion of EGFR and 5/13 patients (38.5%) with L858R. None of three patients with an uncommon EGFR mutation harbored T790M. T790M was detected in 14/29 patients (48.3%) with a partial response to afatinib, 1/4 patients (25%) with stable disease, and 1/4 patients (25%) with progressive disease as the best response. Median progression-free survival after initiation of afatinib treatment was significantly (P = 0.043) longer in patients who acquired T790M (11.9 months; 95% confidence interval, 8.7-15.1) than in those who did not (4.5 months; 95% confidence interval, 2.0-7.0). Together, our results show that EGFR-mutated NSCLC patients treated with afatinib as first-line EGFR-TKI acquire T790M at the time of progression at a frequency similar to that for patients treated with gefitinib or erlotinib. They further underline the importance of rebiopsy for detection of T790M in afatinib-treated patients.The T790M secondary mutation of the epidermal growth factor receptor (EGFR) gene accounts for 50% to 60% of cases of resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. The prevalence of T790M in EGFR mutation–positive patients who acquire resistance to the irreversible, second-generation EGFR-TKI afatinib has remained unclear, however. We here determined the frequency of T790M acquisition at diagnosis of progressive disease in patients with EGFR-mutated non–small cell lung cancer (NSCLC) treated with afatinib as first-line EGFR-TKI. Among 56 enrolled patients, 37 individuals underwent molecular analysis at rebiopsy. Of these 37 patients, 16 individuals (43.2%) had acquired T790M, including 11/21 patients (52.4%) with an exon 19 deletion of EGFR and 5/13 patients (38.5%) with L858R. None of three patients with an uncommon EGFR mutation harbored T790M. T790M was detected in 14/29 patients (48.3%) with a partial response to afatinib, 1/4 patients (25%) with stable disease, and 1/4 patients (25%) with progressive disease as the best response. Median progression-free survival after initiation of afatinib treatment was significantly (P = 0.043) longer in patients who acquired T790M (11.9 months; 95% confidence interval, 8.7–15.1) than in those who did not (4.5 months; 95% confidence interval, 2.0–7.0). Together, our results show that EGFR-mutated NSCLC patients treated with afatinib as first-line EGFR-TKI acquire T790M at the time of progression at a frequency similar to that for patients treated with gefitinib or erlotinib. They further underline the importance of rebiopsy for detection of T790M in afatinib-treated patients.

Phase I study of weekly irinotecan combined with weekly cisplatin in patients with advanced solid tumors.

Background: Previous studies have reported a synergistic effect between irinotecan and cisplatin. We have conducted a phase I trial combining these agents to find the optimal dose of irinotecan in combination with a fixed dose of cisplatin. Methods: Patients with advanced solid tumors, aged ≤75 years, performance status ≤2, and adequate organ function were enrolled in this study. They were treated at 4-week intervals with irinotecan plus 20 mg/m2 cisplatin on days 1, 8, and 15. The starting dose of irinotecan of 40 mg/m2 was escalated in 10 mg/m2 increments until a maximum dose of 90 mg/m2 was reached. Results: The recommended dose for phase II studies is 90 mg/m2 of irinotecan and 20 mg/m2 of cisplatin on days 1, 8, and 15. Overall response to the chemotherapy was 35% (95% confidential interval, 19.2–54.6%). Conclusion: This combination seems to be active against lung cancer with acceptable toxicity. A phase II study is now ongoing.

Quantitation of HLA-A*0201 bound tumor associated antigens on a peptide pulsed B cell line.

CTLs recognize 8- to 10-mer peptides on MHC class I molecules. Recent studies have shown that human CTLs kill autologous tumor cells in an HLA-restricted and peptide-specific manner, and that artificial pep- tides can stimulate tumor-specific CTLs both in vitro and in vivo. Accordingly, several human clinical trials using such peptides are ongoing worldwide. In such methods, the amount of peptide-MHC complexes that remain on the cell surface of APCs after peptide administration is crucial, because CTL activation depends on the number of ligated TCRs and co-stimulation. However, it remains uncertain how many peptide-MHC complexes are reconstituted and remain on live cells after peptide administration. We herein examined the binding affinities of five HLA-A*0201 restricted peptides-four TAAs and one HIV antigen-to HLA-A*0201 molecules and their decay rates on a live B cell line using tandem mass spectrometry. Our experiments showed that nearly 10(5) peptide-MHC complexes per cell could be reconstituted on a cell surface by pulsing a high dose of peptide even if the binding affinities were intermediate or low. However, the decay rates observed for these pep- tide-MHC complexes on a B cell line were faster than previously estimated.

Preventive effect of kampo medicine (hangeshashin-to, TJ-14) plus minocycline against afatinib-induced diarrhea and skin rash in patients with non-small cell lung cancer

Purpose Diarrhea and oral mucositis induced by afatinib can cause devastating quality of life issues for patients undergoing afatinib treatment. Several studies have shown that hangeshashin-to (TJ-14) might be useful for chemotherapy-induced diarrhea and oral mucositis. In this study, we investigated the prophylactic effects of TJ-14 for afatinib-induced diarrhea and oral mucositis and minocycline for afatinib-induced skin rash. Patients and methods First- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors have become the standard first-line treatment in patients with EGFR-mutated non-small cell lung cancer. The incidence of diarrhea was higher with afatinib than with gefitinib, and we conducted a single-arm Phase II study with afatinib. Patients who had previously undergone treatment with afatinib were ineligible. Both TJ-14 (7.5 g/day) and minocycline (100 mg/day) were administered simultaneously from the start of afatinib administration. The primary end point was the incidence of ≥ grade 3 (G3) diarrhea (increase of ≥7 stools/day over baseline) during the first 4 weeks of treatment. The secondary end points were the incidence of ≥ G3 oral mucositis (severe pain interfering with oral intake) and

Polycyclic Aromatic Hydrocarbon Carcinogens Increase Ubiquitination of p21 Protein after the Stabilization of p53 and the Expression of p21

G3 skin toxicity (severe or medically significant but not immediately life-threatening). Results A total of 29 patients (nine men and 20 women; median age, 66 years; performance status, 0/1/2: 18/10/1) were enrolled from four centers. Four patients had undergone prior treatment with chemotherapy, including gefitinib or erlotinib. In all, 20 (68.9%) patients and one (3.4%) patient had diarrhea of any grade and ≥ G3, respectively. One (3.4%) patient had ≥ G3 oral mucositis; no patients had ≥ G3 skin rash. A total of 18 (62%) of the 29 patients achieved a partial response. Conclusion The present study indicated a trend in which TJ-14 reduced the risk of afatinib-induced diarrhea and minocycline reduced the risk of afatinib-induced skin rash.