Efficacy and safety of the C5 inhibitor crovalimab in complement inhibitor-naive patients with PNH (COMMODORE 3): A multicenter, Phase 3, single-arm study.

The Phase 3 single-arm COMMODORE 3 study (ClinicalTrials.gov, NCT04654468) evaluated efficacy and safety of crovalimab (novel C5 inhibitor) in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). COMMODORE 3 enrolled patients from five China centers. Eligible complement inhibitor-naive patients with PNH were ≥12 years old, had lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN), and had ≥4 transfusions of packed red blood cells within the prior 12 months. Patients received crovalimab loading doses (one intravenous, four subcutaneous) and subsequent every-4-weeks subcutaneous maintenance doses per weight-based tiered-dosing schedule. Co-primary efficacy endpoints were mean proportion of patients with hemolysis control (LDH ≤1.5 × ULN) from Week (W)5 through W25 and difference in proportion of patients with transfusion avoidance from baseline through W25 versus within 24 weeks of prescreening in patients who had ≥1 crovalimab dose and ≥1 central LDH assessment after first dose. Between March 17 and August 24, 2021, 51 patients (15-58 years old) were enrolled; all received treatment. At primary analysis, both co-primary efficacy endpoints were met. Estimated mean proportion of patients with hemolysis control was 78.7% (95% CI: 67.8-86.6). Difference between proportion of patients with transfusion avoidance from baseline through W25 (51.0%; n = 26) versus within 24 weeks of prescreening (0%) was statistically significant (p < .0001). No adverse events led to treatment discontinuation. One treatment-unrelated death (subdural hematoma following a fall) occurred. In conclusion, crovalimab, with every-4-weeks subcutaneous dosing is efficacious and well tolerated in complement inhibitor-naive patients with PNH.

Disease burden and remaining unmet need in patients with haemophilia A treated with primary prophylaxis.

AIMS: There is evidence that people with haemophilia A still experience morbidity and functional limitation due to joint damage despite prophylaxis. This study aimed to compare their quality of life and work-related function with that of the general population and patients with osteoarthritis. METHODS: Data from the Cost of Haemophilia in Europe: a Socioeconomic Survey (CHESS) database were compared with published data from normative populations and patients with osteoarthritis in Europe and the United States. RESULTS: In the predominantly young (age 18-35 years) adult CHESS population treated with primary prophylaxis, about 30% reported a target joint; the average frequency of bleeds was one per year; half reported chronic pain. Levels of anxiety and depression were similar to those reported by people using on-demand treatment. Employment and productivity were lower than in the general population. The level of presenteeism (attending work with impairment) was comparable with that reported for a much older population with osteoarthritis who had more extensive joint damage and greater prevalence of pain. CONCLUSION: Compared with the general population, clinical outcomes and quality of life are indicated to be impaired for young adults whose haemophilia is managed by primary prophylaxis. Primary prophylaxis is not associated with lower levels of anxiety and depression than on-demand treatment, and pain is common. The level of presenteeism is comparable to that reported in people with osteoarthritis, an older population with more joint disease. Further studies are needed to fully assess the implications of compromised work performance among young adults with haemophilia as they seek to build a career.

Early Quality of Life Outcomes After Robotic-Assisted Minimally Invasive and Open Esophagectomy.

BACKGROUND: Minimally invasive esophagectomy may improve some perioperative outcomes over open approaches; effects on quality of life are less clear. METHODS: A prospective trial of robotic-assisted minimally invasive esophagectomy (RAMIE) and open esophagectomy was initiated, measuring quality of life via the Functional Assessment of Cancer Therapy-Esophageal and Brief Pain Inventory. Mixed generalized linear models assessed associations between quality of life scores over time and by surgery type. RESULTS: In total, 106 patients underwent open esophagectomy; 64 underwent minimally invasive esophagectomy (98% RAMIE). The groups did not differ in age, sex, comorbidities, histologic subtype, stage, or induction treatment (P = .42 to P > .95). Total Functional Assessment of Cancer Therapy-Esophageal scores were lower at 1 month (P < .001), returned to near baseline by 4 months, and did not differ between groups (P = .83). Brief Pain Inventory average pain severity (P = .007) and interference (P = .004) were lower for RAMIE. RAMIE had lower estimated blood loss (250 vs 350 cm3; P < .001), shorter length of stay (9 vs 11 days; P < .001), fewer intensive care unit admissions (8% vs 20%; P = .033), more lymph nodes harvested (25 vs 22; P = .05), and longer surgical time (6.4 vs 5.4 hours; P < .001). Major complications (39% for RAMIE vs 52% for open esophagectomy; P > .95), anastomotic leak (3% vs 9%; P = .41), and 90-day mortality (2% vs 4%; P = .85) did not differ between groups. Pulmonary (14% vs 34%; P = .014) and infectious (17% vs 36%; P = .029) complications were lower for RAMIE. CONCLUSIONS: RAMIE is associated with lower immediate postoperative pain severity and interference and decreased pulmonary and infectious complications. Ongoing data accrual will assess mid-term and long-term outcomes in this cohort.

Treatment regimens and outcomes in severe and moderate haemophilia A in the UK: The THUNDER study.

INTRODUCTION: The THUNDER study provides an analysis of treatment patterns and outcomes in UK patients with severe or moderate haemophilia A (SHA/MHA) in 2015. METHODS: Patients with SHA or MHA registered with the UK National Haemophilia Database (NHD) were segregated by severity, inhibitor status and age. Haemophilia joint health score (HJHS) was derived from NHD records and treatment regimen and annualized bleed/joint-bleed rate (ABR/AJBR) from Haemtrack (HT) in HT-compliant patients. RESULTS: We report 1810 patients with SHA and 864 with MHA. Prophylaxis was used in 94.9% (n = 130/137) of HT-compliant children <12 years with SHA, falling to 74.1% (n = 123/166) aged ≥40 years. Median ABR increased with age (1.0, IQR 0.0-5.0, <12 years; 3.0 IQR, 1.0-8.0, ≥40 years). Inhibitors were present in 159 (8.8%) SHA and 34 (3.9%) MHA. Median ABR increased from 2.0 (<12 years) to 21.0 (≥40 years) in SHA inhibitor patients using prophylaxis. Prophylaxis was used by 68.8% of HT-compliant MHA patients (n = 106) (median FVIII baseline 0.01 IU/mL) associated with a median (IQR) ABR of 3.0 (1.0-7.0). Median HJHS (n = 453) increased with age in SHA and MHA. Median (IQR) HJHS was higher in SHA inhibitor (17.0, 0.0-64.5) than non- or past inhibitor patients (7.0, 0.0-23.0). CONCLUSIONS: Increasing ABR with age persists despite current prophylaxis regimens. SHA and MHA had similar ABR/AJBR and HJHS, leading to a suspicion that a subgroup of MHA may be relatively undertreated. More intensive prophylaxis may improve outcomes, but this requires further study.

Vismodegib Use in Clinical Practice: Analysis of a United States Medical Claims Database.

BACKGROUND: Information is limited on the use of vismodegib for treatment of advanced basal cell carcinoma beyond the setting of clinical trials. OBJECTIVE: To investigate the treatment patterns and characteristics of patients treated with vismodegib in clinical practice. METHODS: A longitudinal, retrospective cohort study was undertaken using data from a US commercial insurance claims (Truven Health Analytics MarketScan) database. Eligible patients were ≥18 years of age, with ≥1 claim for vismodegib from January 2012 to December 2015. RESULTS: A total of 321 patients were included in the analysis. Approximately 20% of the patients took 1 or more treatment breaks of ≥ 30 days each before treatment discontinuation. Median duration of vismodegib treatment before the first treatment break and discontinuation was 4.0 and 5.5 months, respectively. Older age ( > 65 years) and absence of Gorlin syndrome were associated with increased risk for treatment interruption or discontinuation. Overall, 47% and 36% of patients underwent surgery or radiotherapy within the 6 months before and after vismodegib initiation, respectively. CONCLUSIONS: Real-world evidence indicates that vismodegib is being used in clinical practice as part of combination treatment strategies. J Drugs Dermatol. 2018;17(2):143-148.

Risk of cutaneous squamous cell carcinoma after treatment of basal cell carcinoma with vismodegib.

BACKGROUND: Vismodegib is a first-in-class agent targeting the hedgehog signaling pathway for treatment of patients with locally advanced basal cell carcinoma (BCC) and metastatic BCC. There have been concerns about the development of squamous cell carcinoma (SCC) in patients treated with this drug. OBJECTIVE: We sought to determine whether treatment with vismodegib is associated with an increase in the risk of cutaneous SCC. METHODS: In this retrospective cohort study, patients treated with vismodegib as part of phase I and II clinical studies were compared with participants from the University of California, San Francisco, Nonmelanoma Skin Cancer Cohort who received standard therapy for primary BCC. In total, 1675 patients were included in the analysis, and the development of SCC after vismodegib exposure was assessed. RESULTS: The use of vismodegib was not associated with an increased risk of subsequent development of SCC (adjusted hazard ratio, 0.57; 95% confidence interval, 0.28-1.16). Covariates including age, sex, history of previous nonmelanoma skin cancer, and number of visits per year were significantly associated with the development of SCC. LIMITATIONS: A limitation of the study was that a historic control cohort was used as a comparator. CONCLUSIONS: Vismodegib was not associated with an increased risk of subsequent SCC when compared with standard surgical treatment of BCC.

Long-term Survival Based on the Surgical Approach to Lobectomy For Clinical Stage I Nonsmall Cell Lung Cancer: Comparison of Robotic, Video-assisted Thoracic Surgery, and Thoracotomy Lobectomy.

OBJECTIVE: To compare the long-term outcomes among robotic, video-assisted thoracic surgery (VATS), and open lobectomy in stage I nonsmall cell lung cancer (NSCLC). BACKGROUND: Survival comparisons between robotic, VATS, and open lobectomy in NSCLC have not yet been reported. Some studies have suggested that survival after VATS is superior, for unclear reasons. METHODS: Three cohorts (robotic, VATS, and open) of clinical stage I NSCLC patients were matched by propensity score and compared to assess overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed to identify factors associated with the outcomes. RESULTS: From January 2002 to December 2012, 470 unique patients (172 robotic, 141 VATS, and 157 open) were included in the analysis. The robotic approach harvested a higher number of median stations of lymph nodes (5 for robotic vs 3 for VATS vs 4 for open; P < 0.001). Patients undergoing minimally invasive approaches had shorter median length of hospital stay (4 d for robotic vs 4 d for VATS vs 5 d for open; P < 0.001). The 5-year OS for the robotic, VATS, and open matched groups were 77.6%, 73.5%, and 77.9%, respectively, without a statistically significant difference; corresponding 5-year DFS were 72.7%, 65.5%, and 69.0%, respectively, with a statistically significant difference between the robotic and VATS groups (P = 0.047). However, multivariate analysis found that surgical approach was not independently associated with shorter OS and DFS. CONCLUSIONS: Minimally invasive approaches to lobectomy for clinical stage I NSCLC result in similar long-term survival as thoracotomy. Use of VATS and robotics is associated with shorter length of stay, and the robotic approach resulted in greater lymph node assessment.

KRAS Mutation Is a Significant Prognostic Factor in Early-stage Lung Adenocarcinoma.

The potential clinical impact of KRAS and epidermal growth factor receptor (EGFR) mutations has been investigated in lung adenocarcinomas; however, their prognostic value remains controversial. In our study, we sought to investigate the prognostic significance of driver mutations using a large cohort of early-stage lung adenocarcinomas. We reviewed patients with pathologic early-stage, lymph node-negative, solitary lung adenocarcinoma who had undergone surgical resection (1995 to 2005; stage I/II=463/19). Tumors were classified according to the IASLC/ATS/ERS classification and genotyped by Sequenom MassARRAY system and polymerase chain reaction-based assays. In stage I disease, the Kaplan-Meier method and cumulative incidence of recurrence analyses were used to estimate the probability of overall survival (OS) and recurrence, respectively. Of all, 129 (27%) patients had mutations in KRAS, 86 (18%) in EGFR, 8 (2%) in BRAF, 8 (2%) in PIK3CA, 4 (1%) in NRAS, and 1 (0.2%) in AKT1. EGFR L858R mutation correlated with lepidic predominant histology (P=0.006), whereas exon 19 deletion correlated with acinar predominant histology (P<0.001). EGFR mutations were not detected in invasive mucinous adenocarcinomas (P=0.033). The 5-year OS of patients with KRAS-mutant tumors was significantly worse (n=124; 5-year OS, 63%) than those with KRAS wild-type (n=339; 77%; P<0.001). In solid predominant tumors, KRAS mutations correlated with worse OS (P=0.008) and increased risk of recurrence (P=0.005). On multivariate analysis, KRAS mutation was an independent prognosticator of OS in all patients (hazard ratio, 1.87; P<0.001) and recurrence in solid predominant tumors (hazard ratio, 4.73; P=0.012). In patients with resected stage I lung adenocarcinomas, KRAS mutation was an independent prognostic factor for OS and recurrence, especially in solid predominant tumors.

Attaining Proficiency in Robotic-Assisted Minimally Invasive Esophagectomy While Maximizing Safety During Procedure Development.

OBJECTIVE: Robotic-assisted minimally invasive esophagectomy (RAMIE) is an emerging complex operation with limited reports detailing morbidity, mortality, and requirements for attaining proficiency. Our objective was to develop a standardized RAMIE technique, evaluate procedure safety, and assess outcomes using a dedicated operative team and 2-surgeon approach. METHODS: We conducted a study of sequential patients undergoing RAMIE from January 25, 2011, to May 5, 2014. Intermedian demographics and perioperative data were compared between sequential halves of the experience using the Wilcoxon rank sum test and the Fischer exact test. Median operative time was tracked over successive 15-patient cohorts. RESULTS: One hundred of 313 esophageal resections performed at our institution underwent RAMIE during the study period. A dedicated team including 2 attending surgeons and uniform anesthesia and OR staff was established. There were no significant differences in age, sex, histology, stage, induction therapy, or risk class between the 2 halves of the study. Estimated blood loss, conversions, operative times, and overall complications significantly decreased. The median resected lymph nodes increased but was not statistically significant. Median operative time decreased to approximately 370 minutes between the 30th and the 45th cases. There were no emergent intraoperative complications, and the anastomotic leak rate was 6% (6/100). The 30-day mortality was 0% (0/100), and the 90-day mortality was 1% (1/100). CONCLUSIONS: Excellent perioperative and short-term patient outcomes with minimal mortality can be achieved using a standardized RAMIE procedure and a dedicated team approach. The structured process described may serve as a model to maximize patients' safety during development and assessment of complex novel procedures.

Physician-Driven Variation in Nonrecommended Services Among Older Adults Diagnosed With Cancer.

IMPORTANCE: Interventions to address overuse of health care services may help reduce costs and improve care. Understanding physician-level variation and behavior patterns can inform such interventions. OBJECTIVE: To assess patterns of physician ordering of services that tend to be overused in the treatment of patients with cancer. We hypothesized that physicians exhibit consistent behavior. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of patients 66 years and older diagnosed with cancer between 2004 and 2011, using population-based Surveillance, Epidemiology, and End Results (SEER)-Medicare data to assess physician-level variation in 5 nonrecommended services. Services included imaging for staging and surveillance in low-risk disease, intensity-modulated radiation therapy (IMRT) after breast-conserving surgery, and extended fractionation schemes for palliation of bone metastases. MAIN OUTCOME AND MEASURES: To assess variation in service use between physicians, we used a random effects model and a logistic regression model with a lag variable to assess whether a physician's use of a service for a prior patient predicts subsequent service use. RESULTS: Cohorts ranged from 3464 to 89 006 patients. The total proportion of patients receiving each service varied from 14% for imaging in staging early breast cancer to 41% in early prostate cancer. From the random effects analysis, we found significant unexplained variation in service use between physicians (P < .001 for each service; ICC, 0.04-0.59). Controlling for case mix, whether a physician ordered a service for the prior patient was highly predictive of service use, with adjusted odds ratios (aORs) ranging from 1.12 (95% CI, 1.07-1.18) for surveillance imaging for patients with breast cancer (28% service use if prior patient had imaging vs 25% if not), to 24.91 (95% CI, 22.86-27.15) for IMRT for whole breast radiotherapy (69% vs 7%, respectively). CONCLUSIONS AND RELEVANCE: Physicians' utilization of nonrecommended services that tend to be overused exhibit patterns that suggest consistent behavior more than personalized patient care decisions. Reducing overuse may require understanding cognitive drivers of repetitive inappropriate decisions.

Minimally invasive (robotic assisted thoracic surgery and video-assisted thoracic surgery) lobectomy for the treatment of locally advanced non-small cell lung cancer.

BACKGROUND: Insufficient data exist on the results of minimally invasive surgery (MIS) for locally advanced non-small cell lung cancer (NSCLC) traditionally approached by thoracotomy. The use of telerobotic surgical systems may allow for greater utilization of MIS approaches to locally advanced disease. We will review the existing literature on MIS for locally advanced disease and briefly report on the results of a recent study conducted at our institution. METHODS: We performed a retrospective review of a prospective single institution database to identify patients with clinical stage II and IIIA NSCLC who underwent lobectomy following induction chemotherapy. The patients were classified into two groups (MIS and thoracotomy) and were compared for differences in outcomes and survival. RESULTS: From January 2002 to December 2013, 428 patients {397 thoracotomy, 31 MIS [17 robotic and 14 video-assisted thoracic surgery (VATS)]} underwent induction chemotherapy followed by lobectomy. The conversion rate in the MIS group was 26% (8/31) The R0 resection rate was similar between the groups (97% for MIS vs. 94% for thoracotomy; P=0.71), as was postoperative morbidity (32% for MIS vs. 33% for thoracotomy; P=0.99). The median length of hospital stay was shorter in the MIS group (4 vs. 5 days; P<0.001). The 3-year overall survival (OS) was 48.3% in the MIS group and 56.6% in the thoracotomy group (P=0.84); the corresponding 3-year DFS were 49.0% and 42.1% (P=0.19). CONCLUSIONS: In appropriately selected patients with NSCLC, MIS approaches to lobectomy following induction therapy are feasible and associated with similar disease-free and OS to those following thoracotomy.

Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers. Pathologic classification and optimal therapies are debated. We report the clinicopathologic features, treatment and survival of a series of patients with stage IV LCNEC. MATERIALS AND METHODS: Cases of pathologically-confirmed stage IV LCNEC evaluated at Memorial Sloan Kettering Cancer Center from 2006 to 2013 were identified. We collected demographic, treatment, and survival data. Available radiology was evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. RESULTS: Forty-nine patients with stage IV LCNEC were identified. The median age was 64 years, 63% of patients were male, and 88% were smokers. Twenty-three patients (n = 23/49; 47%) had brain metastases, 17 at diagnosis and 6 during the disease course. Seventeen LCNEC patients (35%) had molecular testing, of which 24% had KRAS mutations (n = 4/17). Treatment data for first-line metastatic disease was available on 37 patients: 70% (n = 26) received platinum/etoposide and 30% (n = 11) received other regimens. RECIST was completed on 23 patients with available imaging; objective response rate was 37% (95% confidence interval, 16%-62%) with platinum/etoposide, while those treated with other first-line regimens did not achieve a response. Median overall survival was 10.2 months (95% confidence interval, 8.6-16.4 months) for the entire cohort. CONCLUSION: Patients with stage IV LCNEC have a high incidence of brain metastases. KRAS mutations are common. Patients with stage IV LCNEC do not respond as well to platinum/etoposide compared with historic data for extensive stage small-cell lung cancer; however, the prognosis is similar. Prospective studies are needed to define optimum therapy for stage IV LCNEC.

ReCAP: Detection of Potentially Avoidable Harm in Oncology From Patient Medical Records.

PURPOSE: Widespread consensus exists about the importance of addressing patient safety issues in oncology, yet our understanding of the frequency, spectrum, and preventability of adverse events (AEs) across cancer care is limited. METHODS: We developed a screening tool to detect AEs across cancer care settings through medical record review. Members of the study team reviewed the scientific literature and obtained structured input from an external multidisciplinary panel of clinicians by using a modified Delphi process. RESULTS: The screening tool comprises 76 triggers-readily identifiable findings to screen for possible AEs that occur during cancer care. Categories of triggers are general care, vital signs, medication related, laboratory tests, other orders, and consultations. CONCLUSION: Although additional testing is required to assess its performance characteristics, this tool may offer an efficient mechanism for identifying possibly preventable AEs in oncology and serve as an instrument for quality improvement.

Serum Biomarkers Associated with Clinical Outcomes Fail to Predict Brain Metastases in Patients with Stage IV Non-Small Cell Lung Cancers.

BACKGROUND: Lung cancers account for the majority of brain metastases which pose major therapeutic challenges. Biomarkers prognosticating for the development of brain metastases in patients with non-small cell lung cancers (NSCLC) may improve personalized care. Six serum proteomic biomarkers were previously investigated at Memorial Sloan Kettering but their associations with brain metastases were unknown. METHODS: Serum NSE, CYFRA 21-1, ProGRP, SCC-Ag, TIMP1, and HE4 by ELISA-based proteomic assays were prospectively collected from consecutive patients with stage IV NSCLC. Pre-treatment serum biomarker levels as well as age, histology, and epidermal growth factor receptor (EGFR) mutation status were evaluated for association with the baseline presence of brain metastases using logistic regression and multivariable analysis. For patients without brain metastases at baseline, the cumulative incidence of subsequent brain metastases were compared according to baseline biomarkers and clinical factors using Gray's test. RESULTS: A total of 118 patients were enrolled, 31 (26%; 95% CI 0.19-0.35) had brain metastases at baseline and a further 26 (22%; 95% CI 0.15-0.30) developed brain metastases subsequently. Pre-treatment serum biomarker levels were available in 104 patients. There was no significant association between the six serum biomarkers and the baseline presence or subsequent development of brain metastases. Age younger than 65 years was the only clinical factor significantly associated with brain metastasis at baseline (OR 3.00; 95% CI 1.22-7.34, P = 0.02) by multivariable analysis. A trend toward increased cumulative incidence of subsequent brain metastases was observed in patients with EGFR mutation (p = 0.2), but this was not statistically significant possibly due to small sample size. CONCLUSIONS: Serum NSE, CYFRA 21-1, Pro-GRP, SCC-Ag, TIMP1, and HE4 are not significantly associated with brain metastases. Our methods taking into account follow-up time may be applied to independent datasets to identify a patient cohort with a higher biologic propensity for developing brain metastases. Such information may be useful for the study of agents targeting the development of brain metastases.

Prevalence and Safety of Off-Label Use of Chemotherapeutic Agents in Older Patients With Breast Cancer: Estimates From SEER-Medicare Data.

BACKGROUND: Prescribing drugs outside of the label indication is legal and may reflect standard practice; however, some off-label use may be inappropriate. This study measured the prevalence and safety of off-label use both in accordance with practice guidelines and inconsistent with practice guidelines in older patients with breast cancer. PATIENTS AND METHODS: The SEER-Medicare data set was used to identify women diagnosed with breast cancer. Intravenous chemotherapy was identified using Medicare claims and classified as either on-label, off-label but included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer ("off-label/supported"), or off-label and not included in the NCCN Guidelines ("off-label/unsupported"). Hospitalization/emergency department (ED) admission rates were compared. RESULTS: A total of 13,347 women were treated with 16,127 regimens (12% of women switched regimen); 64% of regimens were off-label/supported, 25% were on-label, and 11% were off-label/unsupported, and hospitalization/ED admission occurred in 27%, 25%, and 32% of regimens, respectively (P<.0001). Drugs never included in the NCCN Guidelines for Breast Cancer accounted for 19% of off-label/unsupported use (1% of total use). CONCLUSIONS: Off-label use without scientific support was not common, whereas 64% of use was off-label/supported, reflecting the fact that widely accepted indications are often not tested in registration trials. Off-label/supported use will likely increase as more drugs are expected to have activity across cancer sites, and therefore understanding the implications of such use is critical.

Feasibility and clinical impact of sharing patient-reported symptom toxicities and performance status with clinical investigators during a phase 2 cancer treatment trial.

BACKGROUND: Clinicians can miss up to half of patients' symptomatic toxicities in cancer clinical trials and routine practice. Although patient-reported outcome questionnaires have been developed to capture this information, it is unclear whether clinicians will make use of patient-reported outcomes to inform their own toxicity documentation, or to prompt symptom management activities. METHODS: 44 lung cancer patients that participated in a phase 2 treatment trial self-reported 13 symptomatic toxicities derived from the National Cancer Institute's Common Terminology Criteria for Adverse Events and Karnofsky Performance Status via tablet computers in waiting areas immediately preceding scheduled visits. During visits, clinicians viewed patients' self-reported toxicity and performance status ratings on a computer interface and could agree or disagree/reassign grades ("shared" reporting). Agreement of clinicians with patient-reported grades was tabulated, and compared using weighted kappa statistics. Clinical actions in response to patient-reported severe (grade 3/4) toxicities were measured (e.g. treatment discontinuation, dose reduction, supportive medications). For comparison, 45 non-trial patients with lung cancer being treated in the same clinic by the same physicians were simultaneously enrolled in a parallel cohort study in which patients also self-reported toxicity grades but reports were not shared with clinicians ("non-shared" reporting). RESULTS: Toxicities and performance status were reported by patients and reviewed by clinicians at (780/782) 99.7% of study visits in the phase 2 trial which used "shared" reporting. Clinicians agreed with patients 93% of the time with kappas 0.82-0.92. Clinical actions were taken in response to 67% of severe patient-reported toxicities. In the "non-shared" reporting comparison group, clinicians agreed with patients 56% of the time with kappas 0.04-0.48 (significantly worse than shared reporting for all symptoms), and clinical actions were taken in response to 44% of severe patient-reported toxicities. CONCLUSION: Clinicians will frequently agree with patient-reported symptoms and performance status, and will use this information to guide documentation and symptom management. (ClinicalTrials.gov: NCT00807573).

Pretreatment Dysphagia in Esophageal Cancer Patients May Eliminate the Need for Staging by Endoscopic Ultrasonography.

BACKGROUND: Neoadjuvant therapy is commonly administered to patients with localized disease who have T3-4 esophageal disease as staged by endoscopic ultrasound (EUS). Previously, we noted that patients who present with dysphagia have a higher EUS T stage. We hypothesized that the presence of dysphagia is predictive of EUS T3-4 disease and that staging EUS could be forgone for esophageal cancer patients with dysphagia. METHODS: We performed a prospective, intent-to-treat, single-cohort study in which patients with potentially resectable esophageal cancer completed a standardized four-tier dysphagia score survey. EUS was performed as part of our standard evaluation. To determine whether the presence of dysphagia predicted EUS T3-4 disease, the dysphagia score was compared with EUS T stage. RESULTS: The study enrolled 114 consecutive patients between August 2012 and February 2014: 77% (88 of 114) received neoadjuvant therapy, 18% (20 of 114) did not, and 5% (6 of 114) pursued treatment elsewhere. In total, 70% (80 of 114) underwent esophagectomy; of these, 54% (61 of 114) had dysphagia and 46% (53 of 114) did not. Dysphagia scores were 66% (40 of 61) grade 1, 25% (15 of 61) grade 2, and 10% (6 of 61) grade 3 to 4. Among patients with dysphagia, 89% (54 of 61) had T3-4 disease by EUS; among those without dysphagia, only 53% (28 of 53) had T3-4 disease by EUS (p < 0.001). CONCLUSIONS: The presence of dysphagia in patients with esophageal cancer was highly predictive of T3-4 disease by EUS. On the basis of this finding, approximately 50% of patients currently undergoing staging EUS at our institution could potentially forgo EUS before neoadjuvant therapy. Patients without dysphagia, however, should still undergo EUS.

International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification predicts occult lymph node metastasis in clinically mediastinal node-negative lung adenocarcinoma.

OBJECTIVES: We investigated the role of the 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) classification in predicting occult lymph node metastasis in clinically mediastinal node-negative lung adenocarcinoma. METHODS: We reviewed lung adenocarcinoma patients who had clinically N2-negative status, were evaluated by preoperative positron emission tomography combined with computed tomography (PET/CT) and had undergone lobectomy or pneumonectomy at Memorial Sloan Kettering Cancer Center (n = 297). Tumours were classified according to the 2011 IASLC/ATS/ERS classification. The associations between occult lymph node metastasis and clinicopathological variables were analysed using Fisher's exact test and logistic regression analysis. RESULTS: Thirty-two (11%) cN0-1 patients had occult mediastinal lymph node metastasis (pN2) whereas 25% of cN1 patients had pN2 disease. Increased micropapillary pattern was associated with increased risk of pN2 disease (P = 0.001). On univariate analysis, high maximum standard uptake value of the primary tumour on PET/CT (P = 0.019) and the presence of micropapillary (P = 0.014) and solid pattern (P = 0.014) were associated with occult pN2 disease. On multivariable analysis, micropapillary pattern was positively associated with risk of pN2 disease (odds ratio = 3.41; 95% confidence intervals = 1.42-8.19; P = 0.006). CONCLUSIONS: The presence of micropapillary pattern is an independent predictor of occult mediastinal lymph node metastasis. Our observations have potential therapeutic implications for management of early-stage lung adenocarcinoma.

Impact of Concurrent PIK3CA Mutations on Response to EGFR Tyrosine Kinase Inhibition in EGFR-Mutant Lung Cancers and on Prognosis in Oncogene-Driven Lung Adenocarcinomas.

INTRODUCTION: In patients with epidermal growth factor receptor (EGFR)-mutant or KRAS-mutant lung adenocarcinomas, the prognostic impact of a concurrent PIK3CA mutation remains unclear. Although preclinical data suggest that sensitivity to EGFR tyrosine kinase inhibition (TKI) is decreased in EGFR-mutant lung cancers also harboring a PIK3CA mutation, this interaction has not been explored clinically. METHODS: Patients with lung adenocarcinomas harboring a PIK3CA mutation concurrent with a separate driver mutation were identified through mutational hotspot testing, multiplex sizing assays, and fluorescence in situ hybridization. Overall survival and outcomes with EGFR TKI monotherapy (EGFR-mutant) were estimated using Kaplan-Meier methods and compared between double-mutant (EGFR-mutant or KRAS-mutant, concurrent PIK3CA-mutant) and single-mutant patients (EGFR-mutant or KRAS-mutant, PIK3CA wild-type) using log-rank tests. RESULTS: In EGFR-mutant and KRAS-mutant lung cancers, a concurrent PIK3CA mutation was associated with a decrease in median overall survival: 18 versus 33 months (EGFR double mutant, n = 10 versus single mutant, n = 43, p = 0.006), and 9 versus 16 months (KRAS double mutant, n = 16 versus single mutant, n = 47, p = 0.020). In EGFR-mutant lung cancers, a concurrent PIK3CA mutation did not impact benefit from EGFR TKI monotherapy. Single versus double mutant: objective response rate, 83% (n = 29) versus 62% (n = 6, p = 0.80); median time to progression, 11 (n = 29) versus 8 months (n = 6, p = 0.84); and median duration of TKI therapy, 15 (n = 32) versus 15 months (n = 10, p = 0.65). CONCLUSION: A concurrent PIK3CA mutation is a poor prognostic factor in patients with advanced EGFR-mutant or KRAS-mutant lung adenocarcinomas. There was no evidence that clinical benefit from EGFR TKI monotherapy is affected by a concurrent PIK3CA mutation in EGFR-mutant lung cancers.

Prognostic Impact of Immune Microenvironment in Lung Squamous Cell Carcinoma: Tumor-Infiltrating CD10+ Neutrophil/CD20+ Lymphocyte Ratio as an Independent Prognostic Factor.

INTRODUCTION: We previously reported the prognostic significance of the lung adenocarcinoma immune microenvironment. In this study, we preformed comprehensive analysis of immune markers and their associations with prognosis in patients with lung squamous cell carcinoma. METHODS: We reviewed surgically resected, solitary lung squamous cell carcinoma patients (n = 485; 1999-2009) who were randomly split into a training cohort (n = 331) and validation cohort (n = 154). We constructed tissue microarrays and performed immunostaining for CD3, CD45RO, CD8, CD4, FoxP3, CD20, CD68, CXCL12, CXCR4, CCR7, interleukin-7 receptor, and interleukin-12 receptor ß2. Overall survival (OS) was analyzed using the log-rank test and the Cox proportional hazards model. RESULTS: Analysis of single immune cell infiltration revealed that high tumor-infiltrating CD10(+) neutrophils were associated with worse prognoses in the training cohort (p = 0.021). Analysis of biologically relevant immune cell combinations identified that patients with high CD10 neutrophil and low CD20(+) lymphocyte had a significantly worse OS (5-year OS, 42%) than those with other combinations of CD10 and CD20 (5-year OS, 62%; p < 0.001); this was confirmed in the validation cohort (p = 0.032). For the multivariate analysis, high CD10/low CD20 immune cell infiltration was an independent predictor of OS in both the training cohort (hazard ratio = 1.61, p = 0.006) and the validation cohort (hazard ratio = 1.75; p = 0.043). CONCLUSION: High CD10(+)/low CD20(+) immune cell infiltration ratio is a significant prognostic factor of lung squamous cell carcinoma. Immunomodulatory therapy of tumor-specific neutrophil and B-lymphocyte responses may have applicability in the treatment of lung squamous cell carcinoma.