Chemotherapy following immune checkpoint inhibitors in recurrent or metastatic head and neck squamous cell carcinoma: clinical effectiveness and influence of inflammatory and nutritional factors.

Chemotherapy Distant metastasis Head and neck cancer Immune checkpoint inhibitor Platelet to lymphocyte ratio Recurrent

Journal

Discover. Oncology
ISSN: 2730-6011
Titre abrégé: Discov Oncol
Pays: United States
ID NLM: 101775142

Informations de publication

Date de publication:
29 Aug 2023
Historique:
received: 18 05 2023
accepted: 18 08 2023
medline: 29 8 2023
pubmed: 29 8 2023
entrez: 29 8 2023
Statut: epublish

Résumé

This study aimed to evaluate the clinical effectiveness of chemotherapy following immune checkpoint inhibitors (ICI). The association between inflammatory and nutritional factors and prognosis has also been investigated. We retrospectively reviewed the medical records of recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC) patients who received chemotherapy following ICI therapy. The response rate and survival after chemotherapy, and nutritional and inflammatory factors, were examined. The ICI before chemotherapy was nivolumab in 36 patients (70.6%) and pembrolizumab in 15 patients (29.4%). The chemotherapy regimens consisted of PTX in 32 patients (62.7%), PTX + Cmab in 9 (17.6%), and S1 in 10 (19.6%). The median overall survival (OS) was 20 months (95% CI 12-25), the estimated 12-month OS rate was 63.3%, the median progression-free survival (PFS) was 5 months (CI 4-6), and the 12-month PFS estimate was 8.9%. Univariate analysis significantly correlated Neutrophil-to-Lymphocyte Ratio (NLR), platelet-to-lymphocyte ratio (PLR), controlling nutritional status score (CONUT), and prognostic nutrition index (PNI) with OS and PFS. Additionally, these factors were significantly correlated with OS and PFS in the log-rank tests. Chemotherapy following ICI is highly effective. There were no significant differences in the chemotherapy regimens. Inflammatory and nutritional factors may associate with patient prognosis after chemotherapy.

Identifiants

pubmed: 37642856
doi: 10.1007/s12672-023-00774-4
pii: 10.1007/s12672-023-00774-4
pmc: PMC10465419
doi:

Types de publication

Journal Article

Langues

eng

Pagination

158

Informations de copyright

© 2023. Springer Science+Business Media, LLC.

Références

Jacobs C, Lyman G, Velez-García E, Sridhar KS, Knight W, Hochster H, Goodnough LT, Mortimer JE, Einhorn LH, Schacter L, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992;10:257–63.
pubmed: 1732427 doi: 10.1200/JCO.1992.10.2.257
Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol. 1992;10:1245–51.
pubmed: 1634913 doi: 10.1200/JCO.1992.10.8.1245
Brockstein B, Haraf DJ, Rademaker AW, Kies MS, Stenson KM, Rosen F, Mittal BB, Pelzer H, Fung BB, Witt ME, et al. Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience. Ann Oncol. 2004;15:1179–86.
pubmed: 15277256 doi: 10.1093/annonc/mdh308
Cohen MH, Chen H, Shord S, Fuchs C, He K, Zhao H, Sickafuse S, Keegan P, Pazdur R. Approval summary: cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer. Oncologist. 2013;18:460–6.
pubmed: 23576486 pmcid: 3639534 doi: 10.1634/theoncologist.2012-0458
Hitt R, Irigoyen A, Cortes-Funes H, Grau JJ, Garcia-Saenz JA, Cruz-Hernandez JJ, Spanish H. Neck Cancer Cooperative G: Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Ann Oncol. 2012;23:1016–22.
pubmed: 21865152 doi: 10.1093/annonc/mdr367
Leon X, Hitt R, Constenla M, Rocca A, Stupp R, Kovacs AF, Amellal N, Bessa EH, Bourhis J. A retrospective analysis of the outcome of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck refractory to a platinum-based chemotherapy. Clin Oncol (R Coll Radiol). 2005;17:418–24.
pubmed: 16149284 doi: 10.1016/j.clon.2005.02.014
Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856–67.
pubmed: 27718784 pmcid: 5564292 doi: 10.1056/NEJMoa1602252
Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G, Jr., Psyrri A, Baste N, Neupane P, Bratland A, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394:1915–28.
pubmed: 31679945 doi: 10.1016/S0140-6736(19)32591-7
Matsuo M, Yasumatsu R, Masuda M, Toh S, Wakasaki T, Hashimoto K, Taura M, Uchi R, Nakagawa T. Relationship between immune-related adverse events and the long-term outcomes in recurrent/metastatic head and neck squamous cell carcinoma treated with nivolumab. Oral Oncol. 2020;101: 104525.
pubmed: 31863963 doi: 10.1016/j.oraloncology.2019.104525
Matsuki T, Okamoto I, Fushimi C, Takahashi H, Okada T, Kondo T, Sato H, Ito T, Tokashiki K, Tsukahara K, et al. Real-world, long-term outcomes of nivolumab therapy for recurrent or metastatic squamous cell carcinoma of the head and neck and impact of the magnitude of best overall response: a retrospective multicenter study of 88 patients. Cancers (Basel). 2020;12:3247.
doi: 10.3390/cancers12113427
Cabezas-Camarero S, Cabrera-Martin MN, Merino-Menendez S, Paz-Cabezas M, Garcia-Barberan V, Saiz-Pardo Sanz M, Iglesias-Moreno M, Alonso-Ovies A, Perez-Segura P. Safety and efficacy of cetuximab-based salvage chemotherapy after checkpoint inhibitors in head and neck cancer. Oncologist. 2021;26:e1018–35.
pubmed: 33751752 pmcid: 8176971 doi: 10.1002/onco.13754
Fushimi C, Baba D, Masubuchi T, Yamazaki M, Kitani Y, Kitajima T, Tanaka J, Hanyu K, Tanaka N, Miura K, Tada Y. Weekly cetuximab and paclitaxel for recurrent or metastatic head and neck squamous cell carcinoma. In Vivo. 2020;34:2653–7.
pubmed: 32871796 pmcid: 7652519 doi: 10.21873/invivo.12084
Kurosaki T, Mitani S, Tanaka K, Suzuki S, Kanemura H, Haratani K, Fumita S, Iwasa T, Hayashi H, Yoshida T, et al. Safety and efficacy of cetuximab-containing chemotherapy after immune checkpoint inhibitors for patients with squamous cell carcinoma of the head and neck: a single-center retrospective study. Anticancer Drugs. 2021;32:95–101.
pubmed: 32976215 doi: 10.1097/CAD.0000000000001006
Wakasaki T, Manako T, Yasumatsu R, Hara H, Toh S, Masuda M, Yamauchi M, Kuratomi Y, Nishimura E, Takeuchi T, et al. Effectiveness and safety of weekly paclitaxel and cetuximab as a salvage chemotherapy following immune checkpoint inhibitors for recurrent or metastatic head and neck squamous cell carcinoma: a multicenter clinical study. PLoS ONE. 2022;17: e0271907.
pubmed: 35901098 pmcid: 9333293 doi: 10.1371/journal.pone.0271907
Yasumatsu R, Shimizu Y, Hanai N, Kariya S, Yokota T, Fujii T, Tsukahara K, Ando M, Hanyu K, Ueda T, et al. Outcomes of long-term nivolumab and subsequent chemotherapy in Japanese patients with head and neck cancer: 2-year follow-up from a multicenter real-world study. Int J Clin Oncol. 2022;27:95–104.
pubmed: 34773525 doi: 10.1007/s10147-021-02047-y
Wakasaki T, Yasumatsu R, Uchi R, Taura M, Matsuo M, Komune N, Nakagawa T. Outcome of chemotherapy following nivolumab treatment for recurrent and/or metastatic head and neck squamous cell carcinoma. Auris Nasus Larynx. 2020;47:116–22.
pubmed: 31128940 doi: 10.1016/j.anl.2019.05.001
Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dunlop DJ. Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer. Br J Cancer. 2003;89:1028–30.
pubmed: 12966420 pmcid: 2376960 doi: 10.1038/sj.bjc.6601242
Lin Q, Li C, Lin X, Lin S, Chen W, Chen X, Huang X, Wang D. Prognostic value of controlling nutritional status score in advanced hypopharyngeal cancer. Laryngoscope. 2023. https://doi.org/10.1002/lary.30568 .
doi: 10.1002/lary.30568 pubmed: 37909678
Onodera T, Goseki N, Kosaki G. Prognostic nutritional index in gastrointestinal surgery of malnourished cancer patients. Nihon Geka Gakkai Zasshi. 1984;85:1001–5.
pubmed: 6438478
Luo Z, Zhou L, Balde AI, Li Z, He L, ZhenWei C, Zou Z, Huang S, Han S, Wei Zhou M, et al. Prognostic impact of preoperative prognostic nutritional index in resected advanced gastric cancer: a multicenter propensity score analysis. Eur J Surg Oncol. 2019;45:425–31.
pubmed: 30366877 doi: 10.1016/j.ejso.2018.09.004
Tokunaga R, Sakamoto Y, Nakagawa S, Ohuchi M, Izumi D, Kosumi K, Taki K, Higashi T, Miyamoto Y, Yoshida N, et al. CONUT: a novel independent predictive score for colorectal cancer patients undergoing potentially curative resection. Int J Colorectal Dis. 2017;32:99–106.
pubmed: 27726014 doi: 10.1007/s00384-016-2668-5
Magnes T, Melchardt T, Weiss L, Mittermair C, Neureiter D, Klieser E, Gampenrieder S, Moser G, Gaggl A, Greil R, Egle A. Prognostic score in patients with recurrent or metastatic carcinoma of the head and neck treated with cetuximab and chemotherapy. PLoS ONE. 2017;12: e0180995.
pubmed: 28686697 pmcid: 5501656 doi: 10.1371/journal.pone.0180995
Migita K, Matsumoto S, Wakatsuki K, Ito M, Kunishige T, Nakade H, Kitano M, Nakatani M, Sho M. The prognostic significance of inflammation-based markers in patients with recurrent gastric cancer. Surg Today. 2018;48:282–91.
pubmed: 28836056 doi: 10.1007/s00595-017-1582-y
Ying HQ, Deng QW, He BS, Pan YQ, Wang F, Sun HL, Chen J, Liu X, Wang SK. The prognostic value of preoperative NLR, d-NLR, PLR and LMR for predicting clinical outcome in surgical colorectal cancer patients. Med Oncol. 2014;31:305.
pubmed: 25355641 doi: 10.1007/s12032-014-0305-0
Wakasaki T, Yasumatsu R, Masuda M, Takeuchi T, Manako T, Matsuo M, Jiromaru R, Uchi R, Komune N, Noda T, Nakagawa T. Prognostic biomarkers of salvage chemotherapy following nivolumab treatment for recurrent and/or metastatic head and neck squamous cell carcinoma. Cancers (Basel). 2020;12:2299.
pubmed: 32824226 doi: 10.3390/cancers12082299
Mariani P, Russo D, Maisto M, Troiano G, Caponio VCA, Annunziata M, Laino L. Pre-treatment neutrophil-to-lymphocyte ratio is an independent prognostic factor in head and neck squamous cell carcinoma: meta-analysis and trial sequential analysis. J Oral Pathol Med. 2022;51:39–51.
pubmed: 34797592 doi: 10.1111/jop.13264
Diem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, Templeton AJ, Fruh M. Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer. 2017;111:176–81.
pubmed: 28838390 doi: 10.1016/j.lungcan.2017.07.024
Xu H, He A, Liu A, Tong W, Cao D. Evaluation of the prognostic role of platelet-lymphocyte ratio in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Int Immunopharmacol. 2019;77: 105957.
pubmed: 31677498 doi: 10.1016/j.intimp.2019.105957
Kano S, Homma A, Hatakeyama H, Mizumachi T, Sakashita T, Kakizaki T, Fukuda S. Pretreatment lymphocyte-to-monocyte ratio as an independent prognostic factor for head and neck cancer. Head Neck. 2017;39:247–53.
pubmed: 27617428 doi: 10.1002/hed.24576
Hu B, Yang XR, Xu Y, Sun YF, Sun C, Guo W, Zhang X, Wang WM, Qiu SJ, Zhou J, Fan J. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clin Cancer Res. 2014;20:6212–22.
pubmed: 25271081 doi: 10.1158/1078-0432.CCR-14-0442
Wang YT, Kuo LT, Weng HH, Hsu CM, Tsai MS, Chang GH, Lee YC, Huang EI, Tsai YT. Systemic immune-inflammation index as a predictor for head and neck cancer prognosis: a meta-analysis. Front Oncol. 2022;12: 899518.
pubmed: 35814369 pmcid: 9263088 doi: 10.3389/fonc.2022.899518
Tanoue K, Tamura S, Kusaba H, Shinohara Y, Ito M, Tsuchihashi K, Shirakawa T, Otsuka T, Ohmura H, Isobe T, et al. Predictive impact of C-reactive protein to albumin ratio for recurrent or metastatic head and neck squamous cell carcinoma receiving nivolumab. Sci Rep. 2021;11:2741.
pubmed: 33531609 pmcid: 7854616 doi: 10.1038/s41598-021-82448-1
Ikoma T, Shimokawa M, Matsumoto T, Boku S, Yasuda T, Shibata N, Kurioka Y, Takatani M, Nobuhisa T, Namikawa T, et al. Inflammatory prognostic factors in advanced or recurrent esophageal squamous cell carcinoma treated with nivolumab. Cancer Immunol Immunother. 2022;72:427.
pubmed: 35927359 doi: 10.1007/s00262-022-03265-7
Ignacio de Ulíbarri J, González-Madroño A, de Villar NG, González P, González B, Mancha A, Rodríguez F, Fernández G. CONUT: a tool for controlling nutritional status. First validation in a hospital population. Nutr Hosp. 2005;20:38–45.
pubmed: 15762418
Jiang C, Xiu Y, Zhang S, Yu X, Qiao K, Huang Y. A novel inflammatory and nutritional prognostic scoring system for nonpathological complete response breast cancer patients undergoing neoadjuvant chemotherapy. Dis Markers. 2022;2022:8044550.
pubmed: 36569222 pmcid: 9788886 doi: 10.1155/2022/8044550
Kasymjanova G, MacDonald N, Agulnik JS, Cohen V, Pepe C, Kreisman H, Sharma R, Small D. The predictive value of pre-treatment inflammatory markers in advanced non-small-cell lung cancer. Curr Oncol. 2010;17:52–8.
pubmed: 20697515 pmcid: 2913830
Matsuo M, Yasumatsu R, Masuda M, Toh S, Wakasaki T, Hashimoto K, Jiromaru R, Manako T, Nakagawa T. Inflammation-based prognostic score as a prognostic biomarker in patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with nivolumab therapy. In Vivo. 2022;36:907–17.
pubmed: 35241549 pmcid: 8931916 doi: 10.21873/invivo.12780
Otsuki S, Hori R, Shinohara S, Kojima T, Tamaki H, Asato R, Kitamura M, Ichimaru K, Kitani Y, Kumabe Y, et al. Real-world 2-year long-term outcomes and prognostic factors in patients receiving nivolumab therapy for recurrent or metastatic squamous cell carcinoma of the head and neck. Auris Nasus Larynx. 2022;49:834–44.
pubmed: 35232636 doi: 10.1016/j.anl.2022.02.006
Saleh K, Daste A, Martin N, Pons-Tostivint E, Auperin A, Herrera-Gomez RG, Baste-Rotllan N, Bidault F, Guigay J, Le Tourneau C, et al. Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Eur J Cancer. 2019;121:123–9.
pubmed: 31574417 doi: 10.1016/j.ejca.2019.08.026
Suzuki S, Toyoma S, Kawasaki Y, Koizumi K, Iikawa N, Shiina K, Endo T, Abe T, Kouga T, Yamada T. Clinical outcomes of cetuximab and paclitaxel after progression on immune checkpoint inhibitors in recurrent or metastatic head and neck squamous cell carcinoma. Medicina (Kaunas). 2021;57:1151.
pubmed: 34833369 doi: 10.3390/medicina57111151
Guiard E, Clatot F, Even C, Perreard M, Abdeddaim C, Johnson A, Vauleon E, Rambeau A. Impact of previous nivolumab treatment on the response to taxanes in patients with recurrent/metastatic head and neck squamous cell carcinoma. Eur J Cancer. 2021;159:125–32.
pubmed: 34743067 doi: 10.1016/j.ejca.2021.09.025
Fukuoka O, Saito Y, Mukai T, Hayashi T, Yamamura K, Sakai T, Kobayashi K, Akashi K, Yoshida M, Ando M, Yamasoba T. Efficacy of chemotherapy after immune checkpoint inhibitor discontinuation in head and neck cancer. Laryngoscope. 2023. https://doi.org/10.1002/lary.30851 .
doi: 10.1002/lary.30851 pubmed: 37377185
Ueki Y, Takahashi T, Ota H, Shodo R, Yamazaki K, Horii A. Role of programmed death-ligand 1 in predicting the treatment outcome of salvage chemotherapy after nivolumab in recurrent/metastatic head and neck squamous cell carcinoma. Head Neck. 2020;42:3275–81.
pubmed: 32671898 doi: 10.1002/hed.26374
Matsuo M, Yasumatsu R, Masuda M, Toh S, Wakasaki T, Hashimoto K, Uchi R, Jiromaru R, Sato K, Manako T, Nakagawa T. Drug-induced interstitial lung disease in recurrent and/or metastatic head and neck cancer patients treated with cetuximab and/or nivolumab. Oral Oncol. 2021;113: 105129.
pubmed: 33360023 doi: 10.1016/j.oraloncology.2020.105129
Matsuki T, Okamoto I, Fushimi C, Sawabe M, Kawakita D, Sato H, Tsukahara K, Kondo T, Okada T, Tada Y, et al. Hematological predictive markers for recurrent or metastatic squamous cell carcinomas of the head and neck treated with nivolumab: a multicenter study of 88 patients. Cancer Med. 2020;9:5015–24.
pubmed: 32441463 pmcid: 7367642 doi: 10.1002/cam4.3124
Sakai A, Iijima H, Ebisumoto K, Yamauchi M, Teramura T, Yamazaki A, Watanabe T, Inagi T, Maki D, Okami K. Prognostic value of inflammatory and nutritional biomarkers of immune checkpoint inhibitor treatment for recurrent or metastatic squamous cell carcinoma of the head and neck. Cancers (Basel). 2023;15:2021.
pubmed: 37046684 doi: 10.3390/cancers15072021
Matsumoto H, Horita N, Ito K, Ebina-Shibuya R, Hara Y, Kobayashi N, Kaneko T. Disease control and objective responsive rates in randomized phase II trials evaluating non-first-line chemotherapy for non-small cell lung cancer: a systematic review of 74 trials. Transl Lung Cancer Res. 2021;10:2278–89.
pubmed: 34164275 pmcid: 8182707 doi: 10.21037/tlcr-20-1120
Kassassir H, Karolczak K, Siewiera KM, Wojkowska DW, Braun M, Watala CW. Time-dependent interactions of blood platelets and cancer cells, accompanied by extramedullary hematopoiesis, lead to increased platelet activation and reactivity in a mouse orthotopic model of breast cancer - implications for pulmonary and liver metastasis. Aging (Albany NY). 2020;12:5091–120.
pubmed: 32191918 doi: 10.18632/aging.102933
Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature. 2001;411:380–4.
pubmed: 11357146 doi: 10.1038/35077246
Takenaka Y, Oya R, Kitamiura T, Ashida N, Shimizu K, Takemura K, Yamamoto Y, Uno A. Platelet count and platelet-lymphocyte ratio as prognostic markers for head and neck squamous cell carcinoma: meta-analysis. Head Neck. 2018;40:2714–23.
pubmed: 30102821 doi: 10.1002/hed.25366
Chen N, Li W, Huang K, Yang W, Huang L, Cong T, Li Q, Qiu M. Increased platelet-lymphocyte ratio closely relates to inferior clinical features and worse long-term survival in both resected and metastatic colorectal cancer: an updated systematic review and meta-analysis of 24 studies. Oncotarget. 2017;8:32356–69.
pubmed: 28404961 pmcid: 5458290 doi: 10.18632/oncotarget.16020
Lu C, Gao P, Yang Y, Chen X, Wang L, Yu D, Song Y, Xu Q, Wang Z. Prognostic evaluation of platelet to lymphocyte ratio in patients with colorectal cancer. Oncotarget. 2017;8:86287–95.
pubmed: 29156795 pmcid: 5689685 doi: 10.18632/oncotarget.21141
Ding T, Li W, Liu Y, Liu L, Dong Y. Prognostic value of preoperative controlling nutritional status in hypopharyngeal cancer patients undergoing surgery-oriented comprehensive treatment. Ear Nose Throat J. 2023. https://doi.org/10.1177/01455613221148314 .
doi: 10.1177/01455613221148314 pubmed: 37715691

Auteurs

Akihiro Sakai (A)

Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan. asakai-ygc@umin.ac.jp.

Koji Ebisumoto (K)

Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan.

Hiroaki Iijima (H)

Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan.

Mayu Yamauchi (M)

Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan.

Takanobu Teramura (T)

Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan.

Aritomo Yamazaki (A)

Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan.

Takane Watanabe (T)

Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan.

Toshihide Inagi (T)

Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan.

Daisuke Maki (D)

Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan.

Kenji Okami (K)

Department of Otolaryngology, Head and Neck Surgery, Tokai University, School of Medicine, Isehara, Japan.

Classifications MeSH