Summary Background Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an ...engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population. Methods For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov , number NCT02108652. Findings Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% 95% CI 19–37, p<0·0001; IC1/2/3: 18% 13–24, p=0·0004) and in all patients (15% 11–20, p=0·0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18–36) in the IC2/3 group, 18% (13–24) in the IC1/2/3 group, and 15% (11–19) overall in all 310 patients. With a median follow-up of 11·7 months (95% CI 11·4–12·2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3–4 treatment-related adverse events, of which fatigue was the most common (five patients 2%), occurred in 50 (16%) of 310 treated patients. Grade 3–4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study. Interpretation Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma. Funding F Hoffmann-La Roche Ltd.
Carotid blowout syndrome is a life-threatening complication for patients with head and neck cancer. Temporizing stent graft procedures improve short-term survival and can be the definitive treatment ...for various reasons, including a poor oncologic prognosis, unsuitability for definitive reconstruction, or a lack of operative options. A second carotid blowout will often be fatal. Preventing such events requires multidisciplinary strategic planning because of a hostile reoperative field. We have described a case of a 44-year-old man with a history of laryngeal cancer who had experienced a carotid blowout. Treated with a stent graft, the patient had experienced a second event 6 weeks later. Treatment involved excision and suture ligation with rotational muscle flap coverage.
Summary Surgery is essential for global cancer care in all resource settings. Of the 15·2 million new cases of cancer in 2015, over 80% of cases will need surgery, some several times. By 2030, we ...estimate that annually 45 million surgical procedures will be needed worldwide. Yet, less than 25% of patients with cancer worldwide actually get safe, affordable, or timely surgery. This Commission on global cancer surgery, building on Global Surgery 2030, has examined the state of global cancer surgery through an analysis of the burden of surgical disease and breadth of cancer surgery, economics and financing, factors for strengthening surgical systems for cancer with multiple-country studies, the research agenda, and the political factors that frame policy making in this area. We found wide equity and economic gaps in global cancer surgery. Many patients throughout the world do not have access to cancer surgery, and the failure to train more cancer surgeons and strengthen systems could result in as much as US$6·2 trillion in lost cumulative gross domestic product by 2030. Many of the key adjunct treatment modalities for cancer surgery—eg, pathology and imaging—are also inadequate. Our analysis identified substantial issues, but also highlights solutions and innovations. Issues of access, a paucity of investment in public surgical systems, low investment in research, and training and education gaps are remarkably widespread. Solutions include better regulated public systems, international partnerships, super-centralisation of surgical services, novel surgical clinical trials, and new approaches to improve quality and scale up cancer surgical systems through education and training. Our key messages are directed at many global stakeholders, but the central message is that to deliver safe, affordable, and timely cancer surgery to all, surgery must be at the heart of global and national cancer control planning.
Study objective We determine the optimal correction factor for cerebrospinal fluid WBC counts in infants with traumatic lumbar punctures. Methods We performed a secondary analysis of a retrospective ...cohort of infants aged 60 days or younger and with a traumatic lumbar puncture (cerebrospinal fluid RBC count ≥10,000 cells/mm3 ) at 20 participating centers. Cerebrospinal fluid pleocytosis was defined as a cerebrospinal fluid WBC count greater than or equal to 20 cells/mm3 for infants aged 28 days or younger and greater than or equal to 10 cells/mm3 for infants aged 29 to 60 days; bacterial meningitis was defined as growth of pathogenic bacteria from cerebrospinal fluid culture. Using linear regression, we derived a cerebrospinal fluid WBC correction factor and compared the uncorrected with the corrected cerebrospinal fluid WBC count for the detection of bacterial meningitis. Results Of the eligible 20,319 lumbar punctures, 2,880 (14%) were traumatic, and 33 of these patients (1.1%) had bacterial meningitis. The derived cerebrospinal fluid RBCs:WBCs ratio was 877:1 (95% confidence interval CI 805 to 961:1). Compared with the uncorrected cerebrospinal fluid WBC count, the corrected one had lower sensitivity for bacterial meningitis (88% uncorrected versus 67% corrected; difference 21%; 95% CI 10% to 37%) but resulted in fewer infants with cerebrospinal fluid pleocytosis (78% uncorrected versus 33% corrected; difference 45%; 95% CI 43% to 47%). Cerebrospinal fluid WBC count correction resulted in the misclassification of 7 additional infants with bacterial meningitis, who were misclassified as not having cerebrospinal fluid pleocytosis; only 1 of these infants was older than 28 days. Conclusion Correction of the cerebrospinal fluid WBC count substantially reduced the number of infants with cerebrospinal fluid pleocytosis while misclassifying only 1 infant with bacterial meningitis of those aged 29 to 60 days.
Objective The objective was to study associations between clinical variables, demographic factors, and outcome after endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA). Methods ...Data of consecutive patients who underwent EVAR between 1997 and 2011 at a tertiary center were analyzed. Comorbidity scores stratified patients into low/normal-risk (score ≤ 10) or high-risk categories (score > 10). The primary end point was mortality; secondary end points were morbidities, reinterventions, conversions, and ruptures. Results The study included 934 patients, 117 women (13%) and 817 men (87%) (mean age, 76 ± 7.3 years; range, 51-99 years). There were 870 (93%) asymptomatic, 36 (3.9%) symptomatic, and 28 (3.0%) ruptured AAAs. The 30-day mortality was 1.4% (13 of 934), 1.0% (9 of 870) for asymptomatic patients, 2.8% (1 of 36) for patients with symptomatic AAAs, and 11% (3 of 28) for patients with ruptured AAAs ( P = .004). Clinical presentation with symptoms or rupture was associated with more complications ( P = .02), reinterventions ( P = .003), and a lower 5-year survival ( P = .04). Association between surgical risk, female gender, age, and outcome was studied in 870 asymptomatic patients. Both 30-day mortality and complication rates were higher for high-risk vs low/normal-risk patients (2.3% vs 0.2%, P = .003; 15% vs 10%, P = .04); reintervention rates were equivalent (3.8% vs 4.4%; P = .67). The 30-day mortality and complication rates were similar in women and men (2.8% vs 0.8%, P = .09; 17% vs 11%, P = .11), but reintervention rate was higher in women (8.5% vs 3.5%; P = .02). Follow-up averaged 3.8 years (1 month-13.5 years). In asymptomatic patients, 5-year survival was 74% for low/normal-risk patients and 54% for high-risk patients ( P < .001); both had similar rates of freedom from complications (65% vs 63%; P = .24), reinterventions (71% vs 75%; P = .36), or rupture (99.3% vs 99.7%; P = .42). Women had more complications (47% vs 34%; P = .04) and reinterventions than men did (39% vs 26%; P = .02); freedom from rupture was the same (100% vs 99.3%; P = .30). There were eight ruptures, all in asymptomatic patients. In multivariate analysis, high surgical risk and age were associated with all-cause mortality ( P < .001); female gender was associated with complications and reinterventions ( P < .05) but not mortality. Conclusions Clinical presentation predicts early mortality and complications, age predicts both early and late mortalities after EVAR. Although women had an increased rate of complications and reinterventions, women did not have significantly higher mortality than men.
Objective The objective of this report was to define the natural history of penetrating aortic ulcers (PAUs) in the descending thoracic and abdominal aorta. Methods Data from consecutive patients ...with PAU from January 1, 1998 to December 31, 2012 were retrospectively reviewed. Computed tomography (CT) scans were analyzed for anatomic changes. End points analyzed were changes in size, development of symptoms or signs of rupture, morbidity, and mortality. Results Ninety-three patients were identified; 57 were followed up with two or more CT studies 3 months apart (group 1), and 20 had immediate repair (group 2). Sixteen had one CT scan and no intervention or follow-up and were excluded from analysis. In group 1, mean age was 75 years (29 men, 28 women), with 28 descending thoracic aorta and 29 abdominal aorta PAUs. Fifty patients were asymptomatic, whereas five had pain and two had emboli. Mean follow-up was 38 months (range, 3-108 months). Ulcer growth rate was as follows: length, 2.0 mm/y; depth, 1.2 mm/y; and aortic diameter, 2.2 mm/y. Thirteen (23%) went on to repair at a mean of 37 months after diagnosis because of size (54%; 7/13), rapid growth (31%; 4/13), and high-risk morphology (15%; 2/13). During surveillance, 11 patients died, 10 of unrelated causes, and 1 of rupture after refusing repair. All repairs in group 1 were endovascular. The 30-day surgical mortality was 0%. One patient had an access site complication requiring bypass after descending thoracic aorta PAU repair. At a mean follow-up of 32 months, all ulcers were excluded on CT; one (8%) had a type II endoleak. Group 2 included 13 men and seven women with a mean age of 70 years, with 12 descending thoracic and eight abdominal aorta PAUs. Repair indications were rupture (n = 3), symptoms (n = 10), or size (n = 7) and included one open and 19 endovascular repairs with 0% 30-day mortality. Major complications (3/20; 15%) included myocardial infarction, access site disruption, and hematoma; four of 20 patients had type II endoleaks. Conclusions PAU growth rate and risk of rupture are low. Endovascular repair of symptomatic, ruptured, and large PAUs is safe and effective with excellent long-term results. For asymptomatic PAUs, serial CT surveillance is associated with a low rate of rupture or complications.
Objective The objective of this study was to compare outcomes after open repair (OR) vs endovascular aneurysm repair (EVAR) of infrarenal abdominal aortic aneurysms (AAAs). Methods Clinical data of ...consecutive patients treated for asymptomatic AAA between 2000 and 2011 were reviewed. Patients were stratified into low/normal-risk (comorbidity score ≤ 10) and high-risk (score > 10) categories. The primary end point was all-cause mortality; secondary end points were complications, reinterventions, conversions, and ruptures. Propensity score-based matching was performed to compare outcomes. Results There were 1534 patients, of whom 207 were women (13%); 641 (42%) were treated with OR and 893 (58%) with EVAR. After propensity score matching, we selected 558 pairs of OR and EVAR (mean age, 73 ± 7.6 years); 158 were women (14%). The 30-day mortality rate was 1.3% after OR and 0.9% after EVAR ( P = .56). In multivariable analysis, only high risk was an independent predictor of early mortality (odds ratio, 4.65; 95% confidence interval CI, 1.20-18; P = .03). The early complication rate was lower for EVAR (13%; odds ratio, 0.5; 95% CI, 0.4-0.8; P < .001) than for OR (24%). Median follow-up was 7.6 years (31 days-13.1 years). The cumulative 5-year survival rate was 72% after EVAR and 81% after OR (hazard ratio, 1.44; 95% CI, 1.19-1.73; P < .001). The 5-year survival was not significantly different in matched cohorts operated on after 2005 (77% vs 81%; P = .57). High risk, advanced age, cancer history, AAA size, and EVAR predicted all-cause mortality. Freedom from reintervention was 74% after EVAR and 88% after OR (hazard ratio, 2.60; 95% CI, 1.92-3.51; P < .001). Freedom from rupture was 99.2% after EVAR and 99.8% after OR ( P = .04). In multivariable models, female gender was associated with complications; EVAR was associated with reinterventions ( P < .05). Conclusions In this retrospective propensity score-matched study, early mortality was similarly low after both EVAR and OR, significantly different from all except one large randomized controlled trial. EVAR had fewer early complications, but it was associated with late all-cause mortality and reinterventions and had a small but definite risk of late rupture. Significantly increased mortality at 5 years was no longer observed when operations were performed after 2005. High risk, advanced age, cancer history, and AAA size predicted late all-cause mortality. This study failed to confirm early or late survival benefit for EVAR vs OR. Improved surveillance, longer follow-up, and analysis of factors affecting late death in prospective studies are warranted.
Objective This study was conducted to determine the outcomes and predictive factors for success during percutaneous endovascular aneurysm repair (PEVAR) using vascular closure devices (VCDs). Methods ...The clinical data of patients who underwent PEVAR between 2005 and 2012 were retrospectively reviewed. Patient demographics, body mass index, sheath size, device types, diameter of femoral arteries, and extent and location of femoral artery calcification were recorded. Included were all consecutive patients treated by PEVAR with sheath sizes ranging from 12F to 24F. End points were technical success, conversion to open femoral artery repair, and complications. Results During this period, 752 patients were treated by EVAR. Of these, 391 femoral arteries in 222 patients (29.5%; 197 men, 25 women), with a mean age of 74.8 years (range, 51-93.7 years), underwent PEVAR (169 bilateral and 53 unilateral percutaneous access). Patients with >50% anterior femoral artery calcifications or those with previous femoral artery reconstructions were not offered PEVAR. Technical success of PEVAR was 96.4% (377 of 391), with an average of two VCDs used per groin. Fourteen intraoperative failures were managed with open femoral conversion using primary repair (five) or patch angioplasty (nine). In nine patients, the procedure was converted from local to general anesthesia. Four patients required a perioperative blood transfusion. There were no significant differences in body mass index ( P = .26), femoral artery size preprocedure ( P = .33) or postprocedure ( P = .37), sheath size (≥20F vs ≤18F), or type of VCD used between the success and failure groups. Pairwise comparisons revealed increased failure rate ( P < .001) between patients with <50% anterior wall calcification vs none, <50% anterior wall calcification vs <50% posterior wall calcification, and none vs >50% posterior calcification. There was no significant difference ( P = .53) between patients with <50% posterior wall calcification and those with no calcification. The 30-day mortality of the entire group was 0.9% (2 of 222 patients). No deaths occurred after conversion to open femoral closure. At a mean follow-up of 30 months (range, 1-85.2 months), there were no long-term groin complications or iliac limb occlusions. Conclusions PEVAR using VCDs can be performed with high technical success in patients with <50% anterior wall calcification, regardless of the size of the access sheath or the patient's body mass index. Femoral artery calcification, however, is a major determinant of failure.
Background Up to 15% to 30% of patients develop pancreatic fluid collections (PFCs) after pancreatic tail resection. Percutaneous and endoscopic methods have been used to drain these collections, ...though few data are available that compare outcomes of these modalities. Study Design From December 1998 to April 2011, we identified all patients who underwent pancreatic tail resection and developed PFCs requiring intervention. The primary aim was to compare overall success rates in resolution of PFCs using endoscopic and percutaneous modalities. Success rates, hospital length of stay, number of CT scans, sinograms and endoscopies performed, and days with drain(s) in place were compared. Results Forty-eight patients were identified. Percutaneous drainage was performed a median of 25 days postoperatively, compared with 85 days for endoscopic drainage (p < 0.001). Endoscopic and percutaneous methods had similar rates of technical success (100% vs 97%, p = 0.50) and treatment success (80% vs 81%, p = 0.92), respectively. Recurrence rates were 16.6% for the endoscopic group and 23% for the percutaneous group (p = 0.65), and adverse events occurred in 9.4% of those treated endoscopically vs 13.3% of those treated percutaneously (p = 0.68). Location and characteristics of PFCs did not influence success rates. Recurrences were often treated by “salvage” drainage via the other modality. Median hospital stay was longer after primary percutaneous drainage compared with primary endoscopic drainage (5.5 days vs 2 days, p = 0.046). Primary percutaneous drainage patients also had more CT scans (median 3 vs 2, p = 0.03). Conclusions Endoscopic drainage and percutaneous drainage appear to be equally effective and complementary interventions for PFCs occurring after pancreatic tail resection. Primary endoscopic drainage may be associated with shorter hospital stay and fewer CT scans.
Abstract Objective The purpose of this study was to evaluate whether maximal aortic diameter affects outcome after endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA). Methods ...Clinical data of patients undergoing EVAR between 1997 and 2011 for nonruptured asymptomatic AAAs in a tertiary center were reviewed. Patients were classified according to diameter of AAA: group 1, <5.0 cm; group 2, 5.0 to 5.4 cm; group 3, 5.5 to 5.9 cm; and group 4, ≥6.0 cm. The primary end point was all-cause mortality; secondary end points were complications, reinterventions, and ruptures. Results There were 874 patients studied (female, 108 12%; group 1, 119; group 2, 246; group 3, 243; group 4, 266); mean age was 76 ± 7.2 years. The 30-day mortality rate was 1.0%, not significantly different between groups ( P = .22); complication and reintervention rates were 13% and 4.1%, respectively, similar between groups ( P < .05). Five-year survival was 68%; freedom from complications and reinterventions was 65% and 74%, respectively; rupture rate was 0.5%. Multivariate analysis revealed that factors associated with all-cause mortality included maximal aortic diameter, age, gender, surgical risk, cancer history, and endograft type ( P < .05). Group 4 had increased risks of mortality (hazard ratio HR, 2.0; 95% confidence interval CI, 1.38-2.85; P = .002) and complications (HR, 1.6; 95% CI, 1.2-2.7; P = .009) relative to group 1. Reinterventions were more frequent for aneurysms ≥6.0 cm (HR, 2.0; 95% CI, 1.2-3.3; P = .01). Late rupture rate after EVAR was not different between groups. Conclusions Maximal aortic diameter is associated with long-term outcomes after elective EVAR. Patients with large AAAs (≥6.0 cm) have higher all-cause mortality, complication, and reintervention rates after EVAR than those with smaller aneurysms. We continue to recommend that AAAs be repaired when they reach 5.5 cm as recommended by the guidelines of the Society for Vascular Surgery. On the basis of our data, EVAR should be considered even in high-risk patients with a maximal aortic diameter between 5.5 and 6.0 cm because surgical risk with aneurysm size above 6.0 cm will increase significantly.
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