Nomograms in oncology: more than meets the eye Balachandran, Vinod P, Dr; Gonen, Mithat, PhD; Smith, J Joshua, MD ...
The lancet oncology,
04/2015, Letnik:
16, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Summary Nomograms are widely used as prognostic devices in oncology and medicine. With the ability to generate an individual probability of a clinical event by integrating diverse prognostic and ...determinant variables, nomograms meet our desire for biologically and clinically integrated models and fulfill our drive towards personalised medicine. Rapid computation through user-friendly digital interfaces, together with increased accuracy, and more easily understood prognoses compared with conventional staging, allow for seamless incorporation of nomogram-derived prognosis to aid clinical decision making. This has led to the appearance of many nomograms on the internet and in medical journals, and an increase in nomogram use by patients and physicians alike. However, the statistical foundations of nomogram construction, their precise interpretation, and evidence supporting their use are generally misunderstood. This issue is leading to an under-appreciation of the inherent uncertainties regarding nomogram use. We provide a systematic, practical approach to evaluating and comprehending nomogram-derived prognoses, with particular emphasis on clarifying common misconceptions and highlighting limitations.
Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues
. Although ILC2s are found in cancers of these tissues
, their roles in cancer immunity and immunotherapy ...are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8
T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1
TILC2s and PD-1
T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.
Background Despite the potentially severe impact of bile leakage on patients’ perioperative and long-term outcome, a commonly used definition of this complication after hepatobiliary and pancreatic ...operations has not yet been established. The aim of the present article is to propose a uniform definition and severity grading of bile leakage after hepatobiliary and pancreatic operative therapy. Methods An international study group of hepatobiliary and pancreatic surgeons was convened. A consensus definition of bile leakage after hepatobiliary and pancreatic operative therapy was developed based on the postoperative course of bilirubin concentrations in patients’ serum and drain fluid. Results After evaluation of the postoperative course of bilirubin levels in the drain fluid of patients who underwent hepatobiliary and pancreatic operations, bile leakage was defined as bilirubin concentration in the drain fluid at least 3 times the serum bilirubin concentration on or after postoperative day 3 or as the need for radiologic or operative intervention resulting from biliary collections or bile peritonitis. Using this criterion severity of bile leakage was classified according to its impact on patients’ clinical management. Grade A bile leakage causes no change in patients’ clinical management. A Grade B bile leakage requires active therapeutic intervention but is manageable without relaparotomy, whereas in Grade C, bile leakage relaparotomy is required. Conclusion We propose a simple definition and severity grading of bile leakage after hepatobiliary and pancreatic operative therapy. The application of the present proposal will enable a standardized comparison of the results of different clinical trials and may facilitate an objective evaluation of diagnostic and therapeutic modalities in the field of hepatobiliary and pancreatic operative therapy.
Gastrointestinal stromal tumor (GIST) has become a model for targeted therapy in cancer. The vast majority of GISTs contain an activating mutation in either the KIT or platelet-derived growth factor ...A (PDGFRA) gene. GIST is highly responsive to several selective tyrosine kinase inhibitors. In fact, this cancer has been converted to a chronic disease in some patients. Considerable progress has been made recently in our understanding of the natural history and molecular biology of GIST, risk stratification, and drug resistance. Despite the efficacy of targeted therapy, though, surgery remains the only curative primary treatment and cures >50% of GIST patients who present with localized disease. Adjuvant therapy with imatinib prolongs recurrence-free survival and may improve overall survival. Combined or sequential use of tyrosine kinase inhibitors with other agents following tumor molecular subtyping is an attractive next step in the management of GIST.
Background Liver surgery for perihilar cholangiocarcinoma (PHC) is associated with postoperative mortality ranging from 5% to 18%. The aim of this study was to develop a preoperative risk score for ...postoperative mortality after liver resection for PHC, and to assess the effect of biliary drainage of the future liver remnant (FLR). Study Design A consecutive series of 287 patients submitted to major liver resection for presumed PHC between 1997 and 2014 at 2 Western centers was analyzed; 228 patients (79%) underwent preoperative drainage for jaundice. Future liver remnant volumes were calculated with CT volumetry and completeness of FLR drainage was assessed on imaging. Logistic regression was used to develop a mortality risk score. Results Postoperative mortality at 90 days was 14% and was independently predicted by age (odds ratio OR per 10 years = 2.1), preoperative cholangitis (OR = 4.1), FLR volume <30% (OR = 2.9), portal vein reconstruction (OR = 2.3), and incomplete FLR drainage in patients with FLR volume <50% (OR = 2.8). The risk score showed good discrimination (area under the curve = 0.75 after bootstrap validation) and ranking patients in tertiles identified 3 (ie low, intermediate, and high) risk subgroups with predicted mortalities of 2%, 11%, and 37%. No postoperative mortality was observed in 33 undrained patients with FLR volumes >50%, including 10 jaundiced patients (median bilirubin level 11 mg/dL). Conclusions The mortality risk score for patients with resectable PHC can be used for patient counseling and identification of modifiable risk factors, which include FLR volume, FLR drainage status, and preoperative cholangitis. We found no evidence to support preoperative biliary drainage in patients with an FLR volume >50%.
Background The indications for minimally invasive (MIS) pancreatectomy have slowly increased as experience, techniques, and technology have improved and evolved to manage malignant lesions in ...selected patients without compromising safety and oncologic principles. There are sparse data comparing laparoscopic, robotic, and open distal pancreatectomy (DP). Study Design All patients undergoing DP at Memorial Sloan Kettering Cancer Center between 2000 and 2013 were analyzed from a prospective database. Clinicopathologic and survival data were analyzed to compare perioperative and oncologic outcomes in patients who underwent DP via open, laparoscopic, and robotic approaches. Results Eight hundred five DP were performed during the study period, comprising 37 robotic distal pancreatectomies (RDP), 131 laparoscopic distal pancreatectomies (LDP), and 637 open distal pancreatectomies (ODP). The 3 groups were similar with respect to American Society of Anesthesiologists (ASA) score, sex ratio, body mass index, pancreatic fistula rate, and 90-day morbidity and mortality. Patients in the ODP group were generally older (p = 0.001), had significantly higher intraoperative blood loss (p < 0.001), and had a trend toward a longer hospital stay (p = 0.05). Of the significant preoperative variables, visceral fat was predictive of conversion on multivariate analysis (p = 0.003). Oncologic outcomes in the adenocarcinoma cases were similar for the 3 groups, with high rates of R0 resection (88% to 100%). The ODP group had a higher lymph node yield than the LDP and RDP groups (15.4, SD 8.7 vs 10.4 SD 8.0 vs 12SD 7.2, p = 0.04). Conclusions The RDP and LDP were comparable with respect to most perioperative outcomes, with no clear advantage of one approach over the other. Both of these MIS techniques may have advantages over ODP in well-selected patients. All approaches achieved a similarly high rate of R0 resection for patients with adenocarcinoma.
Hepatic resection of colorectal liver metastases is associated with long-term survival. This study analyzes actual 10-year survivors after resection of colorectal liver metastases, reports the ...observed rate of cure, and identifies factors that preclude cure.
A single-institution, prospectively maintained database was queried for all initial resections for colorectal liver metastases for the years 1992–2004. Observed cure was defined as actual 10-year survival with either no recurrence or resected recurrence with at least 3 years of disease-free follow-up. Clinical risk score was dichotomized into low (0–2) and high (3–5). Semiparametric proportional hazards mixture cure model was utilized to estimate probability of cure.
We included 1,211 patients with a median follow-up for survivors of 11 years. Median disease-specific survival was 4.9 years (95% CI: 4.4–5.3). 295 patients (24.4%) were actual 10-year survivors. The observed cure rate was 20.6% (n = 250). Among 250 cured patients, 192 (76.8%) had no recurrence and 58 (23.2%) had a resected recurrence with at least 3 years of disease-free follow-up. Extrahepatic disease (n = 88), carcinoembryonic antigen >200 ng/mL (n = 119), positive margin (n = 109), and >10 tumors (n = 31) had observed cure rates less than 10%. In cure model analysis, patients with both extrahepatic disease and high clinical risk score (n = 31) had an estimated probability of cure of 3.5%.
Actual 10-year survival after resection of colorectal liver metastases is 24% with an observed 20% cure rate. Patients with both high clinical risk score and extrahepatic disease have an estimated probability of cure less than 5%. When such factors are identified, strong consideration may be given to preoperative strategies, such as neoadjuvant chemotherapy, to help select patients for surgical therapy.
Background and Aim
Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown.
Approach and Results
...This bi‐institutional study of patients with confirmed iCCA (n = 412) used targeted next‐generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT‐rich interactive domain–containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin‐dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1–associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high‐risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08‐3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95‐5.94; P < 0.001) independently predicted shorter OS, as did high‐risk clinical variables (multifocal liver disease P < 0.001; regional lymph node metastases P < 0.001), whereas KRASmut (HR, 1.69; 95% CI, 0.97‐2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high‐risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high‐risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8‐73.5) or high‐risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6‐not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high‐risk clinical features were notable for limited survival and no benefit of resection over chemotherapy.
Conclusions
TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision‐making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.
Background This study analyzes factors associated with differences in long-term outcomes after hepatic resection for metastatic colorectal cancer over time. Study Design Sixteen-hundred consecutive ...patients undergoing hepatic resection for metastatic colorectal cancer between 1985 and 2004 were analyzed retrospectively. Patients were grouped into 2 eras according to changes in availability of systemic chemotherapy: era I, 1985 to 1998; era II, 1999 to 2004. Results There were 1,037 patients in era I and 563 in era II. Operative mortality decreased from 2.5% in era I to 1% in era II (p = 0.04). There were no differences in age, Clinical Risk Score, or number of hepatic metastases between the 2 groups; however, more recently treated patients (era II) had more lymph node–positive primary tumors, shorter disease-free intervals, more extrahepatic disease, and smaller tumors. Median follow-up was 36 months for all patients and 63 months for survivors. Median and 5-year disease-specific survival (DSS) were better in era II (64 months and 51% versus 43 months and 37%, respectively; p < 0.001); but median and 5-year recurrence-free survival (RFS) for all patients were not different (23 months and 33% era II versus 22 months and 27% era I; p = 0.16). There was no difference in RFS or DSS for high-risk (Clinical Risk Score >2, n = 506) patients in either era. There was a marked improvement in both RFS and DSS for low risk (Clinical Risk Score ≤2, n = 1,094) patients. Conclusions Despite worse clinical and pathologic characteristics, survival but not recurrence rates after hepatic resection for colorectal metastases have improved over time and might be attributable to improvements in patient selection, operative management, and chemotherapy. The improvement in survival over time is largely accounted for by low-risk patients.
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