Studies have suggested that there is increased risk of thromboembolism (TE) associated with coronavirus disease 2019 (COVID-19). However, overall arterial and venous TE rates of COVID-19 and effect ...of TE on COVID-19 mortality is unknown.
We did a systematic review and meta-analysis of studies evaluating TE in COVID-19. We searched PubMed, Cochrane, and Embase for studies published up to June 12, 2020. Random effects models were used to produce summary TE rates and odds ratios (OR) of mortality in COVID-19 patients with TE compared to those without TE. Heterogeneity was quantified with I2.
Of 425 studies identified, 42 studies enrolling 8271 patients were included in the meta-analysis. Overall venous TE rate was 21% (95% CI:17–26%): ICU, 31% (95% CI: 23–39%). Overall deep vein thrombosis rate was 20% (95% CI: 13–28%): ICU, 28% (95% CI: 16–41%); postmortem, 35% (95% CI:15–57%). Overall pulmonary embolism rate was 13% (95% CI: 11–16%): ICU, 19% (95% CI:14–25%); postmortem, 22% (95% CI:16–28%). Overall arterial TE rate was 2% (95% CI: 1–4%): ICU, 5% (95%CI: 3–7%). Pooled mortality rate among patients with TE was 23% (95%CI:14–32%) and 13% (95% CI:6–22%) among patients without TE. The pooled odds of mortality were 74% higher among patients who developed TE compared to those who did not (OR, 1.74; 95%CI, 1.01–2.98; P = 0.04).
TE rates of COVID-19 are high and associated with higher risk of death. Robust evidence from ongoing clinical trials is needed to determine the impact of thromboprophylaxis on TE and mortality risk of COVID-19.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction Data on recurrence after operation for intrahepatic cholangiocarcinoma (ICC) are limited. We sought to investigate rates and patterns of recurrence in patients after operative ...intervention for ICC. Methods We identified 301 patients who underwent operation for ICC between 1990 and 2011 from an international, multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed. Results During the median follow up duration of 31 months (range 1–208), 53.5% developed a recurrence. Median RFS was 20.2 months and 5-year actuarial disease-free survival, 32.1%. The most common site for initial recurrence after operation of ICC was intrahepatic ( n = 98; 60.9%), followed by simultaneous intra- and extrahepatic disease ( n = 30; 18.6%); 33 (21.0%) patients developed extrahepatic recurrence only as the first site of recurrence. Macrovascular invasion (hazard ratio HR, 2.08; 95% confidence interval CI, 1.34–3.21; P < .001), nodal metastasis (HR, 1.55; 95% CI, 1.01–2.45; P = .04), unknown nodal status (HR, 1.57; 95% CI, 1.10–2.25; P = .04), and tumor size ≥5 cm (HR, 1.84; 95% CI, 1.28–2.65; P < .001) were independently associated with increased risk of recurrence. Patients were assigned a clinical score from 0 to 3 according to the presence of these risk factors. The 5-year RFS for patients with scores of 0, 1, 2, and 3 was 61.8%, 36.2%, 19.5%, and 9.6%, respectively. Conclusion Recurrence after operative intervention for ICC was common. Disease recurred both at intra- and extrahepatic sites with roughly the same frequency. Factors such as lymph node metastasis, tumor size, and vascular invasion predict highest risk of recurrence.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Biliary tract cancers have dismal prognoses even when cytotoxic chemotherapy is administered. There is an unmet need to develop precision treatment approaches using comprehensive genomic profiling. A ...total of 121 patients with biliary tract cancers were analyzed for circulating‐tumor DNA (ctDNA) and/or tissue‐based tumor DNA (tissue‐DNA) using clinical‐grade next‐generation sequencing: 71 patients (59%) had ctDNA; 90 (74%), tissue‐DNA; and 40 (33%), both. Efficacy of targeted therapeutic approaches was assessed based upon ctDNA and tissue‐DNA. At least one characterized alteration was detected in 76% of patients (54/71) for ctDNA median, 2 (range, 0‐9) and 100% (90/90) for tissue‐DNA median, 4 (range, 1‐9). Most common alterations occurred in TP53 (38%), KRAS (28%), and PIK3CA (14%) for ctDNA vs TP53 (44%), CDKN2A/B (33%) and KRAS (29%) for tissue‐DNA. In 40 patients who had both ctDNA and tissue‐DNA sequencing, overall concordance was higher between ctDNA and metastatic site tissue‐DNA than between ctDNA and primary tumor DNA (78% vs 65% for TP53, 100% vs 74% for KRAS and 100% vs 87% for PIK3CA But not statistical significance). Among 80 patients who received systemic treatment, the molecularly matched therapeutic regimens based on genomic profiling showed a significantly longer progression‐free survival (hazard ratio 95%confidence interval, 0.60 0.37‐0.99. P = .047 multivariate) and higher disease control rate (61% vs 35%, P = .04) than unmatched regimens. Evaluation of ctDNA and tissue‐DNA is feasible in biliary tract cancers.
What's new?
There is an unmet need for investigating precision therapy approaches in biliary tract cancers using next‐generation sequencing techniques. This study shows that circulating tumour DNA (ctDNA) and tissue DNA tests are complementary, since they often reveal different alterations likely due to tumour heterogeneity. Most biliary tract cancer patients had at least one characterised alteration in ctDNA and in tissue DNA. Among 80 patients who received systemic chemotherapy, molecularly‐matched therapeutic regimens based on genomic profiling were associated with better treatment response and progression‐free survival than unmatched therapies. Evaluation of ctDNA and tissue‐DNA is feasible and potentially beneficial in biliary tract cancers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival.
From an international ...multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses.
Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio HR, 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34).
Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis.
Background To establish a reliable definition of postoperative hepatic insufficiency (PHI) in noncirrhotic patients undergoing major hepatectomy. No standard definition of PHI has been established, ...but one is essential for meaningful comparison of outcomes data across studies. Methods Data from 1,059 noncirrhotic patients who underwent major hepatectomy (3 or more liver segments) at 3 centers from 1995 to 2005 were analyzed. Receiver operating characteristics (ROC) analysis of peak postoperative bilirubin (Peak Bil) and international normalized ratio (Peak INR) were used to define PHI. Results A total of 669 patients (63%) underwent resection of 3 to 4 liver segments; 390 (37%) underwent resection of 5 or more segments. Complications occurred in 453 (43%). The 90-day all-cause mortality rate was 4.7%, which is 47% higher than the 30-day rate (3.2%). Twenty (1.9%) patients died of causes unrelated to the liver. Of the remaining 1,039 patients, 30 (2.8%) died a median 36 days from liver-related causes (liver failure with or without multiorgan failure). ROC analysis revealed cut-offs that predict liver-related death arePeak Bil 7.0 mg/dL (area under the curve 0.982; sensitivity 93.3%; specificity 94.3%) andPeak INR 2.0 (area under the curve 0.846; sensitivity 76.7%; specificity 82.0%).Peak Bil > 7.0 mg/dL was the most powerful predictor of any (odds ratio OR = 83.3) or major complication (OR = 10.0), 90-day mortality (OR = 10.8), and 90-day liver-related mortality (OR = 250) (all p < 0.0001). Conclusions PHI defined asPeak Bil > 7.0 mg/dL accurately predicts liver-related death and worse outcomes after major hepatectomy. Standardized reporting of complications, PHI, and 90-day mortality is essential to accurately determine the risk of major hepatectomy and to compare outcomes data.
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GEOZS, NUK, OILJ, SBJE, UL, UPUK
IMPORTANCE Intrahepatic cholangiocarcinoma (ICC) is a primary cancer of the liver that is increasing in incidence, and the prognostic factors associated with outcome after surgery remain poorly ...defined. OBJECTIVE To combine clinicopathologic variables associated with overall survival after resection of ICC into a prediction nomogram. DESIGN, SETTING, AND PARTICIPANTS We performed an international multicenter study of 514 patients who underwent resection for ICC at 13 major hepatobiliary centers in the United States, Europe, and Asia from May 1, 1990, through December 31, 2011. Multivariate Cox proportional hazards regression modeling with backward selection using the Akaike information criteria was used to select variables for construction of the nomogram. Discrimination and calibration were performed using Kaplan-Meier curves and calibration plots. INTERVENTIONS Surgical resection of ICC at a participating hospital. MAIN OUTCOMES AND MEASURES Long-term survival, effect of potential prognostic factors, and performance of proposed nomogram. RESULTS Median patient age was 59.2 years, and 53.1% of the patients were male. Most patients (74.7%) had a solitary tumor, and median tumor size was 6.0 cm. Patients were treated with an extended hepatectomy (202 39.3%), a hemihepatectomy (180 35.0%), or a minor liver resection (<3 segments) (132 25.7%). Most patients underwent R0 resection (87.9%), and 35.7% of patients had N1 disease. Using the backward selection of clinically relevant variables, we found that age at diagnosis (hazard ratio HR, 1.31; P < .001), tumor size (HR, 1.50; P < .001), multiple tumors (HR, 1.58; P < .001), cirrhosis (HR, 1.51; P = .08), lymph node metastasis (HR, 1.78; P = .01), and macrovascular invasion (HR, 2.10; P < .001) were selected as factors predictive of survival. On the basis of these factors, a nomogram was created to predict survival of ICC after resection. Discrimination using Kaplan-Meier curves, calibration curves, and bootstrap cross-validation revealed good predictive abilities (C index, 0.692). CONCLUSIONS AND RELEVANCE On the basis of an Eastern and Western experience, a nomogram was developed to predict overall survival after resection for ICC. Validation revealed good discrimination and calibration, suggesting clinical utility to improve individualized predictions of survival for patients undergoing resection of ICC.
A positive surgical margin (PSM) following cancer resection oftentimes necessitates adjuvant treatments and carries significant financial and prognostic implications. We sought to compare PSM rates ...for the ten most common solid cancers in the United States, and to assess trends over time. Over 10 million patients were identified in the National Cancer Data Base from 1998-2012, and 6.5 million had surgical margin data. PSM rates were compared between two time periods, 1998-2002 and 2008-2012. PSM was positively correlated with tumor category and grade. Ovarian and prostate cancers had the highest PSM prevalence in women and men, respectively. The highest PSM rates for cancers affecting both genders were seen for oral cavity tumors. PSM rates for breast cancer and lung and bronchus cancer in both men and women declined over the study period. PSM increases were seen for bladder, colon and rectum, and kidney and renal pelvis cancers. This large-scale analysis appraises the magnitude of PSM in the United States in order to focus future efforts on improving oncologic surgical care with the goal of optimizing value and improving patient outcomes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
The purpose of this study was to define the learning curves for laparoscopic pancreaticoduodenectomy (LPD) with and without laparoscopic reconstruction, using paired surgical teams ...consisting of advanced laparoscopic-trained surgeons and advanced oncologic-trained surgeons.
Methods
All patients undergoing PD without vein resection at a single institution were retrospectively analyzed. LPD was introduced by initially focusing on laparoscopic resection followed by open reconstruction (hybrid) for 18 months prior to attempting a totally LPD (TLPD) approach. Cases were compared with Chi square, Fisher’s exact test, and Kruskal–Wallis analysis of variance (ANOVA).
Results
Between March 2010 and June 2013, 140 PDs were completed at our institution, of which 56 (40 %) were attempted laparoscopically. In 31/56 procedures we planned to perform only the resection laparoscopically (hybrid), of which 7 (23 %) required premature conversion before completion of resection. Following the first 23 of these hybrid cases, a total of 25 TLPDs have been performed, of which there were no conversions to open. For all LPD, a significant reduction in operative times was identified following the first 10 patients (median 478.5 vs. 430.5 min;
p
= 0.01), approaching open PD levels. After approximately 50 cases, operative times and estimated blood loss were consistently lower than those for open PD.
Conclusions
In our experience of building an LPD program, the initial ten cases represent the biggest hurdle with respect to operative times. For an experienced teaching center using a staged and team-based approach, LPD appears to offer meaningful reductions in operative time and blood loss within the first 50 cases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background Although hepatic metastasectomy is well established for colorectal and neuroendocrine cancer, the approach to hepatic metastases from other sites is not well defined. We sought to examine ...the management of noncolorectal non-neuroendocrine liver metastases. Study Design A retrospective review from 4 major liver centers identified patients who underwent liver resection for noncolorectal non-neuroendocrine metastases between 1990 and 2009. The Kaplan-Meier method was used to analyze survival, and Cox regression models were used to examine prognostic variables. Results There were 420 patients available for analysis. Breast cancer (n = 115; 27%) was the most common primary malignancy, followed by sarcoma (n = 98; 23%), and genitourinary cancers (n = 92; 22%). Crude postoperative morbidity and mortality rates were 20% and 2%, respectively. Overall median survival was 49 months, and 1, 3, and 5-year Kaplan-Meier survival rates were 73%, 50%, and 31%. Survival was not significantly different between the various primary tumor types. Recurrent disease was found after hepatectomy in 66% of patients. In multivariable models, lymphovascular invasion (p = 0.05) and metastases ≥5 cm (p = 0.04) were independent predictors of poorer survival. Median survival was shorter for resections performed between 1990 and 1999 (n = 101, 32 months) when compared with resections between 2000 and 2009 (n = 319, 66 months; p = 0.003). Conclusions Hepatic metastasectomy for noncolorectal non-neuroendocrine cancers is safe and feasible in selected patients. Lymphovascular invasion and metastases ≥5 cm were found to be associated with poorer survival. Patients undergoing metastasectomy in more recent years appear to be surviving longer, however, the reasons for this are not conclusively determined.
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GEOZS, NUK, OILJ, SBJE, UL, UPUK
Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide ...downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC.
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