Identifying healthy carriers of germline pathogenic variants in high penetrance cancer susceptibility genes offers the potential for risk-reducing surgery. The NHS England National Genomic Test Directory offers germline and somatic testing to patients with certain cancers or rare and inherited diseases, or, in some cases, to their relatives. This review summarises current UK guidelines for risk-reducing surgical interventions available for individuals with no personal history of cancer, who are determined to carry germline pathogenic variants. An electronic literature search of NICE guidelines and PubMed citable articles was performed. NICE guidelines are available for bilateral mastectomy and are currently in development for risk-reducing bilateral salpingo-oophorectomy. Guidelines developed with affiliation to, or through relevant British Surgical Societies or international consensus, are available for risk-reducing hysterectomy, polypectomy, gastrectomy, and thyroidectomy. There is a disparity in the development and distribution of national guidelines for interventions amongst tumour types. Whilst we are focusing on UK guidelines, we anticipate they will be relevant much more generally and so of interest to a wider audience including where there are no national guidelines to refer to. We suggest that, as genetic testing becomes rapidly more accessible, guideline development for interventions should be more closely aligned to those for testing. Germline pathogenic variants (GPVs) in cancer predisposition genes play an important role in cancer susceptibility , 2. The BRCA1/2 testing in ovarian cancer [The NHS GMS is at the forefront of integrating genomic testing into routine care and aims to provide equity of genomic testing, aiming to sequence 500,000 whole genomes in England by 2024 [n cancer . Increasn cancer . With inCurrent management options for carriers of GPVs can include active surveillance, medical, endoscopic, and surgical management. Options for medication which reduces the risk of cancer are currently limited, therefore cancer prevention in this setting is usually in the form of risk-reducing surgery (RRS).This review focuses on summarising the current UK guidelines for risk-reducing surgical interventions available for individuals who are found to have GPVs with no personal history of cancer. It also discusses the implications of increased genomic testing on the management of people found to have GPVs.For the purposes of this review, a GPV is defined as per the Cancer Variant Interpretation Group UK classification , and doeBRCA1, BRCA2, PALB2, ATM, CHEK2), ovarian cancer , gastrointestinal cancers including Lynch syndrome , familial adenomatous polyposis, adenomatous polyposis coli (APC), MUTYH-associated polyposis (MUTYH), Juvenile polyposis syndrome , hereditary diffuse gastric cancer (CDH1), PTEN hamartoma-tumour syndrome (PTEN), Peutz–Jeghers syndrome (STK11), Li Fraumeni syndrome (TP53), and multiple endocrine neoplasia type 2 (RET). Figure GPVs were shortlisted for literature review based on current germline testing being offered by the NHS England National Genomic Test Directory (April 2022) , the UK Clinical guidelines from the National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) were screened to identify any existing recommendations for the management of GPVs. Search terms ‘preventative’, ‘prevention’, ‘prophylaxis’, ‘prophylactic’, ‘surveillance’, ‘risk-reducing’ and ‘genetic’ were used to manually screen both guidelines and guidelines in development.An electronic literature review was performed using PubMed to identify any journal articles summarising UK guidelines for the management of cancer-predisposing genetic syndromes. In the absence of any existing published UK management guidelines, further PubMed searches were performed to identify peer-reviewed publications outlining the management of individual hereditary cancer syndromes. All identified articles published in English language between January 1951 and May 2022 were assessed for suitability. Search terms included are detailed in supplementary table British society guidelines were manually searched via their websites. Following the completion of the literature search, local expertise was sought to ensure no further UK guidelines were missed. Overview of literature search and outcomes is provided in Table For this review, we created a hierarchy of evidence-based available UK guidelines, and the highest level of evidence has been used to summarise current UK guidelines for each hereditary cancer syndrome. NICE guidelines, are linked to the commissioning of services in England, Wales, and Northern Ireland, whilst SIGN guidance applies in Scotland. These have been considered as higher ranking to other guidelines, followed by national or speciality society guidelines, non-British-society-affiliated journal articles and local guidelines or expertise, respectively. This review has been developed with input from consultants in oncology, surgery and clinical genetics. All sub-speciality guidelines have been reviewed by a surgeon of that speciality.BRCA1, BRCA2, PALB2. It can also be indicated for other ‘high risk’ variants, including PTEN, TP53, CDH1 and STK11 [Breast cancer is the most common cancer in women . Approxind STK11 . BRRM isnd STK11 .BRCA1, BRCA2, PALB2, ATM, CHEK2, RAD51C and RAD51D truncating variants) are outlined in the NHS England National Genomic Test Directory which is updated twice per year  [Testing criteria for inherited breast and ovarian cancer (tories/) . Testingtories/)  and the tories/) –20 to caPTEN gene. For individuals with GPVs of the PTEN gene, there is a lifetime risk of developing breast cancer of between 67 and 85% [PTEN GPVs is indicated in affected individuals with clinical features  or in a deceased individual if appropriate tissue is available and no living affected individual is available for genetic testing [PTEN hamartoma-tumour syndrome (PHTS) is a multi-system disorder which predisposes an individual to an increased risk of breast, thyroid and renal cancers. It may also be associated with endometrial, colorectal, and skin cancer. It is caused by GPVs of the  and 85% –25. TestTP53 gene cause a TP53-related cancer syndrome (Li Fraumeni syndrome). It is associated with increased risk of multiple cancers including bone and soft tissue sarcomas, early-onset breast cancer, adrenocortical cancers, and malignant tumours of the central nervous system. Women have a risk of developing breast cancer of up to 85% by 60 years of age, the majority of which is early-onset breast cancer, with median age at diagnosis of 34 years [GPVs in the 34 years . TestingCDH1 tumour suppressor gene are known to cause hereditary diffuse gastric cancer (HDGC) and hereditary lobular breast cancer (HLBC). HLBC is classified as the presence of a CDH1 GPV in either an affected individual or a family with one or more lobular breast cancer cases, but without any diffuse gastric cancer. In those with CDH1 GPV with a personal or familial history of diffuse gastric cancer, this is recategorized as HDGC [CDH1 GPV, there is an estimated 39–55% risk of developing lobular breast cancer by age 80 [GPVs of the  as HDGC . For femy age 80 , 28. Geny age 80 . It can STK11 (LKB1) GPV. It is associated with tumours of the gastrointestinal tract, female reproductive system , breast, pancreas, and biliary tract. There is a lifetime female breast cancer risk of 19.3–54% in PJS, making it borderline for being a high-risk gene especially where no family history of breast cancer [Peutz–Jeghers syndrome (PJS) is a multi-system disorder caused by a t cancer . GeneticThe NHS England National Genomic Test Directory allows testing outside of the criteria; however, it must be deemed appropriate by a specialist MDT .BRCA1, BRCA2 and TP53 GPVs and carriers of PTEN, CDH1 and STK11 GPVs [NICE guidelines stratify breast cancer risk as ‘near population risk’, ‘moderate risk’ and ‘high risk’. These categories have slightly different definitions based upon lifetime risk from age 20 to risk between ages 40 and 50. High risk of breast cancer is defined as a lifetime risk from age 20 of greater than or equal to 30%, a risk between age 40 and 50 of greater than 8% or known carriers of K11 GPVs . GPVs inNICE recommends that all women at high risk should be offered a discussion about BRRM. There are several prerequisites prior to this procedure taking place. All cases should be managed by a multidisciplinary team and should take into consideration individual risk factors including comorbidities, the woman’s current age and life expectancy. Women who are eligible for BRRM should have genetic counselling under the care of a specialist cancer genetic clinic including pre-operative counselling about psychosocial and sexual consequences of BRRM and directed towards support groups. BRRM should be carried out by a surgical team with specialist oncoplastic/breast reconstructive skills . Breast CDH1 carriers state BRRM can be considered in hereditary lobular breast cancer and hereditary diffuse gastric cancer, however it is not generally recommended for those aged under 30 years or over 60 years [STK11 GPVs in the UK [NICE guidelines for BRRM, do not detail the age threshold for performing risk-reducing surgery. US guidelines and Hanson et al. suggest that BRRM should be considered from age 20 for female carriers of TP53 GPVs . Guideli60 years . Risk-re60 years , howevern the UK .BRCA1/2 or TP53 GPV. Annual MRI breast surveillance is available for young women (aged <50 years) with or at high risk of being a BRCA or TP53 carrier who meet set criteria. The PHTS guideline development group of the GENTURIS European Reference Network suggest screening in individuals with PTEN GPVs should ideally be with annual MRI surveillance, however, this is not NICE guidance [The current NHS England breast surveillance programme offers mammographic surveillance every 3 years to all women aged between 50 and 71 in England. For women at a higher than population risk of developing breast cancer additional surveillance is available. NICE guidelines outline breast imaging surveillance, including mammography, offered to women with a moderate- to high risk of breast cancer or those with a known guidance .BRCA1 female carriers [.Medication to reduce the risk of breast cancer is available for women at moderate-to-high risk of breast cancer for up to 5 years. Tamoxifen is a selective oestrogen receptor modulator which offers long period of prevention of breast cancer following 5 years daily use . It is ocarriers , 33.BRCA1, BRCA2, RAD51C, RAD51D and PALB2. Meanwhile, GPVs associated with ovarian cancer but not associated with breast cancer include those found in LS , and BRIP1 [Ovarian cancer can form part of an inherited cancer syndrome with or without association with breast cancer. GPVs which are associated with both ovarian and breast cancer include nd BRIP1 . The Eurnd BRIP1 .SMARCA4 [SMARCA4 testing is outlined in the national genomic test directory, but germline testing is not routinely available [Small cell carcinoma of the ovary, hypercalcaemic type, is a rare and extremely aggressive subtype of ovarian cancer associated with somatic and germline deleterious variants of SMARCA4 , 37. Somvailable . Given tvailable .The NHS England National genomic test directory outlines testing that is appropriate for the affected individual if they have high-grade non-mucinous epithelial ovarian cancer (EOC) at any age or EOC with a family history of EOC (at least one first or second-degree relative or greater than two second- or third-degree relatives). Testing can also be performed on a deceased affected individual if appropriate tissue is available and no affected living relative is available for testing. In inherited ovarian cancer which is associated with breast cancer, this is extended to living unaffected individuals in certain circumstances .BRCA1/2 GPVs [Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is the gold standard for the prevention of ovarian cancer with an 80–96% risk reduction in patients with 1/2 GPVs . RRBSO d1/2 GPVs –40. Conc1/2 GPVs .BRCA1 44% , BRCA2 17% (11–25%) [RAD51C 11% (6–21%), RAD51D 13% (7–23%) [MLH1, MSH2 and MSH6 (LS) 11% (7.4–19.7%), 17.4% (11.8–31.2%) and 10.8% (3.7–38.6%), respectively [PALB2 ~5% (2–10%) and BRIP1 5.8% (3.6–9.1%) [BRCA1 GPVs and those with LS, between 40 and 45 years for those with BRCA2 GPVs, 40 and 50 years for RAD51C or RAD51D carriers and delayed to 45 and 50 years for carriers of BRIP1 or PALB2 [The Royal College of Obstetrics and Gynaecology (RCOG) has produced a summary of guidelines in conjunction with the British Journal of Obstetrics and Gynaecology regarding the role of RRBSO in individuals below the age of natural menopause . RRBSO c(11–25%) , RAD51C  (7–23%) , MLH1, Mectively , PALB2 ~.6–9.1%) , 44. Theor PALB2 .RRBSO is usually undertaken once a woman’s family is complete, although this is considered in the context of her personal circumstances and risk. It is possible to consider the option of fertility preservation with IVF or oocyte freezing, as embryos can be implanted after RRBSO to enable the woman the potential option of completing her family later. For many women RRBSO is performed prior to the age of the natural menopause, resulting in an iatrogenic ‘surgical’ menopause. Consequently, immediate menopausal symptoms are often experienced which may include vasomotor symptoms, mood changes, sleep disturbance, vaginal dryness, and sexual dysfunction. Longer-term consequences of an early menopause include increased risk of cardiovascular disease, osteoporosis, and neurocognitive effects. Hormone replacement therapy (HRT) up to 51 years of age is recommended, in the absence of any contraindication including personal history of breast cancer or venous thromboembolism. It can result in symptom relief and minimises the long-term effect of early menopause; however, it may not completely ameliorate the effects of surgery on sexual function . The impBRCA1/2 GPVs  [The combined oral contraceptive pill (COCP) is a strong protective factor for ovarian cancer in the general population and has been demonstrated to substantially reduce the risk of ovarian cancer in women with GPVs in 19–0.73) , 46. Wom19–0.73) . There i19–0.73) .MLH1, MSH2, MSH6, PMS2 [Lynch syndrome (LS) is associated with GPVs in DNA mismatch repair (MMR) genes including GPVs of H6, PMS2 , 48. GPVH6, PMS2 .In the UK, all new diagnoses of endometrial and colorectal cancer are eligible for tumour immunohistochemistry to identify MMR-deficient or microsatellite instability tumours that may be suggestive of LS. Germline testing can subsequently confirm the presence of GPVs in LS genes. Germline testing is also appropriate for affected individuals or unaffected individuals with family history of LS-related cancer where no affected living individual is available for testing .MLH1, 48.9% in MSH2, 41.1% in MSH6 and 12.8% in PMS2 mutation carriers [The risk of endometrial cancer in LS varies as the genes associated with LS have different penetrance. Cumulative incidence of endometrial cancer at 75 years of age is 37% in carriers .MLH1 (13%), MSH2 (16%)| and MSH6 (11%) GPVs who would have been expected to develop endometrial cancer [MSH2 or MLH1 and after age 40 years for MSH6. There is insufficient evidence for recommending risk-reducing gynaecological surgery for carriers of PMS2 GPVs, however patient representatives have expressed that they should be offered RRS [MSH6 GPVs, the risk of developing ovarian cancer only starts to increase in the post-menopausal years, in contrast to an earlier onset risk for endometrial cancer. In these women, a two-stage RRS approach may be adopted, after counselling, with RRH offered from 40 years, and delayed RRSBO until after 50 years, in circumstances where the woman wishes to avoid surgical menopause and prefers to avoid taking HRT.Risk-reducing hysterectomy (RRH), often performed with bilateral salpingo-oophorectomy (BSO), is an option for patients with LS. RRH at age 40 years has been demonstrated to prevent endometrial cancer by age 50 years in carriers of l cancer . Currentered RRS . The Briered RRS . The BGCered RRS . For womBRCA1 carriers estimated as 3% lifetime risk [Recently, a few studies have reported an increased risk of serous endometrial cancer in ime risk , 54. Thiime risk .There is no population-wide surveillance tool for endometrial cancer in the UK. Current international guidelines do not recommend invasive screening for carriers of MMR GPVs, however there is a recommendation that they may wish to consider the option of annual clinician review from the age of 25 to discuss red flag features of endometrial and ovarian cancer . The BGCThere is strong evidence to show that obesity is associated with a significantly increased risk of endometrial cancer in the general population, whilst use of progestogen-containing hormonal contraceptives, oral or intra-uterine, is potentially associated with a decreased risk . The BGCSeveral syndromes are associated with a predisposition to colorectal cancer. This includes LS, APC-associated polyposis, Peutz–Jeghers Syndrome (PJS), Juvenile Polyposis Syndrome (JPS) and MUTYH-associated polyposis. The British Society of Gastroenterology (BSG), Association of Coloproctology of Great Britain and Ireland (ACPGBI), and the UKCGG have produced extensive guidelines developed in accordance with the BSG NICE-compliant guideline process regarding the management of hereditary colorectal cancer . They reMLH1 48.3%, MSH2 46.6%, MSH6 20.3%, PMS2 10.4%) [LS is the most common heritable cause of colorectal cancer and is associated with 10-48% cumulative risk of developing colorectal cancer by the age of 75 years dependent on the mutated MMR gene  is defined by the presence of GPVs in the APC gene which predisposes an individual to colorectal and upper GI polyposis. The lifetime risk of malignancy in FAP is 100% . GeneticSTK11 and is associated with an increased risk of multiple tumours including a 28–34% cumulative risk of developing colorectal cancer by age 64 years [PJS is a rare autosomal dominant condition which causes hamartomas polyps and mucocutaneous pigmentation. It is caused by a GPV in 64 years , 59. TesSMAD4 or BMPR1A [MUTYH gene and is recessively inherited. It is associated with a 63% cumulative lifetime risk of colorectal cancer at age 60 years [Juvenile polyposis syndrome (JPS) is an autosomal dominant condition associated GPVs in r BMPR1A . It is cr BMPR1A . MUTYH-a60 years .Most interventions for carriers of GPVs which predispose to colorectal cancer involve endoscopic surveillance. However, in some cases, preventative procedures are recommended.In FAP, colonoscopic surveillance is recommended every one to 3 years, commencing from age 12–14 years. Risk-reducing colectomy is an option for patients with FAP. This can be through a total colectomy and subsequent ileorectal anastomosis; or a proctocolectomy with ileal pouch-anal anastomosis; or a proctocolectomy with ileostomy formation. Relative indications for preventative surgical intervention include polyps >10 mm in diameter, high-grade dysplasia within polyps and a significant increase in polyp burden between surveillance examinations . The BSGIn the future, patients with LS may be referred to the NHS Bowel Cancer Screening Programme . In JPS Both NICE and the BSG/ACPGBI/UKCGG recommend daily aspirin to reduce the incidence of LS-related colorectal cancer , 63, 64.CDH1 or CTNNA1 GPV in either an individual with DGC, or unaffected individual with a family pedigree featuring one or more DGC cases in first-degree or second-degree relatives, with or without a personal or family history of lobular breast cancer [Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited condition characterised by a high prevalence of early-onset diffuse-type gastric cancer (DGC) and lobular breast cancer. Recent guidelines from the international gastric cancer linkage consortium (IGCLC) have revised the definition of HDGC to the presence of a t cancer . The cumt cancer , 65.CDH1 GPVs, and soon to include CTNNA1 GPVs, is available for affected individuals who meet the set clinical criteria whereby at least one cancer is histologically confirmed. It can alternatively be performed for a deceased individual where appropriate tissue is available, and no living affected individual is available. Full criteria are detailed in the NHS England National Genomic Test Directory [CTNNA1 testing should be considered for individuals who meet the criteria for genetic testing and no CDH1 GPVs are identified [Genetic testing for irectory . The IGCentified .CDH1 GPVs with a family history of DGC. For carriers of CDH1 GPVs without a family history of DGC, or with a family history of lobular breast cancer only, PTG should still be considered [A recommendation for prophylactic total gastrectomy (PTG) is made for all carriers of nsidered . PTG is nsidered . Surgerynsidered .An overriding principle in PTG is to minimise risk to the patient. Choice of surgical approach should be guided by that least likely to incur a complication as a serious complication following PTG may impact not only the patient but other family members and patients with HDGC in their decision to come forward for surgery. Both minimally invasive and open approaches are well-described with one of the largest series reporting a median one-day improvement in post-operative length of stay with a laparoscopic approach . As the As signet ring cell foci are multifocal and can occur throughout the stomach in HDGC there is no role for endoscopic or limited gastric resection in the treatment of HDGC. Total gastrectomy offers the potential for cure but has several risks and long-term sequalae, therefore it is recommended that patients have pre-operative psychosocial counselling and assessment for comorbid mental illness, particularly eating disorders and addiction . PatientThere are several common consequences of PTG including weight loss, nutritional deficiencies, a risk of dumping syndrome, pancreatic insufficiency, small-intestinal bacterial overgrowth, and hypoglycaemia. Life-long follow-up is needed to monitor for and treat these conditions to reduce their impact on quality of life .Due to the inherent risks of total gastrectomy and the significant lifestyle and nutritional consequences, many patients wish to defer surgery . All patRET gene and has an autosomal dominant inheritance pattern. MEN2 is subcategorised into MEN2a and MEN2b . Both MEN2A/B are associated with medullary thyroid carcinoma. The risk of medullary thyroid cancer is 95% in MEN2a and 100% in MEN2b [PTEN GPVs are associated with a 35% lifetime risk of thyroid cancer development [Multiple endocrine neoplasia type 2 (MEN2) is a multi-system disease associated with GPVs of the in MEN2b . MEN2b ain MEN2b  and is ain MEN2b , 76. In elopment .RET GPVs from those associated with the highest to moderate risk of medullary thyroid carcinoma [RET GPVs with specialist input from clinical genetics [Testing for MEN2 is outlined in the NHS England National Genomic Test Directory . In totaarcinoma . Prenatagenetics .PTEN GPVs is indicated in affected individuals with clinical features  or in a deceased individual if appropriate tissue is available and no living affected individual is available for genetic testing [Testing for  testing .RET GPVs and has dramatically improved outcomes in patients with MEN2. Risk-reducing surgery should be offered to disease-free carriers of RET GPVs. Given that risk-reducing surgery is an option for children, this should be discussed with parents before testing a child for a RET GPV. Timing of risk-reducing surgery is dependent on the risk of the variant such that children with the highest-risk variant, c.2753 T > C (p.Met918Thr), would be recommended to have risk-reducing surgery within the first year of life and those with high-risk RET GPVs (codon 634 changes) are recommended to have risk-reducing surgery before age five Meanwhile, children with moderate risk RET GPVs may delay surgery to beyond 5 years of age [Risk-reducing thyroidectomy is an option for carriers of s of age , and thes of age .RET GPV carriers [PTEN GPVs [Ultrasound neck examination and calcitonin level monitoring are possible and should be introduced in the first year of life for highest-risk RET GPV carriers, or after age 3–5 years for all other carriers , 76. TheTEN GPVs . Risk-reTEN GPVs .This review summarises the current genomic indications for RRS, including mastectomy, bilateral salpingo-oophorectomy, hysterectomy, gastrectomy, polypectomy, and thyroidectomy, as well as highlighting surveillance available for healthy carriers of GPVs. The guidelines vary from NICE guidelines to recommendations by British specialist societies from international consensus guidelines to individual journal article recommendations. Figure BRCA1/2 carriers have increased over the last two decades [The rates of RRS for  decades . However decades .Historically, there has been disparity in the availability of testing across the UK. There are differences in the way in which genomics has become integrated into healthcare across the four nations and the differences in the NHS structure and systems . To the The guidelines for intervention outlined in this review are based upon the presence of a specific GPVs, designated as pathogenic and according to the NHS England National Genomic Test Directory. VUS are variants detected during sequencing, for which there is insufficient evidence for or against pathogenicity . In a reThe Cancer Variant Interpretation Group UK (CanVIG) has developed a detailed framework  regardinVUS and variant reclassification pose a challenge for communication with patients, and a significant problem for clinicians and healthcare systems. CanVIG recently published a framework how to discuss the presence of VUS with patients . The UK Ethical considerations are important when communicating with patients. Surgical prophylaxis is controversial. In most inherited cancer syndromes, the patient will not definitely develop cancer, while surgery is not always guaranteed to prevent the development of cancer and can have life-changing implications. There must be careful consideration of the risk of developing cancer balanced against the effectiveness of a surveillance programme and the morbidity of surgical intervention and potential alternative management strategies. Effective communication is vital when discussing risk with healthy individuals to enable them to make an informed decision. Genomic medicine services often provide letters or leaflets for affected patients carrying GPVs to share with relatives whom it may affect. However, on rare occasions, known carriers may refuse to share information with at-risk relatives, which is ethically challenging. The joint committee on Genomics in Medicine outlines how to approach these situations and, in line with GMC guidance, when it is appropriate to break confidentiality and how to disclose to affected relatives without disclosing confidential information . With thThe UK is at the forefront of integrating genomic testing into routine clinical care . Many chThis review summarises the current indications for risk-reducing surgical procedures for healthy carriers of GPVs. There is currently a disparity in the development and distribution of national guidelines for interventions across tumour sites. For example, there are well-established but outdated NICE guidelines on the role of BRRM, but little guidance on the role of RRS in MEN2. There is a rapid progression of genomics in cancer medicine, however there is a risk of clinicians and patients receiving results without clear guidance for possible interventions, resulting in the potential for variation in and the possibility of inappropriate patient management. We suggest as testing becomes rapidly more accessible, guideline development for intervention needs to be more closely aligned to those of testing.Supplementary material


Background: The treatment of the primary tumour in colorectal cancer with unresectable liver and/or lung metastases but no peritoneal carcinomatosis is still a matter of debate. In the absence of clear evidence and guidelines, our survey was aimed at obtaining a snapshot of the current attitudes and the rationales for the choice of offering resection of the primary tumour (RPT) despite the presence of untreatable metastases. Methods: An online survey was administered to medical professionals worldwide. The survey had three sections: (1) demographics of the respondent, (2) case scenarios and (3) general questions. For each respondent, an “elective resection score” and an “emergency resection score” were calculated as a percentage of the times he or she would offer RPT in the elective and in the emergency case scenarios. They were correlated to independent variables such as age, type of affiliation and specific workload. Results: Most respondents would offer palliative chemotherapy as the first choice in elective scenarios, while a more aggressive approach with RPT would be reserved for younger patients with good performance status and in emergency situations. Respondents younger than 50 years old and those with a specific workload of fewer than 40 cases of colorectal cancer per year tend to be more conservative. Conclusions: In the absence of clear guidelines and evidence, there is a lack of consensus on the treatment of the primary tumour in case of colon cancer with unresectable liver and/or lung metastases and no peritoneal carcinomatosis. Palliative chemotherapy seems to be the first option, but more consistent evidence is needed to guide this choice. Colorectal cancer (CRC) is one of the leading cancers worldwide and is responsible for more than 900,000 deaths every year . DespitePatients with infiltrated regional lymph nodes are not considered metastatic, but distant nodal involvement is considered to be metastatic. According to the TNM system , CRC witHowever, in the past few decades, the prognosis of patients with metastatic CRC has significantly improved with the development of lung and liver resective surgery in case of oligometastatic disease, but in the presence of extensive secondary lesions radical surgery is no longer an option and any treatment is only aimed at prolonging the survival and controlling the symptoms.For elective patients, palliative chemotherapy can be effective, but the advantage it can offer in terms of overall survival is minimal and personalised effective treatments are yet to come .Despite some interesting evidence showing that in selected cases resection of the primary tumour (RPT) can guarantee better survival than chemotherapy alone , palliatwww.google.com/forms/about/ accessed on 16 March 2023). The survey was divided into 3 parts—Part 1: demographics of the respondent; Part 2: 12 clinical scenarios; and Part 3: general clinical questions. The “clinical scenarios” were 7 elective cases and 5 emergency cases. Although each of them can represent a real clinical situation, as all cases are quite general, none of the clinical scenarios were deliberately and overtly taken from experiences of real patients who came under our care and each reference to real persons is to be considered the full result of chance. Questions are reported in www.linkedin.com accessed on 16 March 2023) and by email to the members of the Italian Association of Hospital Surgeons , the Italian Society of Surgical Pathophysiology  and the Tosco-Umbra Society of Surgery (Società Tosco-Umbra di Chirurgia). The link was also emailed to known colleagues in Italy and abroad.An online survey was created using Google Forms . The distribution of responses for every single question was calculated. Subsequently, individual scores were calculated for each respondent based on how often he or she would offer resection of the primary tumour according to the clinical scenarios, both in elective (“elective resection score”) and emergency situations (“emergency resection score”). The scores were calculated as a percentage of responses where “resection” was considered as the first choice on the total of elective or emergency scenarios. The scores are supposed to give an idea of the general attitude of that specific respondent. They were correlated to basic independent variables such as age, type of affiliation and specific workload. The variables were compared using a one-way ANOVA test . All variables were entered into a backward stepwise regression analysis to identify the independent prognostic variables associated with the elective and emergency resection scores.p-values less than 0.05 are considered to be statistically significant. Values of variables are approximated to the tenths. p-values are approximated to the thousandths.Statistics were performed within the same database with the add-on StatPlus for Mac v.7.8.11 . Missing values were excluded listwise. The demographics of the respondents are listed in Responses to the clinical questions  are visup = 0.000). Mean elective resection scores are also significantly lower than emergency resection scores for respondents who are younger and older than 50, for respondents who treat more than 40 colorectal cancers per year, for those affiliated with academic or non-academic hospitals, with or without a proper colorectal multidisciplinary team, and for consultants and non-consultants. Respondents younger than 50 years old have a significantly lower average elective resection score compared to more senior respondents (p = 0) (p = 0.645). Similarly, professionals who managed less than 40 cases of colorectal cancer per year have a higher elective resection score (p = 0.001) (p = 0.710). The elective resection score did not change significantly according to the type of practice. (p = 0) . This di= 0.001) . This diDue to the fact that none of the analysed variables resulted significantly associated with the emergency resection scores, regression analysis was conducted only for elective resections scores , and it Advanced colorectal cancer with non-treatable distant metastases is associated with poor prognosis. Palliative chemotherapy can help prolong survival, but the advantage brought by chemotherapy alone is only marginal, despite huge improvements in targeted and personalised treatments . BearingAfter denying any advantage of RPT for many years and suggesting upfront chemotherapy in all patients with Stage IV CRC, the last edition of the UK NICE  guidelines on colorectal cancer clearly suggest that RPT should be considered in patients with “incurable metastatic colorectal cancer who are receiving systemic anti-cancer therapy and have an asymptomatic primary tumour”  on the gThe guidelines of the Association of Coloproctology of Great Britain and Ireland (ACPGBI), those of the European Society for Medical Oncology (ESMO) and those of the German Guideline Program in Oncology do not mention the possibility of RPT and consider upfront chemotherapy in these cases ,9,10.The US National Comprehensive Cancer Network (NCCN) guidelines and those of the American Society of Colon and Rectal Surgeons (ASCRS) suggest upfront systemic chemotherapy and consider RPT only in case of significant symptoms or complications ,12.The 2020 guidelines of the Italian Association of Medical Oncology (AIOM) almost overlap with the NCCN and the ASCRS guidelines and briefly suggest RPT if the primary tumour is symptomatic, but without discussing the available evidence .Evidently, there is a degree of variability among the several national and international guidelines, reflecting slightly different points of view.The JCOG1007 study from Japan published in 2021 was terminated early due to futility as the first interim analysis showed that the predictive probability of survival being higher in the RPT group than in the chemotherapy group would be quite low at the final analysis if the study were to be continued. In fact, the updated final analysis on 165 patients failed to demonstrate better survival in the RPT group compared to the chemotherapy group .A specific randomized controlled trial comparing RPT to upfront chemotherapy in metastatic CRC, with a median follow-up of 15 months, was recently conducted in South Korea . The stuThe CAIRO4 phase 3 randomized controlled trial focused on 60-day mortality of patients randomized to RPT vs. upfront chemotherapy, and showed that RPT is associated with a higher risk of mortality compared to chemotherapy alone , in partThe FFCD 9601 study proved that the real advantage of RPT vs. upfront chemotherapy is in prolonging survival. In fact, median survival was 16.3 vs. 9.5 months, 2-year survival was 24% vs. 10% and 6-month progression-free survival was 38% vs. 22%. All these results were statistically significant. In multivariate analysis, RPT was the strongest independent factor associated with improved survival. Good performance status and distal location of the tumour were also independently associated with better survival. In other terms, good results in terms of improved survival could be obtained in patients in good general condition undergoing resection of a distal colonic primary tumour even in the presence of unresectable distant metastases [An 11-year-old metanalysis by our team of seven low-quality studies involving 1086 pooled patients failed to find any survival benefit in RPT compared to upfront chemotherapy , but a mA pooled post hoc analysis performed on 1155 cases from four trials showed that RPT guarantees better overall survival compared to chemotherapy alone in patients with unresectable metastatic CRC . As in mOn the contrary, a large observational retrospective cohort study from the US on 6735 patients from the National Cancer Data Base concluded that RPT does not improve survival and may delay the onset of palliative chemotherapy. However, despite the large sample size, the study has multiple limitations, including some degree of selection bias  .Xu et al. retrieved data from the US National Cancer Institute’s Surveillance, Epidemiology and End-Results database, covering about 30% of the US population, and identified 44,514 patients with stage IVa and IVb CRC. Survival gain for patients who had RPT was 7–11 months (median 9 months) compared to those who have been treated only with any form of chemotherapy . RPT was independently related to better survival upon multivariate analysis. Furthermore, RPT patients had also a significantly lower likelihood of all-cause death .Other published papers are low or very low-quality retrospective cohort studies, with most of them showing that RPT is associated with better 2-year survival .Finally, the SYNCHRONOUS study was launched in 2012 and aimed at comparing RPT and chemotherapy in asymptomatic Stage IV CRC patients. Its main endpoint is long-term survival, but its results are still pending .Guidelines and evidence do not fully agree on this subject, and the decision to offer RPT or not is still up to the surgeon, the oncologist and the CRMDT, if present, but unsupported by clear guidance.This study was aimed at obtaining a snapshot of the current attitudes of medical professionals on the treatment of primary tumours in Stage IVa and IVb CRC.Our survey showed that the vast majority of professionals base their decision on age, comorbidities, performance status and symptoms. In fact, about half of the respondents to our survey would consider RPT in patients who presented as emergencies against only one-third who would consider RPT in elective and non-symptomatic patients.Only one-third of the respondents seem to be so confident as to base their decision on the K-RAS status. This finding might have something to do with the fact that most respondents are surgeons, who may not have the knowledge to understand how a naïve or mutant K-RAS gene can influence the therapeutic options. As a matter of fact, the presence of a naïve K-RAS would allow the oncologist to consider second- or third-line chemotherapy with monoclonal antibodies, while patients with mutant K-RAS (or N-RAS or BRAF) may have fewer options available, so cytoreductive surgery may become the last resort.Younger respondents seem to have a less aggressive approach in elective cases. This is quite surprising. A possible explanation could be that more experienced doctors have a more patient-centred attitude, trying to do the maximum for that patient despite all odds, against a more evidence-centred attitude of younger doctors who may be a little more realistic, considering that those patients have a poor prognosis anyway.Much more understandable is the finding that respondents with lower workloads—in terms of the number of CRCs treated per year—would offer RPT more often, to try and increase their surgical experience.These two variables—age and workload—also resulted significantly and independently correlated with the elective resection score upon multivariate analysis, thus confirming the findings of the univariate analysis.The nature of the hospital, the presence of a colorectal multidisciplinary team and professional seniority did not influence the choice to offer resection or not, both in elective and emergency scenarios.The main limitation of this study is the uneven geographical distribution of respondents, with most of them being from Southern Europe (75%), the unbalanced gender distribution, with most of the respondents being men (79%), and the prevalence of surgeons among the respondents (98%). It is not clear how much the results could have been biased because of this unequal distribution. However, we feel that a basis of more than 600 respondents is in any case a good sample size and may fairly represent the general attitude towards a topic that has never been clearly standardised and is probably not fully standardisable anyway. Another eventual downside of this survey is that the 12 clinical scenarios do not cover all the possible situations, and there are still grey areas that have not been explored by the survey. While we can appreciate that this may be a minor issue, we must emphasise that adding more and more questions would have made the survey hardly acceptable to potential respondents. Furthermore, we feel that the depicted clinical scenarios give a very good idea of the general attitude of the medical community towards the delicate topic of the treatment of the primary lesion in metastatic colorectal cancers.The lack of high-level evidence and specific evidence-based guidelines makes the indication of RPT in these patients still a matter of debate. A proper long-term multicentric randomized clinical trial with a large sample would hopefully be able to clarify this topic and shed some light on the decision-making for these patients.In conclusion, this survey has demonstrated that doubts remain in both elective and emergency situations on the treatment of the primary tumour in Stage 4 CRC with non-operable liver and/or lung metastases but no peritoneal carcinomatosis. Palliative chemotherapy seems to be the first option, particularly in elective situations, but more consistent evidence is much needed to guide this choice.


P = 0.015) and less delayed bone age (BA) before GH treatment (P = 0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent’s heights ≤−2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH, a monogenic etiology is frequent, and gene variants affecting the growth plate are the most common. Shorter parent’s height and BA are clinical predictors of monogenic FSS.Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤−2 SD in child and his/her shorter parent); secondary short stature and Turner/Prader–Willi syndrome were excluded criteria. Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by American College of Medical Genetics and Genomics (ACMG) guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, 4 (11%) a variant affecting GH–insulin-like growth factor 1 (IGF1) axis and 3 (8%) a variant in miscellaneous genes. Lower shorter parent’s height ( Familial short stature (FSS) is a term commonly used in clinical practice to describe the vertical transmission of a growth disorder. A short child is classified as having FSS if at least one of his/her parents is also short (height −2 SD or less in both the child and his or her shorter parent) . The etiNPR2 gene were revealed in 2–6% of ISS children   , 13. MutGH1 gene) is one example. Another possibility is rare AD inheritance of mutations in genes affecting pituitary morphogenesis and differentiation  that could cause FSS and multiple pituitary hormone deficiency  –insulin-like growth factor (IGF) axis are also known to cause familial short stature . Growth ficiency , 15. InsB genes) .Despite the substantial advances in understanding the genetic background of short stature, most short children with short parents do not know the real cause of their growth disorder and are classified using only the descriptive diagnosis of FSS . The resFinding a genetic cause of a growth disorder is important both to understand the etiopathogenesis of short stature in the family and to screen for possible comorbidities frequently associated with the specific genetic finding . AccordiThe database of children treated with GH in our center currently includes 747 individuals. After the exclusion of patients with Turner syndrome, Prader-Willi syndrome, and those with secondary causes of their short stature , 528 children remained for further evaluation. Within this group, 125 children had FSS defined as a life-minimum height ≤−2 SD in both the patient and his/her shorter parent. In 95 children with FSS, their legal guardians consented to genetic testing, and those children were enrolled in the study. All study participants or their legal guardians signed written informed consent prior to genetic testing. The study was approved by the institutional Ethics Committees of the 2nd Faculty of Medicine, Charles University in Prague, Czech Republic.The heights of all children were obtained during anthropometric measurements that also focused on body proportionality . Information about their birth parameters was obtained from medical records. The heights of all the parents were measured to the nearest 1 mm, and the heights of more distant relatives were obtained from the parents. All the data were standardized according to recent normative values , 18, 19.The median age of 95 children with FSS at inclusion in the study was 12 years (IQR 9–15 years), and their life-minimum height was −3.0 SD (−3.5 to −2.7 SD) and the height of their shorter parent was −2.7 SD (−2.9 to −2.2 SD). The children had been treated with GH for 5 years (3–7 years), with an average dose during the first year of treatment of 33 µg/kg/day (31−35 µg/kg/day). Within this group, 64/95 (67%) children were classified as having GHD. Their maximum GH level after stimulation was 6.4 µg/L . Forty-seven children had mild GHD with stimulated GH concentrations of 5−10 µg/L, and the remaining 17 children had stimulated GH concentrations <5 µg/L. Fifty-one children (54%) within the study cohort were born SGA . Their median birth weight and birth length were −2.0 (IQR −2.5 to −1.6) and −2.6 SD (IQR −3.1 to −2.3), respectively. Twenty children (20%) were classified as having combined GHD and SGA.in situ hybridization. In all boys with confirmed disproportionate short stature, SHOX deficiency, including point mutations, was examined using Sanger sequencing and multiplex ligation-dependent probe amplification. In children with clinical suspicion of a specific genetic disorder, targeted genetic testing was performed. In 11 children, genetic diagnosis of FSS was elucidated prior to the study (genes SHOX (6), ACAN (2), PTPN11 (2), and NF1). Children with no genetic cause of their short stature elucidated prior to the study were subsequently examined using next-generation sequencing (NGS) methods.All patients underwent basic genetic testing prior to the study, as described previously . In all Genomic DNA was extracted from peripheral blood in all patients included in the study. DNA from the first 26 patients with severe FSS (life-minimum height <−2.5 SD both in the patient and his/her shorter parent) was analyzed using whole-exome sequencing, and DNA from the remaining 58 patients was analyzed using a custom-targeted NGS panel of 398 genes known to be associated or potentially associated with growth , COL2A1 (5), COL11A1 (2), NPR2 (4), ACAN (2), FGFR3 (2), PTPN11 (2), COL11A2, COL1A2, COMP, MATN3, EXT2 and NF1 genes), and 4 children (11%) carried variants affecting the GH–IGF1 axis . The remaining three children carried variants in miscellaneous genes . In all children, heterozygous variants were inherited from their shorter parent. One exception was a pathogenic variant in the SALL4 gene in patient 35 , who inherited the variant not from his short mother (height −2.4 SD) but from his father with normal height (−1 SD) and radial ray defects. Thus, we presume that the SALL4 pathogenic variant is causative for radial ray defects but likely not for short stature in the family. A diagram showing the examination process in detail is shown in Altogether, in 76/95 (80%) children with FSS treated with GH, we found at least one genetic variant of potential clinical importance in genes with a known impact on growth. Finally, monogenic etiology (pathogenic or likely pathogenic genetic variants discovered) was described in 36/95 (38%) children with FSS. Of these, 29 children (81%) carried causative genetic variants affecting the growth plate   , 13, 35.tations) , 37, 38.tations) . In chiltations) . Thus, tClarifying the genetic disorder-specific reactions to GH treatment that would lead to further refinement of indications for GH therapy poses one of the important current challenges of pediatric endocrinology. To achieve this aim, it will be necessary to accumulate large cohorts of children with specific monogenic growth disorders , 40. TheFor the abovementioned reasons, we consider genetic examination an important part of evaluating children with short stature. First, we should exclude Turner syndrome in all girls  and provide a targeted examination in case of clinical features leading to a suspicion of a specific genetic diagnosis  , 33, 34.We acknowledge that our study had several limitations. First, no functional studies have been performed. However, according to current guidelines, other methods can be used to prove the pathogenicity of genetic variants . In our Monogenic etiology is frequent in children with FSS treated with GH, and gene variants affecting the growth plate are the most common. A shorter parent height and the absence of BA delay are the best clinical predictors of monogenic FSS.The authors have no conflicts of interest to declare.This work was supported by the Ministry of Health, Czech Republic, grant number NU22J-07-00014.


The comorbidity burden has a negative impact on lung-cancer survival. Several comorbidity scores have been described and are currently used. The current challenge is to select the comorbidity score that best reflects their impact on survival. Here, we compared seven usable comorbidity scores  with coded administrative data according to the tenth revision of the International Statistical Classification of Diseases and Related Health Problems to select the best prognostic index for predicting four-month survival.This cohort included every patient with a diagnosis of lung cancer hospitalized for the first time in the thoracic oncology unit of our institution between 2011 and 2015. The seven scores were calculated and used in a Cox regression method to model their association with four-month survival. Then, parameters to compare the relative goodness-of-fit among different models , and discrimination parameters (the C-statistic and Harrell’s c-statistic) were calculated. A sensitivity analysis of these parameters was finally performed using a bootstrap method based on 1,000 samples.In total, 633 patients were included. Male sex, histological type, metastatic status, CCI, CCI-lung, Elixhauser score, and Elixhauser-lung were associated with poorer four-month survival. The Elixhauser score had the lowest AIC and BIC and the highest c-statistic and Harrell’s c-statistic. These results were confirmed in the sensitivity analysis, in which these discrimination parameters for the Elixhauser score were significantly different from the other scores.Based on this cohort, the Elixhauser score is the best prognostic comorbidity score for predicting four-month survival for hospitalized lung cancer patients.The online version contains supplementary material available at 10.1186/s12874-023-01994-6. The median age at lung cancer diagnosis is 70 years . Given tThe negative affect of comorbidities on patient survival are well described –6. SinceCertain comorbidity scores are based on the International Statistical Classification of Diseases and Related Health Problems ICD-10), as Quan et al. published ICD-10 codes relative to comorbidities in 2005 . They in0, as QuaYang et al. found that the ACCI was better at predicting three-year overall survival than the CCI and Elixhauser score in a cohort of resected lung-cancer patients  based onAlthough the CCI is the most widely used comorbidity score, it would be informative to assess which score is more predictive of mortality in cohorts with administrative data. Here, we compared the seven comorbidity scores available using administrative data coded using the ICD-10 in predicting four-month survival of our cohort of hospitalized lung-cancer patients.We included patients hospitalized in the Thoracic Oncology Unit of Grenoble Alpes University Hospital from 2011 to 2015 described in an earlier publication . Lung-caThe study was approved by our institutional review board and ethics approval was obtained on September 1, 2021 .The database contains information on individuals including their age, gender, lung cancer’ TNM staging, performance status at their first presentation case in multidisciplinary concertation meetings, and the histological type of the lung cancer.The outcome was median overall survival. Survival data were obtained from our district cancer registry, including the date of the last follow-up and the vital status at the last follow-up. Right censored date point was defined by median overall survival.Age, gender, lung cancer metastatic status, histologic type, age at hospitalization, and age at diagnosis were included as covariates.Data concerning comorbidities were obtained by the Health Information Services Department and coded using the ICD-10. The diagnoses for comorbidities were recorded at the patients’ discharge in our medical unit. Seven comorbidity scores were calculated: CCI, ACCI, CCI-lung, NCI, NCI-lung, Elixhauser, and Elixhauser-lung. We did not record metastatic solid tumors and lung cancer as comorbid conditions. The seven scores are summarized in Table For descriptive analysis, quantitative variables are expressed as medians [Interquartile ranges] and qualitative variables as n (%).Comorbidity scores were calculated and survival estimated as the time between the day of hospitalization and the date of last follow-up . The Kaplan Meier estimator was used to estimate the probability of survival. Log-rank tests were used to compare the probability of the event (death) between populations. The model was adjusted for each score. A Cox proportional hazards regression model was used to perform multivariable analyses of prognostic factors and calculate hazard ratios (HRs) and 95% confidence intervals (95% CI) for median survival for the seven comorbidity scores. A median cut-off was used for continuous variables in the multivariate analysis. Proportional hazards assumptions were verified using the Martingale method . Only coTo compare comorbidity scores, Akaike Information Criteria (AIC), Bayesian Information Criteria (BIC) were used to compare the relative goodness-of-fit among different models. Then, a discrimination analysis using the c-statistic, Harrell’s c-statistic, sensitivity, specificity was performed from a base model containing significant covariables from the multivariate analysis. Sensitivity and specificity were respectively calculated as follow: (True positive = Death estimated by the model) / ); and (true negative = non-dead patients estimated by the model) / .The impact of the scores was compared using the base model  plus each index score alone by multivariable Cox regression. The model with the lowest AIC and BIC indicates which model was the best fit for the data and the highest c statistic and Harrell’s c statistic was considered to be the best predictive model.A sensitivity analysis using a bootstrap method for each statistical indicator, with 1,000 samples from two thirds of the cohort, was performed. Each indicator  was calculated for the 1,000 samples. Boxplots were generated for the four parameters.All statistical analyses were performed using SAS 9.4 for Windows . A p-value < 0.05 was considered significant.In total, 633 patients were enrolled in the study. The demographic characteristics of the population are presented in Table In multivariable analysis, only the presence of metastases, male gender, and histological type were prognostic factors of four-month survival.We assessed the prevalence of each comorbidity that contributed to the score for each comorbidity score , but also in the weight assigned to each comorbidity; some use the beta coefficient obtained from the regression and others the hazard ratio. The beta coefficients and hazard ratios are related to each other by an exponential relationship, and although the use of beta coefficients is preferred when using a summary score , we calcThere are several possible explanations concerning the better performance of the Elixhauser score. The Elixhauser score was developed using a short-term outcome: in-hospital mortality. The median overall survival in our cohort was four months, which is short relative to the other scores , which were constructed using a long-term outcome, such as one- or two-year mortality. This result corroborates another publication concerning in-hospital mortality of non-cancer patients, in which the Elixhauser score outperformed the CCI . AnotherThis study had several limitations. We assessed comorbidities that occurred both before and after lung cancer diagnosis and did not distinguish between death from lung cancer and that from other causes. Extension of this paper results should be done with one caution. Despite we had 71% of men and 74.2% of patients with metastatic status at diagnosis, which is similar to literature, age have a non-significant effect on survival. This may be due to the inclusion criteria which is hospitalized patients and therefore frailty ones with the shortest survivals, and high comorbidity burden (Median Elixhauser score of 6). Because performance test has been performed on the same data used to train the model there will be a need for external validity of the results. There may have also been unknown confounders. Moreover, this was a retrospective monocentric study.The use of ICD-10 codes to identify the comorbidities was a strength of our study, as they can be used to query easily available structured datasets and allow the comparison of comorbidity scores, as well as sensitivity analyses, which confirmed the superiority of the Elixhauser score for estimating four-month survival in our cohort.Despite the extensive use of the CCI in the literature, other comorbidity scores are available, including scores based on administrative data coded using the ICD-10. In this original study, in which we compared seven comorbidity scores using administrative data, the Elixhauser score was the comorbidity score best suited to hospitalized lung-cancer patients for predicting four-month mortality. It could be informative to repeat these analyses with a longer follow-up of the patients.Below is the link to the electronic supplementary material.Supplementary Material 1: Table S1Supplementary Material 2: Figure S1Supplementary Material 3: Table S2Supplementary Material 4: Table S3Supplementary Material 5: Figure S2