British Journal of Surgery

Peng, Wei; Zhang, Xiaoyun; Li, Chuan; Zhu, Xinrui; Li, Qiu; Chen, Weixia; Lu, Wusheng; Liu, Chang; Zhou, Yongjie; Shi, Yujun; Wen, Tianfu; Sun, Xin

doi: 10.1093/bjs/znac334pmid: 36164981

Introduction Most patients with hepatocellular carcinoma (HCC) are diagnosed with intermediate- or advanced-stage disease1 but resection with clear margins offers the best opportunity for cure2. Conversion therapy (to make the tumour resectable) has not been used routinely because of lack of evidence3. The present study described the process of conceptualization, preparation, and implementation of a novel conversion therapy strategy using the IDEAL (Idea, Development, Exploration, Assessment, Long-term study) framework4. Methods This prospective, single-arm, single-centre, IDEAL phase 1 study (10 August 2020 and 10 January 2021) was approved by the ethics committee of West China Hospital (2020-836). It was the initial component of a prospective clinical trial that was registered with ClinicalTrials.gov (NCT04997850). Salvage liver resection after a lenvatinib plus transarterial chemoembolization (TACE) and programmed cell death protein 1 (PD-1) inhibitor (LEN-TAP) strategy for unresectable HCC (uHCC) was initiated after several meetings of the multidisciplinary team for HCC of West China Hospital. Details of the conceptualization of LEN-TAP, patient selection and study design, institutional review board approvals and patient consent, prospective database, LEN-TAP regimen, safeguards, efficacy assessment, and salvage liver resection after LEN-TAP are available in the supplementary material. Results Six of seven patients had advanced HCC with macrovascular invasion. Baseline characteristics are summarized in Table S1. After LEN-TAP therapy, a complete response was recorded in two patients, a partial response in four, and one patient had progressive disease (Table S2 and Fig. S1). Four of six patients who achieved a partial or complete response successfully underwent salvage liver resection. Images obtained before LEN-TAP therapy and before surgery, and photographs of resected specimens are shown in Fig. 1. The other two patients with a partial response did not undergo salvage liver resection because of decompensated liver function (ascites, 25.4 per cent indocyanine green retention at 15 min) and cavernous transformation of the portal vein. Fig. 1 Open in new tabDownload slide Images showing radiological changes and resected specimens for patients who received LEN-TAP therapy a Four patients successfully underwent salvage liver resection. The target lesion and tumour thrombus (indicated by arrows) shrank after treatment. b Three patients did not receive salvage liver resection. A new lesion (indicated by arrow) was found in patient 2 after treatment, target lesion and tumour thrombus (indicated by arrows) and an ongoing partial response was recorded in patients 1 and 4. LEN-TAP, lenvatinib, transarterial chemoembolization, and programmed cell death protein 1 inhibitor therapy. After a median follow-up of 19 months, one patient had died from HCC progression, whereas the other patients remained alive without recurrence or progression (Fig. 2). Adverse events after LEN-TAP therapy and perioperative outcomes for patients who received salvage liver resection are shown in Tables S3 and S4. Fig. 2 Open in new tabDownload slide Survival among patients who received LEN-TAP therapy a Overall (OS) and progression-free (PFS) survival time for patients who did not receive salvage liver resection. b Programmed cell death protein 1 (PD-1) cycles before surgery, pathological response, and survival time for patients who successfully underwent salvage liver resection. LEN-TAP, lenvatinib, transarterial chemoembolization, and PD-1 inhibitor therapy; RFS, recurrence-free survival; pMR, pathological major response; pCR, pathological complete response. Two specific goals of safety and preliminary efficacy of LEN-TAP conversion therapy were achieved in this IDEAL phase 1 study. Figure S2 summarizes the process for evolution of the LEN-TAP strategy. Discussion The IDEAL framework provides methodological guidance for rigorous stepwise complex therapeutic interventions5. LEN-TAP conversion therapy could efficiently convert uHCC to resectable disease with manageable adverse events, and salvage liver resection could offer a favourable survival benefit. Clinical investigators have explored the use of lenvatinib, a tyrosine kinase inhibitor, for patients with uHCC6,7. Their results indicated that a survival benefit might be provided by R0 resection after lenvatinib therapy, but with a low efficacy of conversion. Even though TACE was not recommended for patients with advanced HCC according to the Barcelona Clinic Liver Cancer (BCLC) staging system, some studies8–11 found TACE to be feasible and effective in such patients. Moreover, TACE was recommended for selected patients with advanced HCC in Japanese and Chinese guidelines12–14. In the LAUNCH trial15, the median overall survival time reached 17.8 months with lenvatinib and TACE. Other studies16–18 have reported positive results. A retrospective study19 regarding conversion therapy comprising lenvatinib, TACE, and PD-1 inhibitors reported salvage resection in 29 of 62 patients with uHCC after this triple therapy. The IDEAL framework here allowed introduction of salvage liver resection after LEN-TAP strategy in an evidence-based manner without exposing patients to unacceptable risk. Funding The authors have no funding to declare. Acknowledgements W. Peng and X. Zhang contributed equally to this work . Disclosure W. Peng reports receiving lecture fees from Bayer, Merk, Roche, Hengrui, SciClone. X. Zhang received grant support from Innovent, Eisai and lecture fees from Bayer, Merk, Roche, Hengrui. C. Li received consulting fees from Bayer and Merk. T. Wen reports receiving grant support from AstraZeneca, Zelgen, Merk, Roche, Eisai and Innovent, advisory board fees and lecture fees from Bayer, Merk, Roche, Hengrui. No other potential conflict of interest was reported. Supplementary material Supplementary material is available at BJS online. Data Availability The raw data for this article is available upon request. References 1 Park JW , Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study . Liver Int 2015 ; 35 : 2155 – 2166 Google Scholar Crossref Search ADS PubMed WorldCat 2 Lau WY , Ho SKW, Yu SCH, Lai ECH, Liew CT, Leung TWT. Salvage surgery following downstaging of unresectable hepatocellular carcinoma . Ann Surg 2004 ; 240 : 299 – 305 Google Scholar Crossref Search ADS PubMed WorldCat 3 Sun HC , Zhou J, Wang Z, Liu X, Xie Q, Jia W et al. Alliance of liver cancer conversion therapy CoLCotCA-CA. Chinese expert consensus on conversion therapy for hepatocellular carcinoma (2021 edition) . Hepatobiliary Surg Nutr 2022 ; 11 : 227 – 252 Google Scholar Crossref Search ADS PubMed WorldCat 4 McCulloch P , Cook JA, Altman DG, Heneghan C, Diener MK, Group I. IDEAL Framework for surgical innovation 1: the idea and development stages . BMJ 2013 ; 346 : f3012 Google Scholar Crossref Search ADS PubMed WorldCat 5 Hirst A , Philippou Y, Blazeby J, Campbell B, Campbell M, Feinberg J et al. No surgical innovation without evaluation: evolution and further development of the IDEAL framework and recommendations . Ann Surg 2019 ; 269 : 211 – 220 Google Scholar Crossref Search ADS PubMed WorldCat 6 Kudo M , Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial . Lancet 2018 ; 391 : 1163 – 1173 Google Scholar Crossref Search ADS PubMed WorldCat 7 Shindoh J , Kawamura Y, Kobayashi Y, Kobayashi M, Akuta N, Okubo S et al. Prognostic impact of surgical intervention after lenvatinib treatment for advanced hepatocellular carcinoma . Ann Surg Oncol 2021 ; 28 : 7663 – 7672 Google Scholar Crossref Search ADS PubMed WorldCat 8 Chung GE , Lee JH, Kim HY, Hwang SY, Kim JS, Chung JW et al. Transarterial chemoembolization can be safely performed in patients with hepatocellular carcinoma invading the main portal vein and may improve the overall survival . Radiology 2011 ; 258 : 627 – 634 Google Scholar Crossref Search ADS PubMed WorldCat 9 Xiang X , Lau WY, Wu ZY, Zhao C, Ma YL, Xiang BD et al. Transarterial chemoembolization versus best supportive care for patients with hepatocellular carcinoma with portal vein tumor thrombus: a multicenter study . Eur J Surg Oncol 2019 ; 45 : 1460 – 1467 Google Scholar Crossref Search ADS PubMed WorldCat 10 Luo J , Guo RP, Lai EC, Zhang YJ, Lau WY, Chen MS et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a prospective comparative study . Ann Surg Oncol 2011 ; 18 : 413 – 420 Google Scholar Crossref Search ADS PubMed WorldCat 11 Reig M , Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update . J Hepatol 2022 ; 76 : 681 – 693 Google Scholar Crossref Search ADS PubMed WorldCat 12 Kudo M , Kawamura Y, Hasegawa K, Tateishi R, Kariyama K, Shiina S et al. Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 update . Liver Cancer 2021 ; 10 : 181 – 223 Google Scholar Crossref Search ADS PubMed WorldCat 13 Zhou J , Sun H, Wang Z, Cong W, Wang J, Zeng M et al. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 edition) . Liver Cancer 2020 ; 9 : 682 – 720 Google Scholar Crossref Search ADS PubMed WorldCat 14 Sergio A , Cristofori C, Cardin R, Pivetta G, Ragazzi R, Baldan A et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness . Am J Gastroenterol 2008 ; 103 : 914 – 921 Google Scholar Crossref Search ADS PubMed WorldCat 15 Peng Z , Fan W, Zhu B, Wang G, Sun J, Xiao C et al. Lenvatinib combined with transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma: a phase III, randomized clinical trial (LAUNCH) . J Clin Oncol 2022 : Jco2200392 Google Scholar OpenURL Placeholder Text WorldCat 16 Chen S , Wu Z, Shi F, Mai Q, Wang L, Wang F et al. Lenvatinib plus TACE with or without pembrolizumab for the treatment of initially unresectable hepatocellular carcinoma harbouring PD-L1 expression: a retrospective study . J Cancer Res Clin Oncol 2022 ; 148 : 2115 – 2125 Google Scholar Crossref Search ADS PubMed WorldCat 17 Dendy MS , Ludwig JM, Stein SM, Kim HS. Locoregional therapy, immunotherapy and the combination in hepatocellular carcinoma: future directions . Liver Cancer 2019 ; 8 : 326 – 340 Google Scholar Crossref Search ADS PubMed WorldCat 18 Kimura T , Kato Y, Ozawa Y, Kodama K, Ito J, Ichikawa K et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model . Cancer Sci 2018 ; 109 : 3993 – 4002 Google Scholar Crossref Search ADS PubMed WorldCat 19 Wu JY , Yin ZY, Bai YN, Chen YF, Zhou SQ, Wang SJ et al. Lenvatinib combined with anti-PD-1 antibodies plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: a multicenter retrospective study . J Hepatocell Carcinoma 2021 ; 8 : 1233 – 1240 Google Scholar Crossref Search ADS PubMed WorldCat Author notes Presented in part to the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, San Francisco, USA, January 2022. Abstract was published in Journal of Clinical Oncology 2022 40:4_suppl, 453-453. © The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: [email protected]

Che, Yun; Luo, Zhiwen; Cao, Yanan; Sun, Nan; Xue, Qi; He, Jie

doi: 10.1093/bjs/znac335pmid: 36205121

Introduction This research aimed to identify which subtype of pulmonary large-cell neuroendocrine carcinoma (LCNEC) could benefit from adjuvant chemotherapy (aCT). Unlike other histological types of lung cancer, LCNEC accounts for only 1–3 per cent of all lung cancers with poor prognosis1,2. Neuroendocrine lung tumours consist of typical and atypical carcinoids, which are low-grade tumours, whereas LCNECs and small-cell lung carcinomas (SCLCs) are high-grade tumours. Owing to its rarity, the standard regimen for LCNEC remains controversial, as some physicians favour an SCLC-type regimen, whereas others prefer non-SCLC-type treatment3. Therefore, efforts are ongoing to establish gene expression, specifically for RB1 gene4, activating mutations, and signalling pathways to identify patients with LCNEC5. No effective biomarkers have been reported to date for predicting the superior outcome of aCT in patients with LCNEC4,5. The immune status of tumour cells (TCs) and tumour-infiltrating lymphocytes (TILs) is critical to chemotherapy effectiveness6. Programmed death ligand 1 (PD-L1) expression may predict response to aCT in patients with LCNEC and was assessed here. Methods The study was performed in accordance with the Declaration of Helsinki. All data were analysed anonymously. The Institutional Review Board of National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences, approved this study (2022060809432402). Patients Patients with LCNEC who received surgical treatment (2010–2019) at the National Cancer Centre in China were reviewed retrospectively. The diagnosis of LCNEC was confirmed by two independent reviewers based on the neuroendocrine lung tumour classification in resection specimens7. Patients with preoperative clinical stage below IIB proceeded directly to surgery. Among those with preoperative clinical stage IIIA disease (including cN2), surgery was undertaken in suitable patients after multidisciplinary team discussion. Patients who met the following criteria were excluded: no formalin-fixed paraffin-embedded (FFPE) specimens available; lost to follow-up; follow-up less than 12 months; postoperative treatment uncertainty; died within 3 months after surgery; or underwent other treatment modalities. Patients with complete pathological tissue samples and detailed clinicopathological and prognostic information (overall survival (OS) time) were selected. Immunohistochemistry FFPE tissues were subjected to immunohistochemical (IHC) staining for PD-L1 (22C3; DAKO, Carpinteria, CA 93013, USA). Clinical data are shown in Table S1. PD-L1 expression in the samples was calculated using the HALO digital pathology software platform. The classifier block in HALO v3.0.311.314 analytics software was applied to distinguish TCs from TILs (Fig. S1). An Indica Labs—Multiplex IHC v2.2.0 block was used to count the number of positive cells, total cell number, and, finally, to calculate the percentages of positively stained cells. Statistical analysis Associations between PD-L1 expression and clinical factors were evaluated using χ2 tests. Cox regression models and Kaplan–Meier survival curves were used to compare outcomes between patient groups. OS was calculated from the date of surgery to the date of death or end of follow-up. All statistical tests were two-sided, and P < 0.050 was deemed statistically significant. The best cut-off values for continuous variables were calculated using X-tile software version X86 (Yale University, USA) and the R survminer package (R Foundation for Statistical Computing, Vienna, Austria). Microsoft® Excel version 2016 (Microsoft, Redmond, WA, USA), SPSS® version 25.0 (IBM, Armonk, NY, USA) and R Studio version 3.6.1 software packages were used for data analysis. Results and discussion Of 173 patients, 76 with complete pathological tissue samples and detailed clinicopathological and prognostic information (OS time) were identified. After quality control, 76 patients with and without aCT (surgery + chemotherapy versus surgery alone), comprising 47 and 29 patients respectively, were included in the evaluation of PD-L1 expression (Fig. S2). Because both TCs and TILs expressed PD-L1, the positive cell rate of PD-L1 in TCs and TILs was calculated by the HALO platform. Patients were divided into groups with high PD-L1 in TCs (19 patients; over 11.2 per cent of cells), low tumour PD-L1 (28 patients; less than 11.2 per cent), high PD-L1 in TILs (18 patients; over 26.9 per cent), and low PD-L1 in TILs (29 patients; less than 26.9 per cent) (Figs S3 and S4). Associations between the clinical data for patients with LCNEC and PD-L1 expression are shown in Table S1. The association between OS and PD-L1 levels in patients with LCNEC who received aCT was evaluated by Kaplan–Meier analysis. Patients with high tumour PD-L1 levels had significantly shorter OS (P < 0.001) (Fig. 1a), but PD-L1 in TILs had no relationship with OS (P = 0.92) (Fig. 1d). High tumour PD-L1 levels showed strong predictive ability for OS (3-year OS: area under the curve (AUC) 0.816; 5-year OS: AUC 0.783) (Fig. 1b). Additionally, the receiver operating characteristic (ROC) curve of PD-L1 in TCs for 5-year OS was compared with that for the lung cancer staging system. The data demonstrated that the predictive ability of TC PD-L1 for OS outperformed that of the tumour staging system (Fig. 1c). However, PD-L1 in TILs had no value as prognostic predictor (Fig. 1d–f). TC PD-L1 was a predictor of OS independently of other factors, including sex, age, size, and pTNM stage (Table S2). Fig. 1 Open in new tabDownload slide Impact of programmed death ligand 1 in tumour cells and tumour-infiltrating lymphocytes on overall survival and predictive ability in patients with large-cell neuroendocrine carcinoma who underwent adjuvant chemotherapy and surgery a Overall survival (OS) according to programmed death ligand 1 (PD-L1) expression level in tumour cells (TCs); b receiver operating characteristic (ROC) curves for ability of PD-L1 in TCs to predict OS; c ROC curves for ability of PD-L1 in TCs versus lung staging system to predict 5-year OS; d OS according to PD-L1 expression level in tumour-infiltrating lymphocytes (TILs); e ROC curves for ability of PD-L1 in TILs to predict OS; and f ROC curves for ability of PD-L1 in TILs versus lung staging system to predict 5-year OS. AUC, area under curve. a P < 0.001, b P = 0.92 (log rank test). As LCNEC is rare, there is a lack of extensive literature and RCTs definitively describing an optimal treatment approach3–8. Although discordant results have been reported, chemotherapy appears to provide an additional benefit in early-stage LCNEC9. Among the 47 patients with LCNEC who had aCT in the present cohort, 26 received a SCLC-type regimen and 21 a Non-Small Cell Lung Cancer-type regimen. There was no survival difference between the two chemotherapy regimens (Fig. S5). The surgery group had better OS than the surgery + aCT group (Fig. 2a). However, multivariate Cox regression analysis demonstrated that aCT was not an independent prognostic factor (Table S3). The groups showed no difference in PD-L1 expression (Fig. S6). In the group with high PD-L1 levels in TCs, patients who received aCT had significantly shorter OS than those who underwent surgical treatment alone (P = 0.002) (Fig. 2b). There was a significant survival difference between the surgery + aCT versus surgery alone groups only in the TC PD-L1-positive subgroup (HR 4.39, 95 per cent c.i. 1.06 to 18.12; P = 0.041) (Tables S4–S8). In the TC PD-L1-positive cohort, the surgery + aCT group had a dramatically worse prognosis among patients with early-stage disease, poor differentiation, or smokers (Fig. S7). Fig. 2 Open in new tabDownload slide Overall survival curves for patients with large-cell neuroendocrine carcinoma according to treatment modality in whole cohort and subgroups based on expression level of programmed death ligand 1 in tumour cells and tumour-infiltrating lymphocytes a Whole cohort, b patients with high programmed death ligand 1 (PD-L1) expression in tumour cells (TCs), c patients with low PD-L1 expression in TCs, d patients with high PD-L1 expression in tumour infiltrating lymphocytes (TILs) and e patients with low PD-L1 expression in TILs. aCT, adjuvant chemotherapy. a P = 0.017, b P = 0.002, c P =0.78, d P =0.006, e P = 0.34 (log rank test). Among patients with low PD-L1 expression, OS rates in those who received aCT were similar to those in patients who underwent surgery alone (Figs 2c and 2e). Although patients with high PD-L1 levels in TILs who recieved aCT had shortened OS (Fig. 2d), the 50 per cent OS time was much shorter in the cohort with high PD-L1 levels in TCs. These results showed that patients with LCNEC and high PD-L1 levels in TCs did not benefit from aCT. Funding This work was supported by the National Natural Science Foundation of China (82002610, 82002432); Beijing Hope Run Special Fund of Cancer Foundation of China (LC2019B18, LC2021L01, LC2021B12); Beijing Municipal Science & Technology Commission (Z211100002921058); Beijing Natural Science Foundation (J20010); CAMS Innovation Fund for Medical Sciences (CIFMS) (2020-I2M-C&T-B-071); and China Scholarship Council (CSC) (202106210312). Acknowledgements Yun Che, Zhiwen Luo, and Yanan Cao contributed equally to this work. Disclosure The authors declare no conflict of interest. Supplementary material Supplementary material is available at BJS online. Data Availability Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. References 1 Zheng R , Zhang S, Zeng H, Wang S, Sun K, Chen R et al. Cancer incidence and mortality in China, 2016 . J Natl Cancer Cent 2022 ; 2 : 1 – 9 Google Scholar Crossref Search ADS WorldCat 2 Derks JL , Rijnsburger N, Hermans BCM, Moonen L, Hillen LM, von der Thüsen JH et al. Clinical–pathologic challenges in the classification of pulmonary neuroendocrine neoplasms and targets on the horizon for future clinical practice . J Thorac Oncol 2021 ; 16 : 1632 – 1646 Google Scholar Crossref Search ADS PubMed WorldCat 3 Derks JL , Speel EM, Dingemans AC. Adjuvant chemotherapy in patients with stage I–IIIA large-cell neuroendocrine carcinoma: should a different approach be applied than for small-cell lung cancer? J Clin Oncol 2021 ; 39 : 1508 – 1509 Google Scholar Crossref Search ADS PubMed WorldCat 4 Derks JL , Leblay N, Thunnissen E, van Suylen RJ, den Bakker M, Groen HJM et al. Molecular subtypes of pulmonary large-cell neuroendocrine carcinoma predict chemotherapy treatment outcome . Clin Cancer Res 2018 ; 24 : 33 – 42 Google Scholar Crossref Search ADS PubMed WorldCat 5 Zhuo M , Guan Y, Yang X, Hong L, Wang Y, Li Z et al. The prognostic and therapeutic role of genomic subtyping by sequencing tumor or cell-free DNA in pulmonary large-cell neuroendocrine carcinoma . Clin Cancer Res 2020 ; 26 : 892 – 901 Google Scholar Crossref Search ADS PubMed WorldCat 6 Zhang Z , Zhang C, Zhang G, Luo Y, Xue L, Zeng Q et al. Tumor-infiltrating CD8+ T cell is prognostic and predicts adjuvant chemotherapy benefit in patients with limited-stage small cell esophageal carcinoma . Clin Transl Med 2021 ; 11 : e456 Google Scholar PubMed OpenURL Placeholder Text WorldCat 7 Travis WD , Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB et al. The 2015 World Health Organization classification of lung tumors . J Thorac Oncol 2015 ; 10 : 1243 – 1260 Google Scholar Crossref Search ADS PubMed WorldCat 8 Petrella F , Bardoni C, Casiraghi M, Spaggiari L. The role of surgery in high-grade neuroendocrine cancer: indications for clinical practice . Front Med (Lausanne) 2022 ; 9 : 869320 Google Scholar Crossref Search ADS PubMed WorldCat 9 Dresler MCM , Ritter MJH, Patterson MGA, Ross PE, Bailey RMS, Wick MMR. Clinical–pathologic analysis of 40 patients with large cell neuroendocrine carcinoma of the lung . Ann Thorac Surg 1997 ; 63 : 180 – 185 Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: [email protected]

Crumplin, Michael K H

doi: 10.1093/bjs/znac380pmid: 36346715

Intraoperative and postoperative bleeding and sepsis are two surgical complications that can threaten any surgical procedure. To combat haemorrhage, a couple of centuries ago, pressure (digital or tourniquet) and the use of a few crude tools such as primitive sprung artery forceps or a tenaculum (a sharp hook to transfix and ease out a prominent vessel) followed by ligature were often unsuccessful when complicated by sepsis or inadequate application. Haemostats, arterial forceps, clamps or peans (named after Jules-Emile Péan, 1830–1898, a Parisian surgeon) are pivoted instruments that allow a variable force to crush and control blood vessels. Although the technique of clamping a vessel before ligation may be attributed to Galen, it was Ambroise Paré (1510–1590), a brilliant French Renaissance surgeon, who is generally credited with the technique, in addition to abandoning the use of the actual cautery (that is hot irons or boiling oil) for haemostasis. As anaesthesia allowed calmer and more protracted operations, varied designs of dedicated artery forceps evolved, incorporating a catch and release mechanism situated below the finger bows. The tips of the forceps are serrated in one direction or another for improved grip. As time passed, finer artery forceps were produced. Following application of these instruments, single or double ligatures of silk, linen or catgut were applied before the instrument was released. As surgery became increasingly complex, larger vessels needed to be temporarily occluded or controlled, so a varied selection of lighter, springier, occlusive, non-crushing instruments evolved. This permitted safer cardiac, vascular, and reconstructive surgery, and appropriate control of bleeding. With the advent of free tissue grafts and microanastomoses, very fine atraumatic clips are used. With all such instruments, care is required in accurate application, timely controlled release. and also to pick up and grasp the correct amount of tissue. Artery forceps The Spencer Wells artery forceps (Fig. 1) must feature as one instrument with a notable reputation. Introduced in 1879, it was one of the first dedicated hinged robust artery clips that appeared on the surgical scene. When compressed, its ridged tips can exert a force of 40 N/m². Many designs and sizes of similar forceps have emerged, adapting to varying specialty needs. Clipping the delicate vessels during a thyroidectomy or paediatric procedures will require a finer haemostat (Fig. 2) than clamping more substantial vascular pedicles, such as during hysterectomy or bowel resection. An instrument used in the latter might incorporate an interlocking tooth at its distal point for added security. Fig. 1 Open in new tabDownload slide Spencer Wells artery forceps © 2014 All rights reserved. Courtesy of Surtex Instruments Ltd. Fig. 2 Open in new tabDownload slide Dunhill artery forceps © 2014 All rights reserved. Courtesy of Surtex Instruments Ltd. Sir Thomas Spencer Wells (1818–1897) was surgeon to Queen Victoria. He studied in Leeds, Dublin, Paris, and at St Thomas’ Hospital. After serving in the Royal Navy in Malta, he worked in London and became President of the English College. He specialized in ophthalmic, obstetric, and abdominal surgery. Sir Thomas Dunhill (1876–1957) was an Australian surgeon who worked through the Great War and pioneered surgery for various forms and severity of thyroid goitre, often under local anaesthesia. Thrice appointed a royal surgeon, he repaired Sir Winston Churchill’s hernia. Vascular clamps There is a selection of vascular clamps for application to larger vessels (Figs. 3 and 4). These are usually atraumatic springy steel instruments that allow surgery on, and control of, major vessels requiring anastomosis or tissue resection, for example during hepatic operations. These larger clamps are reasonably atraumatic, allowed for by the finer structure of the instrument, more gentle closing force, and a varied design of the serrations at the tip of the instrument. Such procedures in which these clamps are used might be portocaval anastomosis, or aortic and cardiac surgery. When applying these large clamps in the depth of a wound, care has to be taken not to injure accompanying veins. Useful tools for application after venous injury or for an end-to-side anastomosis on large vessels are the varieties of the Satinski clamp. Here the gentle U-shaped atraumatic tips can be applied on the long axis of the vessel, allowing some continued blood flow during a repair or anastomosis. Fig. 3 Open in new tabDownload slide DeBakey atraumatic aortic clamp © 2014 All rights reserved. Courtesy of Surtex Instruments Ltd. Fig. 4 Open in new tabDownload slide Satinski atraumatic tangential occlusion clamp © 2014 All rights reserved. Courtesy of Surtex Instruments Ltd. Michael DeBakey (1908–2008) was a Lebanese–American cardiovascular surgeon trained in America, France and Germany, and who served in the Second and Korean Wars. He pioneered major vascular surgery, initially making his own Dacron aortic grafts. He performed the first carotid endarterectomy, and was an early champion of coronary artery bypass surgery, and also many other vascular procedures. Victor Satinski (1912–1997) was also an American cardiac surgeon, who made early progress with coronary artery bypass surgery Smaller and microanastomotic vascular clips These are examples of progressively smaller non-crushing vascular clamps used to control bleeding from smaller vessels (Figs 5 and 6). The ‘bulldog’ clip is a well known design, comprising a small sprung cross-over clamp, easily applied and removed by digital pressure. Fig. 5 Open in new tabDownload slide De Bakey atraumatic bulldog clamp © 2014 All rights reserved. Courtesy of Surtex Instruments Ltd. Fig. 6 Open in new tabDownload slide Acland double-vessel microvascular clamp © 2014 All rights reserved. Courtesy of Surtex Instruments Ltd. With use of free full-thickness transfer tissue grafts requiring a new blood supply, microvascular anastomoses are essential. The Acland double-vessel microvascular apparatus allows stable gentle compression and apposition of two ends of very small vessels, and the double clamp is steadied on a bar common to both clamps. Robert Acland (1941–2016) was a pioneer of microvascular and plastic surgery, who left the National Health Service in Scotland to work in the USA. He developed his microvascular clamp as well as employing 10/0 nylon sutures and appropriate needles. He wrote a practical guide to microvascular surgery and an innovative video atlas of human anatomy. Cushing silver clips Of interest in the early days of neurosurgery, Harvey Cushing’s silver wire clips (Fig. 7) were used to gently crush and control bleeding from fragile cerebral vessels. Simply made from cutting V-shaped sections of silver wire, these were gently positioned and tightened with an applicator to the vessel. Fig. 7 Open in new tabDownload slide Cushing silver clips and applicator Courtesy Royal College of Surgeons of England. Harvey Cushing (1869–1939) was an American surgeon famed for developing neurosurgical techniques. He was a meticulous slow surgeon, who pioneered treatment of head injuries in World War I. He championed the use of local anaesthesia and diathermy, and described Cushing’s syndrome. There are tissue forceps and a ventricular cannula named after him. Funding The author has no funding to declare. Disclosure The author declares no conflict of interest. © The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: [email protected]