Beyond tissue biopsy: a diagnostic framework to address tumor heterogeneity in lung cancer.

PURPOSE OF REVIEW: The objective of this review is to discuss the strength and limitations of tissue and liquid biopsy and functional imaging to capture spatial and temporal tumor heterogeneity either alone or as part of a diagnostic framework in non-small cell lung cancer (NSCLC). RECENT FINDINGS: NSCLC displays genetic and phenotypic heterogeneity - a detailed knowledge of which is crucial to personalize treatment. Tissue biopsy often lacks spatial and temporal resolution. Thus, NSCLC needs to be characterized by complementary diagnostic methods to resolve heterogeneity. Liquid biopsy offers detection of tumor biomarkers and for example, the classification and monitoring of EGFR mutations in NSCLC. It allows repeated sampling, and therefore, appears promising to address temporal aspects of tumor heterogeneity. Functional imaging methods and emerging image analytic tools, such as radiomics capture temporal and spatial heterogeneity. Further standardization of radiomics is required to allow introduction into clinical routine. SUMMARY: To augment the potential of precision therapy, improved diagnostic characterization of tumors is pivotal. We suggest a comprehensive diagnostic framework combining tissue and liquid biopsy and functional imaging to address the known aspects of spatial and temporal tumor heterogeneity on the example of NSCLC. We envision how this framework might be implemented in clinical practice.

Preoperative Pazopanib in High-Risk Soft Tissue Sarcoma: Phase II Window-of Opportunity Study of the German Interdisciplinary Sarcoma Group (NOPASS/GISG-04).

BACKGROUND: Preoperative devascularization might improve local control and thus the outcome of patients with soft tissue sarcoma (STS). The multikinase inhibitor pazopanib has antiangiogenic effects and is approved for treating metastatic STS. We conducted a trial of preoperative pazopanib therapy in high-risk STS. METHODS: This single-arm, phase II trial included patients with resectable, non-metastatic, treatment-naïve, high-risk STS. Patients received pazopanib 800 mg daily while waiting for surgery (21-day 'window of opportunity'). The primary endpoint was metabolic response rate (MRR; proportion of patients with ≥ 50% reduction of mean standardized uptake value [SUVmean] in post- vs. pretreatment fluorodeoxyglucose-positron emission tomography/computed tomography [FDG-PET-CT]). Planned sample size was 35 patients (type I error, 5%; type II error, 20%). A translational substudy explored associations between response and concentration of circulating angiogenic factors. RESULTS: Futility analysis was performed after 21 patients (11 female, mean age 67 years; liposarcoma n = 15); 17/21 patients were evaluable for the primary endpoint. The MRR was 1/17 (5.9%, 95% confidence interval < 0.01-0.29). Mean change in SUVmean of post- versus pretreatment PET was a 6% decrease (range 65% decrease to 34% increase); 7/21 (33.3%) patients had 12 grade 3/4 toxicities, and 19/21 (95.2%) patients were resected (all R0). One (4.8%) patient suffered a grade 4 postoperative complication (anastomotic leakage). Circulating endothelial progenitor cells, soluble vascular endothelial growth factor, and angiopoietin-2 concentrations showed no relevant changes during treatment. CONCLUSIONS: Although this study showed that preoperative pazopanib is not effective for unselected high-risk STS patients, relevant treatment effects were observed in a single patient. Future research needs to better define subgroups potentially benefiting from preoperative pazopanib treatment. CLINICALTRIALS. GOV IDENTIFIER: NCT01543802.

Cerebral sodium (23Na) magnetic resonance imaging in patients with migraine - a case-control study.

OBJECTIVE: Evaluation of MRI-derived cerebral 23Na concentrations in patients with migraine in comparison with healthy controls. MATERIALS AND METHODS: In this case-control study, 24 female migraine patients (mean age, 34 ± 11 years) were enrolled after evaluation of standardized questionnaires. Half (n = 12) of the cohort suffered from migraine, the other half was impaired by both migraine and tension-type headaches (TTH). The combined patient cohort was matched to 12 healthy female controls (mean age, 34 ± 11 years). All participants underwent a cerebral 23Na-magnetic resonance imaging examination at 3.0 T, which included a T1w MP-RAGE sequence and a 3D density-adapted, radial gradient echo sequence for 23Na imaging. Circular regions of interests were placed in predetermined anatomic regions: cerebrospinal fluid (CSF), gray and white matter, brain stem, and cerebellum. External 23Na reference phantoms were used to calculate the total 23Na tissue concentrations. Pearson's correlation, Kendall Tau, and Wilcoxon rank sum test were used for statistical analysis. RESULTS: 23Na concentrations of all patients in the CSF were significantly higher than in healthy controls (p < 0.001). The CSF of both the migraine and mixed migraine/TTH group showed significantly increased sodium concentrations compared to the control group (p = 0.007 and p < 0.001). Within the patient cohort, a positive correlation between pain level and TSC in the CSF (r = 0.62) could be observed. CONCLUSION: MRI-derived cerebral 23Na concentrations in the CSF of migraine patients were found to be statistically significantly higher than in healthy controls. KEY POINTS: • Cerebral sodium MRI supports the theory of ionic imbalances and may aid in the challenging pathophysiologic understanding of migraine. • Case-control study shows significantly higher sodium concentrations in cerebrospinal fluid of migraineurs. • Cerebral sodium MRI may become a non-invasive imaging tool for drugs to modulate sodium, and hence migraine, on a molecular level, and influence patient management.

Submucosal injection with waterjet improves endoscopic mucosal resection of colorectal adenoma - a randomised controlled clinical trial.

PURPOSE: Endoscopic mucosal resection (EMR) of colorectal adenomas leads to a reduced incidence of, and mortality from, colorectal carcinoma. Large adenomas are especially difficult to resect. Submucosal injection is a key part of EMR, as it allows for complete resection and decreased complications. We previously demonstrated in both animal models and a clinical trial that a focussed fluid beam applied to the mucosa creates selective fluid cushions in the submucosa selective tissue elevation by pressure (STEP). In this study, we examined the potential of this new technique compared to the standard inject and cut technique. METHODS: This was a monocentric prospective two armed randomised controlled clinical trial comparing the STEP technique to the standard needle injection. We included patients with Yamada I and II adenomas ≥12 mm. RESULTS: One hundred fifty-five patients were treated in the trial. With the STEP technique there was a significantly higher rate of en-bloc resection, whereas piecemeal resection was more common in the standard arm. The odds ratio of piecemeal resection was 2.422 with a 95% confidence interval of 1.163-5.045 (p value .0195). There was no significant difference in resection time between the two techniques, while there was a significant difference in resections speed for the STEP technique. There was also no difference in complication rates. CONCLUSIONS: This study demonstrated that the new STEP technique leads to a higher rate of en-bloc resections than the standard injection technique in endoscopic mucosa resection of colorectal adenomas. The STEP technique can play an important role in the future of EMR.

Transabdominal laparoscopic retroperitoneal neurectomy for chronic pain after inguinal hernia repair and appendicectomy -a matched-pair study.

BACKGROUND: Chronic debilitating pain is a rare but significant cause of postoperative morbidity after inguinal surgery. Such pain is usually of neuropathic origin and frequently caused by intraoperative nerve damage. In this retrospective matched-pair study we analysed results of a minimal-invasive approach to neurectomy on quality of life and pain relief. METHODS: From March 2010 to January 2012, 9 patients developing chronic neuropathic pain after inguinal hernia repair (8 patients) or open appendicectomy (one patient) were operated using a laparoscopic transabdominal approach in our department. Clinical examinations and specific questionnaires on pain and quality of life (PainDetect, SF-36) were completed 6 months to 3 years after neurectomy. Every patient was matched with one patient without chronic pain. RESULTS: Seven of nine patients had severe or very severe pain before neurectomy, two had mild pain but refused a conservative treatment. Four patients were free of pain after neurectomy, three described an improved pain status, whereas two did not observe any change in pain. Within a follow-up period of 14,3 months, no deterioration of pain or other complications were observed. Patients who underwent neurectomy had significantly lower quality of life compared to the control group. No postoperative complications were observed. CONCLUSIONS: Laparoscopic transabdominal neurectomy represents a possible surgical approach in treating patients with chronic disabling postoperative groin pain requiring surgery. This technique was feasible, safe, and effective in our series to relieve chronic debilitating pain in the majority of our patients with comparable results to other published approaches.

Validation for histology-driven diagnosis in non-small cell lung cancer using hsa-miR-205 and hsa-miR-21 expression by two different normalization strategies.

Targeted therapy of non-small cell lung cancer (NSCLC) demands a more accurate tumor classification that is crucial for patient selection in personalized treatment. MicroRNAs constitute a promising class of biomarkers and a helpful tool for the distinction between lung adenocarcinoma (AC) and squamous cell lung carcinoma (SCC). The aim of this study was to evaluate the impact of two different normalization strategies, using U6 snRNA and hsa-miR-103 as reference genes, on hsa-miR-205 and hsa-miR-21 expression levels, in terms of the classification of subtypes of NSCLC. By means of a quantitative real-time polymerase chain reaction (qRT-PCR) microRNA expression levels were evaluated in a classification set of 98 surgically resected NSCLC fresh-frozen samples, and validated findings in an independent set of 42 NSCLC samples. The microRNA expression levels were exploited to develop a diagnostic test using two data normalization strategies. The performance of microRNA profiling in different normalization methods was compared. We revealed the microRNA-based qRT-PCR tests to be appropriate measures for distinguishing between AC and SCC (the concordance of histologic diagnoses and molecular methods greater than 88%). Performance evaluation of microRNA tests, based on the two normalization strategies, showed that the procedure using hsa-miR-103 as reference target has a slight advantage (sensitivity 83.33 and 100% in classification and validation set, respectively) compared to U6 snRNA. Molecular tests based on microRNA expression allow a reliable classification of subtypes for NSCLC and can constitute a useful diagnostic strategy in patient selection for targeted therapy.

A comparison of transcatheter aortic valve implantation and surgical aortic valve replacement in 1,141 patients with severe symptomatic aortic stenosis and less than high risk.

OBJECTIVES: To assess outcomes for patients undergoing transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement but with less than high risk. BACKGROUND: While there is abundant data for high risk patients there is insufficient data for reduced risk. METHODS: Patients undergoing TAVI or SAVR between 2007 and 2012 in Karlsruhe were considered. They were assessed by cardiac computed tomography, transoesophageal echocardiogram, and logistic EuroSCORE I (ES) and groups compared using Propensity Score Matching. RESULTS: The mean ES was 10.1±2.8 in the TAVI group (n = 419) and 5.7 ± 3.2 in the SAVR group (n = 722; P < 0.0001). Mean survival probability over 3 years was higher in patients undergoing surgery (P < 0.0001). A total of 432 patients were considered for the matched-pairs analysis based on propensity scores (216 in each group). Major vascular complications (10.6% vs. 0.0%; P < 0.0001), new pacemaker implantation (13.9% vs. 4.6%; P < 0.001) and moderate aortic insufficiency (3.2% vs. 0.5%; P = 0.03) were more frequent in patients undergoing TAVI. Major (20.8% vs. 4.2%; P < 0.0001) and life-threatening (14.5% vs. 2.3%; P < 0.0001) bleeding complications were more frequent in those undergoing surgery. Survival probability over 3 years in the propensity matched cohort was comparable between both groups (P = 0.16). CONCLUSIONS: In this large, single center, real world dataset there was no difference in mortality between patients undergoing TAVI or SAVR during a 3-year follow-up but there was a TAVI related increase in major vascular complications, new pacemaker implantation and aortic insufficiency and a SAVR related increased bleeding risk.

Oncological outcome of primary non-metastatic soft tissue sarcoma treated by neoadjuvant isolated limb perfusion and tumor resection.

BACKGROUND: Isolated limb perfusion (ILP) is an effective limb salvage strategy in patients with advanced soft tissue sarcoma (STS) where surgery alone would result in significant functional morbidity or mandate an amputation. Most previous reports of patients undergoing ILP focus on limb salvage rates rather than local and distant relapse rates. Here, we report the oncological outcome of sarcoma patients treated by ILP and surgery. METHODS: Data were retrieved from prospective ILP databases from two ILP centers following similar ILP techniques and surgical approaches. Only patients with primary, intermediate, or high grade non-metastatic STS were included. RESULTS: The cohort comprised 90 patients. Median follow-up was 39 months (range 3-165 months). Median tumor size was 11 cm (range 5-34). Twenty of 90 (22%) patients underwent prior debulking surgery outside the centers. Twenty-nine of 90 (32%) had postoperative irradiation. Four of 90 underwent amputation either related to local recurrence or irresectability, 4 of 90 underwent amputation for treatment-related complications. Fifteen of 83 (18%) patients had local recurrences after ILP and limb sparing surgery, 39 of 90 (43%) developed metastatic disease. Twenty-two of 90 (24%) died of disease. CONCLUSION: Preoperative ILP and tumor resection resulted in good local control in a cohort of high-risk STS patients.

Effect on the tensile strength of human acellular dermis (Epiflex®) of in-vitro incubation simulating an open abdomen setting.

BACKGROUND: The use of human acellular dermis (hAD) to close open abdomen in the treatment process of severe peritonitis might be an alternative to standard care. This paper describes an investigation of the effects of fluids simulating an open abdomen environment on the biomechanical properties of Epiflex® a cell-free human dermis transplant. METHODS: hAD was incubated in Ringers solution, blood, urine, upper gastrointestinal (upper GI) secretion and a peritonitis-like bacterial solution in-vitro for 3 weeks. At day 0, 7, 14 and 21 breaking strength was measured, tensile strength was calculated and standard fluorescence microscopy was performed. RESULTS: hAD incubated in all five of the five fluids showed a decrease in mean breaking strength at day 21 when compared to day 0. However, upper GI secretion was the only incubation fluid that significantly reduced the mechanical strength of Epiflex after 21 days of incubation when compared to incubation in Ringer's solution. CONCLUSION: hAD may be a suitable material for closure of the open abdomen in the absence of upper GI leakage and pancreatic fistulae.

Human acellular dermis seeded with autologous fibroblasts enhances bronchial anastomotic healing in an irradiated rodent sleeve resection model.

BACKGROUND: The combination of neoadjuvant radiochemotherapy and parenchyma-preserving sleeve resection for lung cancer remains controversial because of potentially increased rate of anastomotic breakdown. We analyzed the effects of applying a decellularized human dermis transplant seeded with autologous fibroblasts in a rodent sleeve resection model with neoadjuvant radiotherapy. MATERIALS AND METHODS: A total of 64 male Fisher rats underwent a transsection and surgical anastomosis of the left main bronchus and were randomized to receive plus/minus radiation treatment and plus/minus augmentation of the anastomosis with a fibroblast-seeded dermis transplant (2 × 2 factorial design). A µCT scan was performed at postoperative days 7 and 14, and the animals were sacrificed on day 14. Anastomotic bursting pressure and hydroxyproline concentration were measured. RESULTS: In the irradiated groups, the anastomotic bursting pressure was significantly higher in the augmented group at day 7 (100.9 ± 18.3 vs 141.3 ± 18.0 kPa, p = 0.0005) but not at day 14. Hydroxyproline levels showed a similar pattern in the irradiated group with significant differences at day 7 (7 days postoperative 158 ± 11.6 vs 198.2 ± 10.9 nmol/mg, p < 0.0001) but not at day 14 postoperatively. CONCLUSIONS: Augmentation of a bronchial anastomosis by a dermal matrix, seeded with autologous, viable fibroblasts improves early wound breaking strength. Fibroblast-enhanced dermal matrices provide a new and easily usable tool to prevent early anastomotic leakage after neoadjuvant chemoradiation in locally advanced lung cancer.

Steady state vascular imaging with extracellular gadobutrol: evaluation of the additional diagnostic benefit in patients who have undergone a peripheral magnetic resonance angiography protocol.

BACKGROUND: To evaluate the feasibility and additional diagnostic benefit of a high-resolution steady state 3D-volume interpolated breath-hold exam (VIBE) sequence between a continuous table movement (CTM) MR angiography of the entire runoff vasculature and a time-resolved (TWIST) MRA of the calves. METHODS: In this retrospective IRB approved study 224 patients (72 women, 152 men, mean age 67.29 ± 13.9) were included who had undergone a low-dose MR angiographic protocol at 3T (Siemens TimTrio) after injection of 0.1 mmol/kg gadobutrol including a CTM MRA, a time-resolved MRA of the calf station and a steady state 3D VIBE sequence prior to the time-resolved MRA. One board-certified radiologist rated the image quality of the steady state VIBE sequences on an ordinal three point scale (excellent, good, poor) and analyzed the images for additional diagnostic findings of and beyond the vascular system in comparison to the CTM MRA and the time-resolved MRA. Descriptive statistics and demographic patient data were used for further evaluation. RESULTS: The image quality of the steady state imaging of the pelvis, upper and lower leg was excellent in up to 88%, 84% and 47%, respectively, while poor image quality was only detected in the upper (2%) and lower leg (6%). An additional diagnostic benefit was found in 44% of the patients overall. The most common relevant pathologies included inflammatory processes of the soft tissues (26%), thrombi (14%), abscesses (13%) and tumors (11%). In subgroups of patients above the age of 60, 65, 70, 75 and 80 years an additional pathology was found in 50% 33%, 44%, 65% and 58%, respectively. There was no significant difference in terms of additional findings between men and women (46% and 39%, p > 0.05) and inpatients and outpatients (42% and 45%, p > 0.05). CONCLUSION: Steady state imaging is also feasible with extracellular contrast agents with good image quality yielding additional diagnostic findings in up to 44% and above in patients older than 60 years of age irrespective of gender or patient status. Given the short acquisition time of 4 minutes this sequence could be added to all peripheral MRA exams.

Characteristics, treatment and prognostic factors of patients with gynaecological malignancies treated in a palliative care unit at a university hospital.

BACKGROUND: Limited clinical data have been published on patients suffering from advanced gynaecological malignancies treated in palliative care units, and little is known about prognostic factors. METHODS: In a retrospective study, the data of 225 patients with breast, ovarian and cervical cancer treated in the palliative care unit of a university hospital between 1998 and 2009 were assembled. Clinical aspects and baseline symptoms, laboratory parameters, the clinical course, and outcome were evaluated. RESULTS: 225 patients (497 cases; cancer diagnoses: breast 79%, ovarian 13%, and cervix 8%) were included in the analysis. The main symptoms were weakness/fatigue (71%), pain (65%), anorexia/nausea (62%), and dyspnea (46%). Pain control was achieved in 85% of all cases, satisfying control of other symptoms in 80%. The median overall survival (OS) was 59 days. 53% of the patients died at the palliative care unit. In the Cox proportional hazards model, 8 parameters indicated an unfavourable outcome: anorexia/nausea, disordered mental status, elevated lactate dehydrogenase, γ-glutamyltransferase, leukocyte count, hypoalbuminaemia, anaemia and hypercalcaemia. Based on these parameters 3 risk groups were defined: low risk (0-2 factors), intermediate risk (3-5 factors), and high risk (6-8 factors). Median survival for high-risk group was 13 days, for intermediate group 61 days, and for low-risk patients 554 days (p < 0.0001). CONCLUSION: Weakness/fatigue, pain and anorexia were the main symptoms leading to the hospitalisation of patients with gynaecological malignancies. Symptom and pain control was accomplished in 80% of cases. 8 parameters were identified as indicating a poor outcome, and patients showing at least 6 or more of these factors had a very limited prognosis. Although studied retrospectively, these results may be helpful for individual treatment decisions in patients with advanced gynaecological malignancies. Prospective data and the introduction of documentation systems could help to gain more powerful knowledge about the quality of palliative care.

A Systematic Review of Progress toward Unlocking the Power of Epigenetics in NSCLC: Latest Updates and Perspectives.

Epigenetic research has the potential to improve our understanding of the pathogenesis of cancer, specifically non-small-cell lung cancer, and support our efforts to personalize the management of the disease. Epigenetic alterations are expected to have relevance for early detection, diagnosis, outcome prediction, and tumor response to therapy. Additionally, epi-drugs as therapeutic modalities may lead to the recovery of genes delaying tumor growth, thus increasing survival rates, and may be effective against tumors without druggable mutations. Epigenetic changes involve DNA methylation, histone modifications, and the activity of non-coding RNAs, causing gene expression changes and their mutual interactions. This systematic review, based on 110 studies, gives a comprehensive overview of new perspectives on diagnostic (28 studies) and prognostic (25 studies) epigenetic biomarkers, as well as epigenetic treatment options (57 studies) for non-small-cell lung cancer. This paper outlines the crosstalk between epigenetic and genetic factors as well as elucidates clinical contexts including epigenetic treatments, such as dietary supplements and food additives, which serve as anti-carcinogenic compounds and regulators of cellular epigenetics and which are used to reduce toxicity. Furthermore, a future-oriented exploration of epigenetic studies in NSCLC is presented. The findings suggest that additional studies are necessary to comprehend the mechanisms of epigenetic changes and investigate biomarkers, response rates, and tailored combinations of treatments. In the future, epigenetics could have the potential to become an integral part of diagnostics, prognostics, and personalized treatment in NSCLC.

Predicting malignancy in mediastinal lymph nodes by endobronchial ultrasound: a new ultrasound scoring system.

BACKGROUND AND OBJECTIVE: Endobronchial ultrasound (EBUS) is now widely used in patients with resectable non-small-cell lung cancer to sample mediastinal lymph nodes (LN) for preoperative staging. The aim of this study was to investigate prospectively the utility of six ultrasound criteria to predict malignancy in mediastinal LN. METHODS: EBUS was performed in patients with mediastinal lymphadenopathy irrespective of the underlying disease. The following criteria were expected to predict malignancy: short axis >1 cm, heterogeneous pattern, round shape, distinct margin, absence of a central hilar structure and high blood flow in a LN. A sum score prediction model for malignancy was built. If more than two criteria were present, LN was classified as high risk for malignancy. Moreover, interrater variability of two blinded investigators was evaluated. RESULTS: Two hundred eighty-one LN in 145 patients were analysed. Forty-four percent of LN were found malignant, 10% revealed sarcoidosis, and 10% revealed tuberculosis. Interobserver agreement was very good. Positive predictive value was best for heterogeneity (73%), with a negative predictive value of more than 80%. The sum score resulted in an odds ratio of 15.5 if more than two criteria were positive (P < 0.00001). CONCLUSIONS: The assessment of ultrasound criteria during routine EBUS examinations is feasible and reproducible with very good interrater agreement. If less than three of the described criteria are present, a LN has a very low chance of being malignant. The best single criterion to predict malignancy is heterogeneity. The introduction of the sum score of ultrasound criteria could potentially increase diagnostic accuracy.

Implication of FDG-PET/CT in patients with potentially operable colorectal lung metastases.

OBJECTIVES: This prospective study assessed the role of F-18-FDG-PET/CT in clinical staging for patients with colorectal cancer planned for pulmonary metastasectomy by thoracotomy or video-assisted surgery. PATIENTS AND METHODS: In addition to conventional imaging, we performed 86 F-18-FDG-PET/CT studies in 76 patients with potentially resectable metastatic colorectal lung metastases. We then investigated the effect that PET/CT had on further clinical management. Based on the results from the 47 thoracotomies performed, we compared the number of pulmonary metastases discovered after histologic examination with the number predicted by the conventional computed tomography (CT) as an independent part of the F-18-FDG-PET/CT examination and by the F-18-FDG-PET component. RESULTS: F-18-FDG-PET/CT led to changes in treatment regime and diagnostic planning in many patients. In five patients PET/CT revealed previously undetected local recurrence of the primary colorectal cancer, in four patients hepatic metastases, in three patients bone metastases, in two patients soft-tissue metastases, and in three patients histologically preoperatively proven N2 or N3 station lymph node involvement. These all constituted exclusion criteria, and consequently the previously planned pulmonary metastasectomy was not performed. The sensitivity and positive predictive value (PPV) for detection of pulmonary metastases were 84.2% and 36.4% for CT and 75.0% and 61.6% for F-18-FDG-PET study. The calculated sensitivity, specificity, PPV, and NPV of F-18-FDG-PET/CT for detecting thoracic lymph node involvement were 85.7%, 93.0%, 66.7%, and 97.5%, respectively. Furthermore, we found that F-18-FDG-PET/CT may predict thoracic lymph node involvement based on the SUV of pulmonary nodules. CONCLUSIONS: F-18-FDG-PET/CT has a clear role in the diagnostic workup for pulmonary metastatic colorectal cancer and may save patients from futile surgery. It cannot, however, be relied on to detect all possible pulmonary and nodal metastases, which surgeons must always consider when making treatment decisions.

Presentation, treatment, and analysis of prognostic factors of terminally ill patients with gastrointestinal tumors.

BACKGROUND: Few data have been published about terminally ill patients with gastrointestinal tumors treated in palliative care units. PATIENTS AND METHODS: We analyzed the data of 737 admissions of 435 patients that were treated in a palliative care unit, and tried to identify prognostic factors for survival. RESULTS: Most frequent diagnoses at admission were colorectal, gastric, esophageal, and pancreatic cancer. Major clinical symptoms were pain (66.9%), anorexia (60.8%), weight loss (39.2%), and nausea/vomiting (36.6%). In 71.6% of the patients, morphine derivatives were administered. In 33.0% of cases, red blood cell transfusions were applied, parenteral nutrition was given in 31.3%. Median survival, calculated from the day of first hospitalization, was 35 days. On univariate analysis, several clinical and laboratory parameters were identified as prognostically important factors. In the multivariate Cox regression analysis, 5 parameters were significant: ascites and anorexia, elevated leukocyte count and lactate dehydrogenase activity, as well as decreased albumine levels. Using these parameters, patients were divided into 3 risk groups: low-risk (presence of 0-1 factors), intermediate risk (2-3 factors), and poor-risk patients (4-5 factors). Median survival for poor-risk patients was 18 days, intermediate- and low-risk patients survived 43 and 136 days, respectively (p < 0.0001). CONCLUSION: In multivariate analysis, 5 prognostic factors were identified, and 3 patient groups were defined. After multicenter validation, these factors may help to guide treatment decisions in terminally ill patients with gastrointestinal tumors.

Association between the novel classification of lung adenocarcinoma subtypes and EGFR/KRAS mutation status: A systematic literature review and pooled-data analysis.

OBJECTIVES: This study aims to determine the association of EGFR/KRAS mutation status with histological subtypes of lung adenocarcinoma (LAC) based on the IASLC/ATS/ERS classification. METHODS: Pubmed and Cochrane databases were searched from January 2011 to June 2018 for studies that included patients with LAC who underwent surgical resection were classified according to the new IASLC/ATS/ERS classification. EGFR/KRAS status assessment was requireded. The primary outcome was determined by the odds ratio (OR) of the incidence of mutation status of certain of each histological subtype. The reference group consisted of EGFR/KRAS mutation negative patients. RESULTS: Twenty-seven eligible studies involving 9022 patients with mutation gene detection were included for analysis. Among them, 6717 (74.5%) patients were from the Asian region and, 2305 (25.5%) patients were from Non-Asian regions. The most prevalent subtype was acinar (34.7%), followed by papillary (22.9%), lepidic (18.9%), solid (13.6%), micropapillary (6.3%), and invasive mucinous adenocarcinoma (3.5%). EGFR mutations were more common in patients with resected lepidic predominant adenocarcinoma (OR,1.76; 95%CI, 1.38-2.24;p < 0.01) and were rarely found in solid predominant adenocarcinoma (OR,0.28; 95%CI, 0.23-0.34;p < 0.01) or IMA (OR,0.10; 95%CI, 0.06-0.14;p < 0.01). Conversely, KRAS mutations were characterized by IMA (OR,7.01; 95%CI, 5.11-9.62;p < 0.01), and were less frequently identified in lepidic (OR,0.58; 95%CI, 0.45-0.75;p < 0.01) and acinar (OR,0.65; 95%CI, 0.55-0.78;p < 0.01) predominant subtypes. Further analyses were performed in Asian and Non-Asian groups and the results were consistent. CONCLUSIONS: The current study confirms that the IASLC/ATS/ERS classification is associated with driver gene alterations in resected LAC.

Neoadjuvant Pazopanib Treatment in High-Risk Soft Tissue Sarcoma: A Quantitative Dynamic 18F-FDG PET/CT Study of the German Interdisciplinary Sarcoma Group.

The outcome of high-risk soft tissue sarcoma (STS) is poor with radical surgery being the only potentially curative modality. Pazopanib is a multikinase inhibitor approved for the treatment of metastatic STS. Herein, in terms of the German Interdisciplinary Sarcoma Group (GISG-04/NOPASS) trial, we evaluate the potential role of kinetic analysis of fludeoxyglucose F-18 (18F-FDG) data derived from the application of dynamic positron emission tomography/computed tomography (PET/CT) in response assessment to pazopanib of STS patients scheduled for surgical resection. Sixteen STS patients treated with pazopanib as neoadjuvant therapy before surgery were enrolled in the analysis. All patients underwent dynamic PET/CT prior to and after pazopanib treatment. Data analysis consisted of visual (qualitative) analysis of the PET/CT scans, semi-quantitative evaluation based on standardized uptake value (SUV) calculations, and quantitative analysis of the dynamic 18F-FDG PET data, based on two-tissue compartment modeling. Resection specimens were histopathologically assessed and the percentage of regression grade was recorded in 14/16 patients. Time to tumor relapse/progression was also calculated. In the follow-up, 12/16 patients (75%) were alive without relapse, while four patients (25%) relapsed, among them one patient died. Median histopathological regression was 20% (mean 26%, range 5-70%). The studied population was dichotomized using a histopathological regression grade of 20% as cut-off. Based on this threshold, 10/14 patients (71%) showed partial remission (PR), while stable disease (SD) was seen in the rest 4 evaluable patients (29%). Semi-quantitative evaluation showed no statistically significant change in the widely used PET parameters, SUVaverage and SUVmax. On the other hand, 18F-FDG kinetic analysis revealed a significant decrease in the perfusion-related parameter K1, which reflects the carrier-mediated transport of 18F-FDG from plasma to tumor. This decrease can be considered as a marker in response to pazopanib in STS and could be due to the anti-angiogenic effect of the therapeutic agent.

[Data documentation and data management with guidelines, experiences, caveats, and recommendations]. / Datenerhebung und Datenmanagement mit Richtlinien, Erfahrungen, Warnungen und Empfehlungen.

Reliable and correct data capture and safe data management are an inevitable prerequisite to gain valid data in clinical studies. The biostatistical analysis is the basis from which medical consequences about efficacy and safety of the treatment can be driven. The functional role of data capture and data management in relation to the study protocol, development of report forms, data flux between the involved institutions, and the data capture systems will be investigated. Main points of the data capture are the rationale of the study, the protocol, and the statistical analysis plan. Modularity, uniqueness, and reduction on the needs of the study protocol designate a good documentation form. Practical considerations will be given. Prompt and efficient communication between all involved participants is the organizational prerequisite for valid data, independent from the data capture system. Online data capture will displace the classical paper documentation form, however, accurate and careful documentation will remain. Data capture and data management are a crucial and cost-intensive chapter of a clinical study, formed by the technical ability and the team play of clinical principal investigators, biostatisticians, computer scientists, monitors, and the organizers of the study.