Koji Horie

SUMO-1 conjugation to intact DNA topoisomerase I amplifies cleavable complex formation induced by camptothecin

DNA topoisomerase I (Topo1) manages the topological state of DNA. Cleavable complexes, the covalent Topo1–DNA intermediates, become DNA damaged when the catalytic cycles are inhibited by the anti-tumor drug camptothecin (CPT). Intriguingly, Topo1 is modified rapidly and extensively with SUMO-1, a ubiquitin-like protein, in response to CPT. This study shows that the sumoylation enhances the cleavable complex formation and apoptosis induced by CPT. Indeed, substitutions of Lys117 and Lys153, identified as Topo1 sumoylation sites, reduced the CPT-induced cleavable complexes without influencing its in vitro catalytic activity. Consistent with this observation, CPT-induced cleavable complexes of wild-type Topo1 increased in a sumoylation-dependent manner. We also found that Topo1 sumoylation occurred independently of CPT when Topo1 was inactivated by mutation of the catalytic Tyr723. These findings suggested that Topo1 inactivation by CPT treatment can trigger Topo1 sumoylation, leading to enhanced cleavable complex formation.

Monitoring the impact of a national HPV vaccination program in Japan (MINT Study): rationale, design and methods.

We have developed a collaborative hospital-based approach to monitoring the impact of a human papillomavirus vaccine on cervical cancer, its precursor lesions and human papillomavirus type-specific prevalence in Japan. The monitoring will be conducted for a total period of 21 years on women aged <40 who are newly diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia or adenocarcinoma in situ at 21 participating institutes. Women are monitored to determine their vaccine history and will be human papillomavirus-genotyped each year. The primary endpoint is the human papillomavirus16/human papillomavirus18-positive rate in women aged 16-25 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ. The major secondary endpoints are the number of women aged <40 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ, the human papillomavirus type-specific prevalence, and the number of deaths from invasive cervical cancer in women aged <40. Long-term surveillance for human papillomavirus-associated cervical diseases in young females is important for the development of future strategies for cervical cancer prevention in Japan.

Application of deep learning to the classification of images from colposcopy

The objective of the present study was to investigate whether deep learning could be applied successfully to the classification of images from colposcopy. For this purpose, a total of 158 patients who underwent conization were enrolled, and medical records and data from the gynecological oncology database were retrospectively reviewed. Deep learning was performed with the Keras neural network and TensorFlow libraries. Using preoperative images from colposcopy as the input data and deep learning technology, the patients were classified into three groups [severe dysplasia, carcinoma in situ (CIS) and invasive cancer (IC)]. A total of 485 images were obtained for the analysis, of which 142 images were of severe dysplasia (2.9 images/patient), 257 were of CIS (3.3 images/patient), and 86 were of IC (4.1 images/patient). Of these, 233 images were captured with a green filter, and the remaining 252 were captured without a green filter. Following the application of L2 regularization, L1 regularization, dropout and data augmentation, the accuracy of the validation dataset was ~50%. Although the present study is preliminary, the results indicated that deep learning may be applied to classify colposcopy images.

Octreotide Acetate Administration for Malignant Bowel Obstruction Induces Severe Bradycardia in Patients with Terminal Stage Cancer: Two Case Reports

Dear Editor: Octreotide acetate has recently been used in the management of malignant bowel obstruction in patients with terminal stage cancer. Bradycardia is a known side effect of octreotide acetate in carcinoid tumor and acromegaly and other clinical settings, but has not been previously reported in a case of terminal stage cancer. Bradycardia by octreotide acetate mostly occurs at the start of therapy. This report presents two rare cases in which bradycardia developed 6 and 12 days after the start of octreotide acetate administration in a patient with terminal stage cancer.

UGT1A1 genotype-based phase I study for recurrent and refractory gynecologic cancer patients treated with combination therapy of irinotecan and cisplatin (STB-06).

e15503 Background: In addition to polymorphisms of UGT1A1*28, UGT1A1*6 has been recognized as a risk factor for severe irinotecal-related toxicities. We have conducted an UGT1A1 genotype-based dose-escalation study for recurrent and refractory gynecologic cancer patients (pts) treated with combination with irinotecan and cisplatin (CPT-P). METHODS Pts eligible for this study had histologically confirmed uterine cancer or ovarian cancers, who receive CPT-P; a course of therapy consisting of 30-80 mg/m2 of irinotecan on days 1, 8, and 15 and 60 mg/m2 of cisplatin on day 1, q4weeks. According to UGT1A1*28, *6, and *27 polymorphysms, pts were categorized into three groups (wild-type, hetoro-type, homo-type), and three-case cohort study was conducted. Pharmacokinetics of CPT-11, SN-38, SN-38 glucuronide (SN-38G), and platinums were also analyzed. RESULTS During August 2008 and December 2010, 19 pts were enrolled in this study; 14 ovarian cancers and 5 uterine cancers. Genotypes of UGT1A1 were wild in 7 pts, *28 in 4 pts, *6 in 5 pts, *6/*6 in 2 pts, and *6/*28 in 1pt. Recommended dose of irinotecan was determined as 50mg/m2 for wild-type patients, 40mg/m2 for hetero-type patients, and 30mg/m2 for homo-type patients, respectively. Pharmacokinetic analyses revealed both hetero-type and homo-type patients were associated with lower area under time-concentartion curve (AUC) SN-38G to SN-38 (AUCSN-38G/AUCSN-38) compared with wild-type cases, however, there was no significant difference of AUCSN-38 at the recommended dose. CONCLUSIONS The recommended doses of irinotacan for phase II CPT-P regimen according to UGT1A1*28 and *6 genotyping were determined. The results and pharmacokinetic analyses suggested the need of individualized dose of irinotecan, even at a lower dose of the drug.

Clinical significance of UDP-glucurosyltransferase 1A1*6 upon toxicities of combination chemotherapy of irinotecan and cisplatin in gynecologic cancers: A preliminary multi-institutional result

5580 Background: Although the clear impact of UGT1A1*28 on severe irinotecal-related toxicities has been established, the effects of other UGT1A1 polyphisms are not fully understood. Our aim is to ...