Recommendations from a Canadian Delphi consensus study on best practice for optimal referral and appropriate management of severe asthma.

BACKGROUND: In Canada, severe asthma affects an estimated 5-10% of people with asthma and is associated with frequent exacerbations, poor symptom control and significant morbidity from the disease itself, as well as the high dose inhaled, and systemic steroids used to treat it. Significant heterogeneity exists in service structure and patient access to severe asthma care, including access to biologic treatments. There appears to be over-reliance on short-acting beta agonists and frequent oral corticosteroid use, two indicators of uncontrolled asthma which can indicate undiagnosed or suboptimally treated severe asthma. The objective of this modified Delphi consensus project was to define standards of care for severe asthma in Canada, in areas where the evidence is lacking through patient and healthcare professional consensus, to complement forthcoming guidelines. METHODS: The steering group of asthma experts identified 43 statements formed from eight key themes. An online 4-point Likert scale questionnaire was sent to healthcare professionals working in asthma across Canada to assess agreement (consensus) with these statements. Consensus was defined as high if ≥ 75% and very high if ≥ 90% of respondents agreed with a statement. RESULTS: A total of 150 responses were received from HCPs including certified respiratory educators, respirologists, allergists, general practitioners/family physicians, nurses, pharmacists, and respiratory therapists. Consensus amongst respondents was very high in 37 (86%) statements, high in 4 (9%) statements and was not achieved in 2 (5%) statements. Based on the consensus scores, ten key recommendations were proposed. These focus on referrals from primary and secondary care, accessing specialist asthma services, homecare provision for severe asthma patients and outcome measures. CONCLUSIONS: Implementation of these recommendations across the severe asthma care pathway in Canada has the potential to improve outcomes for patients through earlier detection of undiagnosed severe asthma, reduction in time to severe asthma diagnosis, and initiation of advanced phenotype specific therapies.

Morbidity following salvage esophagectomy for squamous cell carcinoma: the MD Anderson experience.

The survival advantage associated with the addition of surgical therapy in esophageal squamous cell carcinoma (ESCC) patients who demonstrate a complete clinical response to chemoradiotherapy is unclear, and many institutions have adopted an organ-preserving strategy of selective surgery in this population. We sought to characterize our institutional experience of salvage esophagectomy (for failure of definitive bimodality therapy) and planned esophagectomy (as a component of trimodality therapy) by retrospectively analyzing patients with ESCC of the thoracic esophagus and GEJ who underwent esophagectomy following chemoradiotherapy between 2004 and 2016. Of 76 patients who met inclusion criteria, 46.1% (35) underwent salvage esophagectomy. Major postoperative complications (major cardiovascular and pulmonary events, anastomotic leak [grade ≥ 2], and 90-day mortality) were frequent and occurred in 52.6% of the cohort (planned resection: 36.6% [15/41]; salvage esophagectomy: 71.4% [25/35]). Observed rates of 30- and 90-day mortality for the entire cohort were 7.9% (planned: 7.3% [3/41]; salvage: 8.6% [3/35]) and 13.2% (planned: 9.8% [4/41]; salvage: 17.1% [6/35]), respectively. In summary, esophagectomy following chemoradiotherapy for ESCC at our institution has been associated with frequent postoperative morbidity and considerable rates of mortality in both planned and salvage settings. Although a selective approach to surgery may permit organ preservation in many patients with ESCC, these results highlight that salvage esophagectomy for failure of definitive-intent treatment of ESCC may also constitute a difficult clinical undertaking in some cases.

Anaplastic Thyroid Carcinoma with Gastric Metastasis.

INTRODUCTION: Carcinomas of the thyroid gland represent 3% of all malignancies, with 1.3 to 9.8% corresponding to anaplastic thyroid carcinomas (ATC). Metastases are present in 50% of patients when ATC is diagnosed. Gastrointestinal metastases are a rare finding in patients with thyroid carcinoma. CASE REPORT: A 68-year old gentleman with a history of papillary thyroid carcinoma (PTC) underwent surgery and radiopharmaceutical therapy. Restaging studies nine months later suggested wall thickening localizing to the distal stomach. Endoscopy results showed a large, infiltrative, subepithelial, and ulcerated gastric mass and biopsies revealed anaplastic thyroid carcinoma Conclusion. Incidental thickening or other findings in the stomach in a patient with ATC without gastrointestinal symptoms should be further investigated with endoscopy and biopsies to rule out gastric metastases from anaplastic thyroid carcinoma.

A Diagnostic Challenge: Pancreatic Cancer or Autoimmune Pancreatitis?

We report a rare case of seronegative autoimmune pancreatitis (AIP) that presented as a pancreatic focal lesion and was considered to be pancreatic cancer based on the clinical presentation and imaging findings. The endoscopic ultrasound-guided biopsies of the pancreatic mass revealed no malignant cells and the pancreatic swelling had become diffuse on repeat imaging. AIP was suspected and a trial of steroids was considered as a diagnostic and therapeutic method. The patient responded dramatically to corticosteroid treatment with resolution of symptoms and normal imagining and laboratory parameters. This case highlights the challenge in the diagnostic approach of a pancreatic mass.

Elevated levels of circulating CD4(+) CRTh2(+) T cells characterize severe asthma.

BACKGROUND: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a receptor for PGD2 and expressed by T cells, eosinophils, basophils, and ILC2 cells. CRTh2 expression by CD4(+) T cells identifies the Th2 subset, and these cells have been characterized as allergen-specific central memory Th2 cells. Recently, activation of the PGD2 -CRTh2 pathway in the lungs was associated with severe asthma. OBJECTIVE: To assess circulating levels of Th2 cells and related mediators in severe asthma and those who experience asthma exacerbations. METHODS: Peripheral blood cells expressing CRTh2 were characterized by flow cytometry and qRT-PCR. Serum IL-13 and PGD2 were measured by ELISA and compared with asthma severity and tendency to exacerbate. RESULTS: Severe asthmatics had more circulating CD4(+) CRTh2(+) T cells, CRTh2 and GATA3 mRNA, and a higher level of serum IL-13 compared to mild/moderate asthmatics. The proportion of CD4(+) CRTh2(+) T cells was associated with lower lung function and was highest in severe asthmatics that exacerbated in the last year. Circulating CD4(+) CRTh2(+) T cells, unlike eosinophils, were positively correlated with inhaled steroid dose. CONCLUSIONS AND CLINICAL RELEVANCE: Elevated levels of circulating CD4(+) CRTh2(+) T cells are a feature of severe asthma, despite high-dose corticosteroids. Tracking the systemic level of these cells may help identify type 2 severe asthmatics at risk of exacerbation.

Defining and treating high-risk multiple myeloma.

Multiple myeloma (MM) is more recently being recognized as a heterogeneous group of disease with variability in outcomes based on specific clinical and biologic predictors. MM patients can be broadly categorized into standard, intermediate and high risk for disease relapse, morbidity and mortality. The high-risk features include patient-specific factors such as old age, poor performance status and comorbidities; clinical features such as primary plasma cell leukemia and extramedullary disease; disease-specific biologic features such as deletion 17p, t(4;14) and high-risk gene expression profiling signatures. The current paper reviews the available data on best therapeutic approaches for high-risk MM.

The emerging role of endoscopic ultrasound-guided core biopsy for the evaluation of solid pancreatic masses.

Pancreatic ductal adenocarcinoma is a lethal cancer with a 5-year survival rate of less than 5%. Surgical resection is the only curative treatment but only 20% are eligible for resection at the time of diagnosis. Early detection of cancer is of paramount importance in the management. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the preferred modality for obtaining tissue diagnosis of pancreatic masses. However, the diagnostic accuracy of EUS-FNA may be limited by several factors like availability of onsite cytopathology, adequacy of tissue core for histology, location of the mass, presence of underlying chronic pancreatitis, and experience of the endoscopist. Modern oncology is focusing on personalizing treatment based on tissue analysis of genetic aberrations and molecular biomarkers which are now available. Core tissue also aids in the diagnosis of disease entities like lymphoma, metastatic tumors, neuroendocrine tumors and autoimmune pancreatitis whose diagnosis rely on preserved tissue architecture and immunohistochemistry. Making accurate diagnosis of solid pancreatic masses is critical to avoid unnecessary resections in patients with benign lesions like focal lesions of chronic pancreatitis and autoimmune pancreatitis which mimic cancer. To overcome the limitations of FNA and to obtain adequate core tissue, a Tru-Cut biopsy needle was developed which met with variable success due to stiffness, cumbersome operation and technical failure using it in the duodenum/pancreatic head. More recently fine needle biopsy needles, with reverse bevel technology have become available in different sizes (19, 22, 25-gauge). The aim of this article was to review the emerging role of core biopsy needles in acquiring tissue in solid pancreatic masses and discuss its potential role in personalized medicine.

[Imaging in smoldering (asymptomatic) multiple myeloma. Past, present and future]. / Bildgebung bei "smoldering" (asymptomatischem) multiplem Myelom. Vergangenheit, Gegenwart und Zukunft.

CLINICAL ISSUE: Emerging clinical trial data support treatment of high-risk smoldering multiple myeloma (SMM) upon diagnosis, and not only at the time of progression to symptomatic complications (multiple myeloma). Early detection of bone and/or bone marrow involvement by sensitive imaging modalities may help define SMM patients at a high risk of progression. STANDARD RADIOLOGICAL METHODS: Current (2011) consensus guidelines recognize skeletal survey as a cornerstone modality for assessment of bone involvement at initial diagnosis and during follow-up of SMM. Skeletal survey has severe limitations related to underdetection of bone lesions and also provides no information on bone marrow abnormalities. METHODICAL INNOVATIONS: Modern imaging strategies such as fluorodeoxyglucose positron-emission tomography/CT (FDG PET/CT) and MRI, in conjunction with functional innovations, provide improved estimates of global abnormalities in the bone marrow and bone compartments. These methods have the potential to objectively quantify early transformation from SMM to multiple myeloma. PERFORMANCE: Although frequently used for staging and risk prognostication in multiple myeloma, modern imaging techniques have only been evaluated to a limited extent in SMM. Scant data in SMM indicate the prognostic value of two or more MRI-detected focal bone marrow abnormalities, which, if present, predict rapid progression to multiple myeloma. Data evaluating the role of FDG PET/CT in detecting early bone marrow abnormalities as an aid to predicting risk or directing treatment in SMM is currently lacking. ACHIEVEMENTS: The superior specificity and sensitivity of modern imaging techniques compared to skeletal survey suggest that these should have a place in standard practice management of patients at a high risk of SMM progression. The model imaging of the future should be an all-in-one strategy offering high diagnostic performance for bone marrow abnormalities and low-volume bone lesions, as well as allowing monitoring by minimizing radiation exposure and the need for contrast agents. PRACTICAL RECOMMENDATIONS: Newer imaging techniques need to be validated in prospective clinical trials assessing the SMM to multiple myeloma transition, with the aim of enabling appropriate management decisions. Efforts are also needed to improve the costs and availability of whole-body MRI and/or FDG PET/CT, in order to facilitate their widespread adoption as first-line detection modalities. Future clinical trials of therapeutic agents using earlier detection strategies will have to be carefully designed and take into consideration the risk of lead-time and length-time biases, which might falsely demonstrate longer overall survival. The English full text version of this article is available at SpringerLink (under "Supplemental").

ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients.

PURPOSE: Operable thoracic esophageal/gastroesophageal junction carcinoma (EC) is often treated with chemoradiation and surgery but tumor responses are unpredictable and heterogeneous. We hypothesized that aldehyde dehydrogenase-1 (ALDH-1) could be associated with response. METHODS: The labeling indices (LIs) of ALDH-1 by immunohistochemistry in untreated tumor specimens were established in EC patients who had chemoradiation and surgery. Univariate logistic regression and 3-fold cross validation were carried out for the training (67% of patients) and validation (33%) sets. Non-clinical experiments in EC cells were performed to generate complimentary data. RESULTS: Of 167 EC patients analyzed, 40 (24%) had a pathologic complete response (pathCR) and 27 (16%) had an extremely resistant (exCRTR) cancer. The median ALDH-1 LI was 0.2 (range, 0.01-0.85). There was a significant association between pathCR and low ALDH-1 LI (p ≤ 0.001; odds-ratio [OR] = 0.432). The 3-fold cross validation led to a concordance index (C-index) of 0.798 for the fitted model. There was a significant association between exCRTR and high ALDH-1 LI (p ≤ 0.001; OR = 3.782). The 3-fold cross validation led to the C-index of 0.960 for the fitted model. In several cell lines, higher ALDH-1 LIs correlated with resistant/aggressive phenotype. Cells with induced chemotherapy resistance upregulated ALDH-1 and resistance conferring genes (SOX9 and YAP1). Sorted ALDH-1+ cells were more resistant and had an aggressive phenotype in tumor spheres than ALDH-1- cells. CONCLUSIONS: Our clinical and non-clinical data demonstrate that ALDH-1 LIs are predictive of response to therapy and further research could lead to individualized therapeutic strategies and novel therapeutic targets for EC patients.

Endoscopic ultrasound-guided radiation therapy in pancreatic cancer.

During the last two decades, endoscopic ultrasound has revolutionized the diagnosis and treatment of gastrointestinal (GI) malignancies. The role of EUS has expanded well beyond its role as a diagnostic modality, and has emerged as a highly sophisticated interventional modality. More recently, EUS has paved its way into radiation oncology by either facilitating highly targeted image guided radiotherapy (IGRT) by insertion of fiducial markers in tumors or by direct instillation of radioactive seeds (brachytherapy). Although the experience regarding these techniques is in a preliminary stage, if developed further, this can potentially provide a highly accurate and minimally invasive approach for implantation of fiducial and radioactive seeds. This review will discuss potential role of EUS in implantation therapy, current literature and also speculate on future prospects for these EUS-guided interventions in pancreatic cancer.

Results of the baseline positron emission tomography can customize therapy of localized esophageal adenocarcinoma patients who achieve a clinical complete response after chemoradiation.

BACKGROUND: Patients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a

A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR). METHODS: Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5-6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used. RESULTS: One hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63-NA], with median OS 45.62 months (95% CI 25.56-NA) in Arm A and 43.68 months (95% CI 27.63-NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms. CONCLUSIONS: These data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial. Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov).

Feasibility study of EUS-NOTES as a novel approach for peroral cholecysto-gastrostomy.

BACKGROUND: EUS-guided cholecysto-gastrostomy might be a useful minimally invasive procedure used for salvage drainage in advanced pancreaticobiliary cancers, but also for drainage of the gallbladder in acute cholecystitis in patients deemed unfit for laparoscopic surgery. OBJECTIVE: Direct EUS-guided cholecysto-gastrostomy with placement of a double flanged expandable metal stents. DESIGN/SETTING: This was an animal pilot/feasibility study. INTERVENTIONS: The feasibility of EUS-guided cholecysto-gastrostomy through a transgastric approach was tested in five pigs. Specially designed EUS-guided devices for initial access in the gallbladder and a double flanged expandable metal stent were used in this study. RESULT: The results showed the feasibility of EUS-guided cholecysto-gastrostomy based on prototype devices for access in the gallbladder and transgastric stent placement. LIMITATIONS: Survival feasibility study with prototype devices in a small number of animals. CONCLUSIONS: EUS guided cholecysto-gastrostomy in a porcine model is feasible but technically demanding due to anatomical limitations of the pig and/or complexity of the procedure and the preliminary stage of development of the accessory devices. ABBREVIATIONS: NOTES - Natural Orifice Translumenal Endoscopic Surgery; EUS - Endoscopic Ultrasound; EUSFNA - Endoscopic Ultrasound Fine Needle Aspiration.

Patterns of relapse and progression in multiple myeloma patients after auto-SCT: implications for patients' monitoring after transplantation.

Auto-SCT (ASCT) is widely used in first-line treatment of multiple myeloma (MM). However, most patients eventually relapse or have progression of disease (R/POD). Although precise knowledge of R/POD patterns would be important to generate evidence-based surveillance recommendations after ASCT, such data is limited in the literature, especially after introduction of the free light chain assay (FLCA). This retrospective study examined the patterns of R/POD after first-line ASCT in 273 patients, using established criteria. At the time of R/POD, only 2% of patients had no associated serological evidence of R/POD. A total of 85% had asymptomatic R/POD, first detected by serological testing, whereas 15% had symptomatic R/POD with aggressive disease, early R/POD and short survival, with poor cytogenetics and younger age identified as risk factors. Although occult skeletal lesions were found in 40% of asymptomatic patients tested following serological R/POD, yearly skeletal surveys and urine testing were poor at heralding R/POD. We found a consistent association between paraprotein types at diagnosis and R/POD, allowing informed recommendations for appropriate serological monitoring and propose a new needed criterion using FLCA for patients relapsing by FLC only. Our findings provide important evidence-based recommendations that strengthen current monitoring guidelines after first-line ASCT in MM.

Association between clinical complete response and pathological complete response after preoperative chemoradiation in patients with gastroesophageal cancer: analysis in a large cohort.

BACKGROUND: Chemoradiation followed by surgery is the preferred treatment of localized gastroesophageal cancer (GEC). Surgery causes considerable life-altering consequences and achievement of clinical complete response (clinCR; defined as postchemoradiation [but presurgery] endoscopic biopsy negative for cancer and positron emission tomographic (PET) scan showing physiologic uptake) is an enticement to avoid/delay surgery. We examined the association between clinCR and pathologic complete response (pathCR). PATIENTS AND METHODS: Two hundred eighty-four patients with GEC underwent chemoradiation and esophagectomy. The chi-square test, Fisher exact test, t-test, Kaplan-Meier method, and log-rank test were used. RESULTS: Of 284 patients, 218 (77%) achieved clinCR. However, only 67 (31%) of the 218 achieved pathCR. The sensitivity of clinCR for pathCR was 97.1% (67/69), but the specificity was low (29.8%; 64/215). Of the 66 patients who had less than a clinCR, only 2 (3%) had a pathCR. Thus, the rate of pathCR was significantly different in patients with clinCR than in those with less than a clinCR (P < 0.001). CONCLUSIONS: clinCR is not highly associated with pathCR; the specificity of clinCR for pathCR is too low to be used for clinical decision making on delaying/avoiding surgery. Surgery-eligible GEC patients should be encouraged to undergo surgery following chemoradiation despite achieving a clinCR.

Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: Approximately 25% of patients with esophageal cancer (EC) who undergo preoperative chemoradiation, achieve a pathologic complete response (pathCR). We hypothesized that a model based on clinical parameters could predict pathCR with a high (≥60%) probability. PATIENTS AND METHODS: We analyzed 322 patients with EC who underwent preoperative chemoradiation. All the patients had baseline and postchemoradiation positron emission tomography (PET) and pre- and postchemoradiation endoscopic biopsy. Logistic regression models were used for analysis, and cross-validation via the bootstrap method was carried out to test the model. RESULTS: The 70 (21.7%) patients who achieved a pathCR lived longer (median overall survival [OS], 79.76 months) than the 252 patients who did not achieve a pathCR (median OS, 39.73 months; OS, P = 0.004; disease-free survival, P = 0.003). In a logistic regression analysis, the following parameters contributed to the prediction model: postchemoradiation PET, postchemoradiation biopsy, sex, histologic tumor grade, and baseline (EUS)T stage. The area under the receiver-operating characteristic curve was 0.72 (95% confidence interval [CI] 0.662-0.787); after the bootstrap validation with 200 repetitions, the bias-corrected AU-ROC was 0.70 (95% CI 0.643-0.728). CONCLUSION: Our data suggest that the logistic regression model can predict pathCR with a high probability. This clinical model could complement others (biomarkers) to predict pathCR.