Factors affecting prognosis in patients treated with bevacizumab plus paclitaxel as first-line chemotherapy for HER2-negative metastatic breast cancer: an international pooled analysis of individual patient data from four prospective observational studies.

BACKGROUND: Bevacizumab (BV) plus paclitaxel (PTX) is a treatment option in patients with HER2-negative metastatic breast cancer (mBC). We conducted an international pooled analysis with individual patient data to evaluate the effectiveness of BV + PTX as a first-line treatment for HER2-negative mBC patients under routine practice. METHODS: A total of 2,474 mBC patients treated with BV + PTX from four prospective observational studies were analyzed. The primary endpoint was overall survival (OS). The other endpoints including identifying independent prognostic factors and validation of the modified Prognostic Factor Index (PFI) developed in the ATHENA trial. RESULTS: Median follow-up time was 10.9 months (M). Median OS were 21.4 M (95% confidential interval 19.8-22.7 M). The seven independent prognostic factors (tumor subtype, age, ECOG performance status (PS), disease-free interval (DFI), liver metastases, number of metastatic organs, and prior anthracycline and/or taxane treatment) for OS found in this analysis included the five risk factors (RFs [DFI < 24 months, ECOG PS 2, liver metastases and/or > 3 metastasis organ sites, TNBC, prior anthracycline and/or taxane therapy]). High- (> 3 RFs [median OS 12.6 M]) and intermediate-risk groups (2 RFs [median OS 18.0 M]) had a significantly worse prognosis than the low-risk group (< 1 RF [median OS 27.4 M]), (p < 0.0001). CONCLUSIONS: This international pooled analysis showed the effectiveness of first-line BV + PTX for HER2-negative mBC patients identifying seven independent prognostic factors as real-world evidence. The usefulness of the modified PFI developed in the ATHENA trial in predicting OS among patients receiving BV + PTX was also verified.

Subcutaneous injection of trastuzumab into the thigh versus abdominal wall in patients with HER2-positive early breast cancer: Pharmacokinetic, safety and patients' preference - Substudy of the randomised phase III GAIN-2 study.

BACKGROUND: Trastuzumab given intravenously in combination with chemotherapy is standard of care for patients with early HER2-positive breast cancer (BC). Different randomised studies have shown equivalent efficacy of a subcutaneous injection into the thigh compared to the intravenous formulation. Other body regions for injection have not been investigated but might be more convenient for patients. METHODS: After surgery, patients were randomised to receive either subcutaneous trastuzumab into the thigh or into the abdominal wall (AW). Patient preferences were evaluated using validated questionnaires (PINT). Primary objectives of this multicentre, non-blinded, randomised substudy of the GAIN-2 study were to investigate pharmacokinetics of the injection into the thigh versus AW and to determine patients' preferences of either administration site versus the previously received intravenous application. RESULTS: 226 patients were randomised and 219 patients (thigh: N = 110; AW: N = 109) formed the modified intent-to-treat (mITT). Overall, 83.5% (out of N = 182 with information about patients' preference) preferred subcutaneous over previous intravenous application or had no preference. Preference was similar between both administration sites (thigh: 80.6%; AW: 86.5; p = 0.322). Pharmacokinetic analysis included 30 patients. Geometric means of Cmax and AUC0-21d were higher in thigh than in AW group (geometric mean ratio with body weight adjustment: Cmax: 1.291, 90%-CI 1.052-1.584; AUC0-21d: 1.291, 90%-CI 1.026-1.626). Safety profile was in line with previous reports of subcutaneous trastuzumab. CONCLUSION: Subcutaneous trastuzumab into the thigh showed an approximately 30% higher bioavailability. Injections were well tolerated and preferred over intravenous administration. The subcutaneous injection into the thigh should remain the standard of care.

Dual HER2 blockade with pertuzumab (P) and trastuzumab (T) in patients with HER2-positive metastatic breast cancer (mBC) relapsing after adjuvant treatment with T: results from a German non-interventional study (NIS) HELENA (NCT01777958).

PURPOSE: NIS HELENA documented outcomes in clinical routine practice of first-line therapy with P plus T and docetaxel (D) of patients with advanced HER2-positive BC and prior (neo)adjuvant T. METHODS: Between 06/2013 through 07/2016, 126 patients (in-label use of P at study start = full analysis set, FAS) in 81 German study sites were included. Intense documentation period was limited to 28 treatment cycles. Maximum follow-up (FU) was 24 months (mos). Safety was assessed in the safety set (SAF = eligible patients with at least one dose of P, n = 132). Median progression-free survival (PFS) was the main parameter of interest. RESULTS: Mean age of FAS patients was 55.1 [30.7-80.2] years, 81.7% (95.2%) were < 65 (75) years of age. 51.6% of the FAS patients were hormone receptor-positive (HR+), 91.3% had distant, 73.0% visceral, and 18.3% non-visceral metastases. Median disease-free interval was 40.2 [6.6-95.9] mos. Effectiveness (FAS): Median PFS was 18.8 [15.1; 24.2] mos. Overall response rate was 64.3% (55.6; 72.1). Median overall survival was 55.9 mos [41.2, not reached]. Safety (SAF): 93.9% of patients had an adverse event (AE), 32.6% a serious AE (SAE). AEs related to P occurred in 53.8% of SAF, SAEs related to P in 13.6%. Diarrhea was the most frequently reported related (S)AE. There were 8 (6.1%) patients with a fatal AE. CONCLUSION: Based on the outcomes from NIS HELENA, results of dual blockade with P+T in patients relapsing after (neo)adjuvant T as reported from the CLEOPATRA study (NCT01777958) can be transferred to routine clinical practice. No new safety signals were detected.

Pathological Response in the Breast and Axillary Lymph Nodes after Neoadjuvant Systemic Treatment in Patients with Initially Node-Positive Breast Cancer Correlates with Disease Free Survival: An Exploratory Analysis of the GeparOcto Trial.

BACKGROUND: The conversion of initially histologically confirmed axillary lymph node-positive (pN+) to ypN0 after neoadjuvant systemic treatment (NAST) is an important prognostic factor in breast cancer (BC) patients and may influence surgical de-escalation strategies. We aimed to determine pCR rates in lymph nodes (pCR-LN), the breast (pCR-B), and both (tpCR) in women who present with pN+ BC, to assess predictors for response and the impact of pCR-LN, pCR-B, and tpCR on invasive disease-free survival (iDFS). METHODS: Retrospective, exploratory analysis of 242 patients with pN+ at diagnosis from the multicentric, randomized GeparOcto trial. RESULTS: Of 242 patients with initially pN+ disease, 134 (55.4%) had a pCR-LN, and 109 (45.0%) a pCR-B. Of the 109 pCR-B patients, 9 (8.3%) patients had involved LN, and 100 (41.3%) patients had tpCR. Those with involved LN still had a bad prognosis. As expected, pCR-B and intrinsic subtypes (TNBC and HER2+) were identified as independent predictors of pCR-LN. pCR-LN (ypN0; hazard ratio 0.42; 95%, CI 0.23-0.75; p = 0.0028 for iDFS) was the strongest independent prognostic factor. CONCLUSIONS: In initially pN+ patients undergoing NAST, the conversion to ypN0 is of high prognostic value. Surgical axillary staging after NAST is still essential in these patients to offer tailored treatment.

Survival analysis of the randomised phase III GeparOcto trial comparing neoadjuvant chemotherapy of intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for patients with high-risk early breast cancer.

BACKGROUND: GeparOcto demonstrated that pathological complete response (pCR) of intense dose-dense epirubicin, paclitaxel and cyclophosphamide (iddEPC) was comparable to weekly paclitaxel/non-pegylated liposomal doxorubicin (plus carboplatin (PM(Cb) in triple-negative breast cancer [TNBC]) in high-risk early breast cancer (BC). Here, we report time-to-event secondary end-points. PATIENTS AND METHODS: Patients were randomised to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (AUC 1.5). Patients with human epidermal growth factor receptor 2-positive (HER2+)BC received trastuzumab (6[loading dose 8]mg/kg q3w) and pertuzumab (420[840]mg q3w) with P and C cycles. RESULTS: 945 patients started treatment (iddEPC n = 470; PM(Cb) n = 475). After a median follow-up of 47.0 (range 1.6-61.5) months, 162 (75 in iddEPC; 87 in PM(Cb)) invasive disease-free survival (iDFS) events and 79 (41 in iddEPC; 38 in PM(Cb)) deaths were reported. No significant difference was observed in 4-year iDFS (81.9% iddEPC versus 79.7% PM(Cb), HR = 1.16 [95%CI 0.85-1.59], log-rank p = 0.334) or 4-year overall survival (OS) (90.3% iddEPC versus 90.6% PM(Cb), HR = 0.90 [95%CI 0.58-1.40], log-rank p = 0.637) overall and in HER2+ and TNBC subgroups. HR+/HER2- BC patients, however, had significantly better 4-year iDFS (77.9% iddEPC versus 62.5% PM, HR = 2.11 [95%CI 1.08-4.10], log-rank p = 0.025) and 4-year OS with iddEPC (94.7% iddEPC versus 80.1% PM, HR = 3.26 [95%CI 1.06-10.00], log-rank p = 0.029). CONCLUSION: While there was no difference in survival for the entire cohort, the HR+/HER2-subgroup significantly benefits from iddEPC. This supports the concept of an additional effect of NACT beyond pCR in patients with HR+/HER2- BC. CLINICALTRIALS. GOV IDENTIFIER: NCT02125344.

Phase III randomised trial comparing intense dose-dense chemotherapy to tailored dose-dense chemotherapy in high-risk early breast cancer (GAIN-2).

BACKGROUND: The GAIN-2 trial was designed to identify a superior intense dose-dense (idd) strategy for high-risk patients with early breast cancer. Here, we report an interim analysis, at which the predefined futility boundary was crossed. PATIENTS AND METHODS: GAIN-2 was an open-label, randomised, multicentre phase III trial. Two thousand eight hundred and eighty seven patients were randomised 1:1 between three courses each of idd epirubicin (E) 150 mg/m2, nab-paclitaxel (nP) 330 mg/m2 and cyclophosphamide (C) 2000 mg/m2 (iddEnPC) versus four cycles of leucocyte nadir-based tailored and dose-dense EC (dtEC) followed by four cycles of tailored and dose-dense docetaxel (dtD) (dtEC-dtD). RESULTS: The duration of median follow-up was 45.8 (range 0.0-88.3) months. Trial objectives included invasive disease-free survival (iDFS) as the primary end-point. A total of 593 patients received the treatment as neoadjuvant chemotherapy. At the time of futility interim analysis, 414 events for iDFS were reported. Overall, there was no difference in iDFS between iddEnPC and dtEC-dtD with 4-year iDFS rates of 84.3% (95% confidence interval (CI) 82.0-86.4%). Among all predefined subgroups, hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-), lobular cancer and ≤50 years subgroups predicted for better iDFS in the dtEC-dtD arm. Overall, 88.1% of patients completed all treatment in both arms. Haematological toxicity grade 3/4 and grade 3/4 non-haematological adverse events were significantly higher with iddEnPC (iddEnPC 50.8% vs dtEC-dtD 45.1%, P = 0.002), especially arthralgia and peripheral sensory neuropathy. Two treatment-related deaths occurred during dtEC-dtD, corresponding to a low mortality rate of 0.07%. CONCLUSIONS: iDFS is equal in both regimens, but tailoring dose-dense chemotherapy improved outcomes in HR+/HER2-, lobular cancer and patients ≤50 years.

Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy.

BACKGROUND: BRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities. METHODS: Patients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III-IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored. RESULTS: Two hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87-1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64-1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p < 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies. CONCLUSIONS: gBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research.

Colon diverticulosis is not a risk factor for the detection of adenomatous polyps - results of a prospective study.

BACKGROUND AND AIMS: Colon diverticula (CD) and adenomatous polyps are frequently found during colonoscopy. Data from the literature contains inconsistent information about whether patients with CD have a higher risk for colon adenomas. A positive correlation might influence the current guidelines for screening colonoscopies. The aim of this study was to examine whether presence of CD is associated with endoscopic adenoma detection. MATERIALS AND METHODS: This was a prospective study at 2 centers in Germany. Patients with an indication for colonoscopy were included. The number and localization of diverticula were recorded. Detected polyps were resected, and histopathological results were captured. Logistic regression models were fitted to the data to evaluate the association between CD and adenoma detection. RESULTS: A total of 938 colonoscopies was included. CD occurred in 49.1 % of the colonoscopies. The polyp and adenoma detection rates (PDR, ADR) were 50.3 % and 32.3 %. In 37.5 % of the patients with diverticula, at least 1 adenoma was detected, whereas this was the case in 27.3 % in the absence of diverticula. The presence of diverticula was positively correlated with the detection of adenomas in univariate analysis (p = 0.001), but no significant association could be found in multivariable analysis (p = 0.775). Increasing age (p < 0.001), male sex (p = 0.005), and longer withdrawal time (p < 0.001) were significant predictors for adenoma detection in the multivariable analysis. Similar results were also observed for both the distal and the proximal colon. DISCUSSION: Diverticula and adenomas are frequently found during colonoscopies. However, diverticula disease was not significantly associated with adenoma detection after adjustment for relevant prognostic factors. Older age, male sex, and duration of withdrawal time are predictors for the detection of adenomatous polyps.

Preliminary assessment of two novel mechanical colonoscopic polypectomy simulators: Description, evaluation and validation.

Background and study aims Colonoscopic polypectomy is an essential endoscopic skill. The simulators available for training are limited and based on raw porcine colons. Animal intestines are inconvenient and offer limited advantages for polypectomy training. These limitations are avoided by two novel mechanical simulators - the magnetic system based simulator (MSPS) and the simulator for polypectomy with high frequency current (HFPS) - described here. They are equipped to demonstrate self-repair of polyps after making a cut and hybrid polyps. The aim of this study was to describe and establish face, content, and construct validity of the two simulators and to assess their perceived utility as training and assessment tools. Methods Ten novice, seven intermediate, and 10 advanced endoscopists participated in this study. Each one performed two polypectomies in MSPS and then one polypectomy and polyp retrieval in HFPS. The median times were compared among the three groups to preliminarily assess construct validity as a primary outcome. To establish face validity, the novices and intermediates completed a questionnaire about the credibility of each simulator after finishing the tasks. For content validity, the experts completed a questionnaire grading different aspects of the simulators' realism and their usefulness for training. Results All 27 participants completed the modules. Median times needed to complete the tasks in both simulators differed significantly between the participants with different levels of experience ( P  < 0.05). Both MSPS and HFPS received favorable scores regarding face and content validity. No technical problems were encountered. Conclusion This study provides preliminary validation for MSPS and HFPS as useful training tools in a preclinical setting as well as during colonoscopy training. Moreover, we demonstrated the construct validity of both simulators, which confirms their use as a skill assessment tool during a colonoscopy training program.

Implementing cell-free DNA of pancreatic cancer patient-derived organoids for personalized oncology.

One of the major challenges in using pancreatic cancer patient-derived organoids (PDOs) in precision oncology is the time from biopsy to functional characterization. This is particularly true for endoscopic ultrasound-guided fine-needle aspiration biopsies, typically resulting in specimens with limited tumor cell yield. Here, we tested conditioned media of individual PDOs for cell-free DNA to detect driver mutations already early on during the expansion process to accelerate the genetic characterization of PDOs as well as subsequent functional testing. Importantly, genetic alterations detected in the PDO supernatant, collected as early as 72 hours after biopsy, recapitulate the mutational profile of the primary tumor, indicating suitability of this approach to subject PDOs to drug testing in a reduced time frame. In addition, we demonstrated that this workflow was practicable, even in patients for whom the amount of tumor material was not sufficient for molecular characterization by established means. Together, our findings demonstrate that generating PDOs from very limited biopsy material permits molecular profiling and drug testing. With our approach, this can be achieved in a rapid and feasible fashion with broad implications in clinical practice.

Final results from IMPROVE: a randomized, controlled, open-label, two-arm, cross-over phase IV study to determine patients' preference for everolimus in combination with exemestane or capecitabine in combination with bevacizumab in advanced HR-positive, HER2-negative breast cancer.

BACKGROUND: The objective of the IMPROVE study was patients' preference for either endocrine-based therapy or combined chemo- and anti-angiogenic therapy in advanced HR-positive/HER2-negative breast cancer. METHODS: In this randomized, cross-over phase IV study, 77 patients were recruited in 26 sites in Germany. Patients were randomized 1:1 to receive either capecitabine plus bevacizumab (Cap+Bev) as first-line therapy followed by cross-over to everolimus plus exemestane (Eve+Exe) as second-line therapy (Arm A) or the reverse sequence (Arm B). The primary endpoint was patients' preference for either regimen, assessed by the Patient Preference Questionnaire 12 weeks after cross-over. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life (QoL). RESULTS: 61.5% of patients preferred Cap+Bev (p = 0.1653), whereas 15.4% preferred Eve+Exe and 23.1% were indecisive. Physicians showed a similar tendency towards Cap+Bev (58.1%) as the preferred regimen versus Eve+Exe (32.3%). Median first-line PFS was longer for Cap+Bev than for Eve+Exe (11.1 months versus 3.5 months). Median second-line PFS was similar between Cap+Bev and Eve+Exe (3.6 months versus 3.7 months). Median OS was comparable between Arm A (28.8 months) and Arm B (24.7 months). 73.0% and 52.6% (first-/second-line, Cap+Bev) and 54.1% and 52.9% (first-/second-line, Eve+Exe) of patients experienced grade 3/4 TEAEs. No treatment-related deaths occurred. QoL and treatment satisfaction were not significantly different between arms or treatment lines. CONCLUSIONS: Patients tended to favor Cap+Bev over Eve+Exe, which was in line with physicians' preference. Cap+Bev showed superior first-line PFS, while QoL was similar in both arms. No new safety signals were reported. TRIAL REGISTRATION: EudraCT No: 2013-005329-22. Registered on 19 August 20.

Endocuff vision-assisted vs. standard polyp resection in the colorectum (the EVASTA study): a prospective randomized study.

BACKGROUND: Cap-assisted colonoscopy is frequently used to facilitate adenoma detection during endoscopy. However, data on how cap assistance influences polyp resection are scarce. We aimed to evaluate the impact of cap assistance with the Endocuff vision device (EVD) on the resection time for colorectal polyps in patients undergoing colonoscopy. METHODS : A randomized, prospective study was performed in a university hospital in Germany. A total of 250 patients were randomly assigned 1:1 to undergo either colonoscopy with the EVD (EVD arm) or standard colonoscopy without the use of a cap (standard arm). The primary outcome was the average duration of polypectomy. Secondary outcomes included adenoma detection rate, cecal and ileal intubation times, and propofol dosage. RESULTS: The use of EVD led to a significant reduction in the median polypectomy time in the EVD vs. standard arm (54 vs. 80 seconds, respectively; P = 0.02). This effect was strongest for polyps ≥ 6 mm. Compared with the standard group, Endocuff assistance also resulted in a shorter cecal intubation time (6 vs. 8 minutes; P = 0.03) and overall colonoscopy time (23 vs. 27 minutes; P = 0.02). In contrast, no difference in withdrawal time was observed. The polyp and adenoma detection rates did not differ significantly between the two groups. CONCLUSION: Endocuff-assisted colonoscopy reduces the duration of polypectomy, which may be due to a more stable scope position during resection. Further studies are needed to investigate whether comparable effects will be seen for other interventions, such as clipping or biopsy sampling.

Development of central nervous system metastases as a first site of metastatic disease in breast cancer patients treated in the neoadjuvant trials GeparQuinto and GeparSixto.

BACKGROUND: The incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear. METHODS: We analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy. RESULTS: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease. In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3-4; HR 1.63, 95% CI 1.08-2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64-4.04, p < 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32-3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89-7.64, p < 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28-12.44, p < 0.001). CONCLUSIONS: Especially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies.

Treatment patterns, health care resource use and outcomes in metastatic triple-negative breast cancer in Germany: retrospective chart review study (OBTAIN).

Background: There is limited data on the real-life situation and outcomes of patients with metastatic triple-negative breast cancer (mTNBC) in Germany. The aim of this chart review was to describe the current treatment patterns, resource use and outcomes in this patient group. Methods: Retrospective data collection in 30 gyneco-oncological sites (hospitals and office-based) across Germany between January and April 2017. Index date was defined as initiation of treatment with gemcitabine, vinorelbin, capecitabine or eribulin therapy following discontinuation of taxane and/or anthracycline therapy. Results: In the 91 evaluable patients, median time between primary diagnosis and index date was 20.9 months (range 0-187 months). Ten percent of patients had no distant metastases, while 57% had newly diagnosed metastases. Cancer stage at index date was mostly IV (82 patients). A number of 135 different regimens (monotherapy or combination therapy) were used. For first-line chemo treatment, 29 patients received monotherapy and 54 patients combination therapy. Bevacizumab and paclitaxel were also the most frequently used single substances among all therapy lines together and for first-line therapy. While taxanes were at least occasionally administered for second-line therapy, no patient received taxanes for third-line therapy. Chemotherapy modifications in terms of dose reduction or treatment interruption were rare. However, the therapy was terminated in more than two thirds of all cases. Fifty-nine patients were hospitalized at least once. For first-, second- and third-line therapy, median overall survival was 19.1/10.8/14.6 months, and median progression-free survival was 7.7/2.5/5.6 months. Conclusion: In clinical routine, a wide variety of treatment approaches is applied, while outcomes in terms of survival are poor. New treatment options are needed for this challenging tumor type.

Near focus NBI endoscopy plus acetic acid for optical polyp characterization in the colorectum - A proof of principle study.

Background and study aim: Optical polyp characterization (OPC) in the colorectum is an upcoming challenge for endoscopists. Narrow band imanging (NBI) has been proposed to be helpful for OPC. However, data from clinical studies have shown that quality of OPC differs markedly between endoscopists. The aim of this study was to test the value of a combined NBI plus acetic acid (NBI + AA) approach for OPC in the colorectum. Patients and methods: This was a prospective, single-arm study at a tertiary referral center in Germany. The study was designed as a proof of principle study. Initially polyps were characterized using High-definition white light (HDWL) only. Additionally, the same polyps were investigated using NBI + AA (1.5% solution) in order to predict polyp pathology in a real time setting. The near focus function was used for both HDWL and NBI + AA assessment. The primary endpoint was accuracy of colorectal polyp prediction when using NBI + AA. Results: A total of 63 polyps were detected in 55 patients. NBI + AA based accuracy of real-time predictions was 85.5% compared to 80.6% using HDWL (p = .450). Accuracy was 90.2% in the high confidence setting for both NBI + AA and HDWL predictions. A higher share of polyps were assessed with high confidence when using NBI + AA compared to HDWL (p = .006). The use of NBI + AA led to a better identification of polyp margins (p < .001) compared to HDWL. Conclusions: The use of acetic acid led to a high level of accuracy and confidence in the prediction of polyp histology. These data justify further investigation in a randomized controlled study.

Cellular Dissociation Grading Based on the Parameters Tumor Budding and Cell Nest Size in Pretherapeutic Biopsy Specimens Allows for Prognostic Patient Stratification in Esophageal Squamous Cell Carcinoma Independent From Clinical Staging.

Initial treatment planning in esophageal squamous cell carcinoma mainly relies on clinical staging. Recently, a highly prognostic grading system based on the cellular dissociation parameters Tumor Budding and Cell Nest Size has been proposed for resected esophageal squamous cell carcinoma. To probe for the transferability and relevance of this established novel grading system in the pretreatment setting, we evaluated Tumor Budding/Cell Nest Size in pretherapeutic biopsies of either primarily resected (cohort 1, n=80) or neoadjuvantly treated (cohort 2, n=75) esophageal squamous cell carcinoma. Grading data were correlated with clinicopathologic and survival parameters. High Tumor Budding Activity and small Cell Nest Size in pretherapeutic biopsies were strongly associated with shortened overall survival, disease-free survival, and disease-specific survival in both cohorts. A modified histopathologic grading system incorporating both factors termed "Cellular Dissociation Grade" showed excellent prognostic demarcation between well (G1), moderately (G2), and poorly differentiated (G3) carcinomas in both scenarios (overall survival: cohort 1: P<0.001; cohort 2: P=0.009) and was predictive for a high pathologic tumor stage and the presence of nodal metastases in primarily resected patients. Multivariate analyses revealed the Cellular Dissociation Grade to be a predictor of poor outcome in the pretherapeutic setting independent of clinical stage (overall survival, disease-free survival, and disease-specific survival: P<0.001). Hazard ratio for disease-free survival was 3.19 for G2 and 5.66 for G3 carcinomas compared with G1 neoplasms. Our data not only prove the transferability of histopathologic grading based on Tumor Budding/Cell Nest Size to biopsy specimens in esophageal squamous cell carcinoma, but also demonstrate that the Cellular Dissociation Grade is a strong outcome predictor in this entity even in the pretreatment scenario. Therefore, we believe that this novel type of grading has the ability to serve as a powerful histology-based pretherapeutic biomarker, that might supplement clinical staging for choosing the most suitable therapy decision.

Improving the quality and acceptance of colonoscopy preparation by reinforced patient education with short message service: results from a randomized, multicenter study (PERICLES-II).

BACKGROUND AND AIMS: Sufficient bowel preparation is crucial for successful screening and surveillance colonoscopy. However, the rates of inadequate preparation are still high. We investigated the effects of reinforcing patient education and guidance by using the short message service (SMS). METHODS: In this prospective, endoscopist-blinded, multicenter study, standard instructions pertaining to split-dose preparation were provided in a verbal and written format to all patients during the initial appointment. Patients were randomly assigned (1:1) to a group that received reinforced education starting 4 days before the colonoscopy (SMS group) or to the control group which did not receive further education. The primary outcome was the percentage of insufficient preparation results (Boston Bowel Preparation Scale [BBPS] score <6). The secondary outcomes included quality of bowel preparation according to the BBPS, polyp and adenoma detection rates, and patients' perceived discomfort in the preparation procedure. RESULTS: The percentage of patients with insufficient bowel preparation was significantly lower in the SMS group (9%) than in the control group (19%) (P = .0013). The mean BBPS score was significantly higher in the SMS group (7.4 ± 0.1) than in the control group (6.5 ± 0.1) (P < .0001). Each colon segment had significantly higher BBPS scores in the SMS group. The adenoma detection rate and number of detected adenomas in the right segment of the colon were higher in the SMS group. SMS messages were accompanied by a lower level of discomfort during preparation (numeric rating scale) (5.2 SMS vs 5.8 controls) (P = .0042). CONCLUSIONS: Reinforced patient education by using SMS messages during the 4 days before colonoscopy increased bowel cleanliness, adenoma detection in the right segment of the colon, and reduced discomfort. (Clinical trial registration number: NCT02272036.).