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We sought to determine dynamics of BCR-ABL mRNA expression levels in 139 patients with chronic myelogenous leukemia (CML) in early chronic phase, randomized to receive imatinib (n=69) or interferon (IFN)/Ara-C (n=70). The response was sequentially monitored by cytogenetics from bone marrow metaphases (n=803) and qualitative and quantitative RT-PCR from peripheral blood samples (n=1117). Complete cytogenetic response (CCR) was achieved in 60 (imatinib, 87%) vs 10 patients (IFN/Ara-C, 14%) after a median observation time of 24 months. Within the first year after CCR, best median ratio BCR-ABL/ABL was 0.087%, (imatinib, n=48) vs 0.27% (IFN/Ara-C, n=9, P=0.025). BCR-ABL was undetectable in 25 cases by real-time PCR, but in only four patients by nested PCR. Median best response in patients with relapse after CCR was 0.24% (n=3) as compared to 0.029% in patients with continuous remission (n=52, P=0.029). We conclude that (i) treatment with imatinib in newly diagnosed CML patients is associated with a rapid decrease of BCR-ABL transcript levels; (ii) nested PCR may reveal residual BCR-ABL transcripts in samples that are negative by real-time PCR; (iii) BCR-ABL transcript levels parallel cytogenetic response, and (iv) imatinib is superior to IFN/Ara-C in terms of the speed and degree of molecular responses, but residual disease is rarely eliminated.Leukemia (2003) 17, 2392-2400. doi:10.1038/sj.leu.2403157 Published online 2 October 2003 [ABSTRACT FROM AUTHOR]

A significant proportion of chronic myeloid leukemia (CML) patients achieve a major cytogenetic remission (MCR) to imatinib therapy after failing interferon (IFN) a-based protocols. We sought to determine levels of residual disease in patients with MCR using various molecular methods and to establish a relation between residual BCR-ABL transcript levels and rate of relapse in complete cytogenetic remission (CCR). Response was measured by conventional cytogenetic analysis, hypermetaphase and interphase fluorescence in situ hybridization (HM-FISH, IP-FISH) of bone marrow (BM) cells, qualitative nested and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts. We investigated 323 peripheral blood (PB) and BM samples from 48 CML patients who achieved a complete (Ph+ 0%; n=41) or partial (Ph+ 1-34%; n=7) cytogenetic remission after 3-20 months of imatinib therapy. Prior to imatinib, 35 patients were in chronic phase (CP), eight in accelerated phase (AP), four in myeloid and one in lymphoid blast crisis. HM-FISH results correlated with ratios BCR-ABL/ABL in PB and BM. In patients with CCR, residual disease was detectable by HM-FISH (31%), IP-FISH (18%), and RT-PCR (100%). During follow-up, BCR-ABL became undetectable in two patients (one CP, one AP) by both nested and quantitative RT-PCR. CCR is ongoing in 30 evaluable patients, 11 patients have relapsed. At the time of best response, median ratios BCR-ABL/ABL were 2.1% (range 0.82-7.8) in patients with subsequent relapse and 0.075% (range 0-3.9) in patients with ongoing remission (P=0.0011). All 16 CP patients, who achieved ratios BCR-ABL/ABL <0.1% as best molecular response are in continuous remission, while 6/13 patients (46%) with ratios ?0.1% have relapsed (P=0.0036). We conclude that: (i) in patients with CCR to imatinib, HM-FISH and RT-PCR usually reveal residual BCR-ABL+ cells; (ii) RT-PCR results derived from PB and BM are comparable in CP CML; and (iii) low levels of residual disease with ratios BCR-ABL/ABL <0.1% are associated with continuous remission.Leukemia (2003) 17, 1687-1694. doi:10.1038/sj.leu.2403033 [ABSTRACT FROM AUTHOR]

Salivary duct carcinomas (SDC) of the parotid gland are rarely occurring highly malignant tumors. A 65-year-old man presented with a preauricular mass. After surgical treatment and histologic examination, the findings were interpreted as a squamous cell carcinoma (SCC) metastasis of the parotid gland deriving from a cancer of unknown primary DD primary SCC of the parotid gland. Adjuvant platinum-based radiochemotherapy was administered in domo. However, re-staging revealed multiple size-progressive pulmonary round lesions. After resection and histological examination of a pulmonary mass and in synopsis with the primary tumor, the initial diagnosis of SCC was revised to SDC of the parotid gland. With positive HER-2 status, off-label trastuzumab/docetaxel was initiated in an individual healing attempt, during which the pulmonary metastases showed clear progression. Consequently, the patient received immunotherapy with nivolumab according to his negative PD-L1 status. After 57 cycles of nivolumab, the patient presents with partial remission and in good condition. We report, for the first time, a robust response of metastatic SDC to checkpoint inhibition with nivolumab without additional radiotherapy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Two headphone systems using different sound systems were compared to investigate the effects of a sound intervention on cardiovascular parameters, indicators of stress, and subjective feelings. Methods: One hundred volunteers who work in the health care sector reporting elevated workplace-related stress were enrolled and randomized to a 12-min sound intervention (classical music) with either conventional headphones ("MEZE 99 Classic") or with the same-but internally modified-headphone (called "Lautsaenger"). Cardiovascular parameters were measured with the VascAssist2.0, both before and after sound interventions. In addition, participants were asked to complete questionnaires on burnout risk and emotions/stress. Results: The study population consisted mainly of female participants ( n  = 83), with the majority being students (42%). Median age was 32.5 years (range 21-71). In terms of cardiovascular parameters, a significant reduction in aortic pulse wave velocity, as measure of arterial stiffness, and heart rate was observed within both treatment arms. Both systolic blood pressure and arterial flow resistance were reduced by sound intervention, while these effects were only documented with Lautsaenger. Treatment groups were comparable in terms of subjective feedback by participants: a significant increase in emotional wellbeing was achieved with both headphone systems. Conclusions: A single short-term sound intervention seems to be able to achieve objective cardiovascular improvements in healthy volunteers reporting subjective symptoms of workplace-related stress, using two different headphone systems. Moreover, significant emotional improvement was reported within both arms. Trial Registration: ISRCTN registry 70947363, date of registration August 13, 2021.

Introduction: Checkpoint inhibitors, such as PD1 inhibitors, represent an important pillar in the therapy of advanced malignancies of the head and neck region. The most relevant complications are immune-related adverse effects (irAEs), which represent an immense burden for patients. Currently, no sufficient stratification measures are available to identify patients at increased risk of irAEs. The aim of this retrospective study was to examine whether demographic, histopathological, clinical, or laboratory values at the start of CPI therapy represent a risk factor for the later occurrence of autoimmune complications., Material and Methods: Data from 35 patients between 2018 and 2021 who received therapy with nivolumab or pembrolizumab for head and neck malignancy were analyzed and assessed for any associations with the subsequent occurrence of irAEs., Results: IrAE developed in 37% of patients, with pneumonitis being the most common form (14%). Pneumonitis was found in patients with an average significantly lower T-stage of primary tumors. An increase in basophilic leukocytes was found in patients with dermatitis later in the course. When thyroiditis developed later, the patients had a higher CPS score and lower monocyte levels., Discussion: Even though individual laboratory values at the beginning of therapy might show a statistical association with the later occurrence of irAEs, neither demographic, histopathological, nor laboratory chemistry values seem to be able to generate a sound and reliable risk profile for this type of complication. Therefore, patients need to be educated and sensitized to irAEs, and regular screening for irAEs should be carried out., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jungbauer, Affolter, Brochhausen, Lammert, Ludwig, Merx, Rotter and Huber.)

Aim: Cancer remains a disease with a significant impact on morbidity and mortality but also on quality of life. This prospective randomized pilot study investigated the effects of a sound intervention on physical and emotional well-being in outpatients with cancer., Methods: Two self-applied sound interventions were used for this purpose, either active "music playing" with a body monochord or passive sound intervention with headphones to listen to a given music compilation. Interventions were carried out over a period of 4 weeks for at least 15 min in the evening before bedtime. The following self-assessment questionnaires were completed both at baseline and after 4 weeks to evaluate the response: the Pittsburgh Sleep Quality Index (PSQI), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), Visual Analogue Scale (VAS) for pain and fatigue, and the Fear of Progression (FoP) questionnaire. Primary endpoint of this exploratory trial was to describe the rate of patients with improvement in at least one dimension without worsening of any other., Results: 73 patients (29 male, 44 female) were included in the study and randomized to either active (n = 34, 47%) or passive sound intervention (n = 39, 53%). Median age was 52.0 years (range 21-79). Fourteen patients (19%) stated that they were musically active. The sound intervention was carried out on a median of 26 days (range 5-28). A higher percentage of patients in the passive group reached the primary endpoint: n = 15 (39%) versus n = 9 (27%). Response differences in favour of the passive group were seen with the VAS fatigue and with QLQ-30 questionnaires. Overall, an improvement in QLQ-30 questionnaire was seen in 12 patients (31%) in the passive group versus 3 patients (9%). Moreover, sound intervention significantly improved social functioning and shortness of breath in the passive group according to QLQ-C30. Significant improvements were also noticed in the passive group in terms of affective reactions as a domain of the FoP questionnaire. No effects on pain or sleep quality could be observed., Conclusion: A 4-week self-administered sound intervention was feasible in outpatients suffering from cancer. Using a panel of 5 questionnaires, passive sound interventions appeared to be more likely to positively influence patient-reported outcomes. In particular, a positive impact was documented in social functioning and fatigue., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Cancer patients (pts) suffer from a significant amount of psychosocial distress related to tumor disease itself or straining treatments. Despite recommendations on how to screen for and to deal with psychosocial distress in cancer pts, data about implementation of psycho-oncological interventions (poi) in outpatient settings of cancer pts are scarce. The aim of this study was to identify outpatients with cancer in need of poi and to evaluate different assessment instruments., Methods: N = 200 outpatients with hemat-/oncological malignancies were interviewed between October 2015 and December 2017 at the University Hospital Mannheim using the Basic Documentation for Psycho-Oncology (PO-Bado) and the Hornheider Screening Instrument (HSI) - both clinician-administered assessment tools - followed by descriptive, univariate, and agreement analysis., Results: N = 61 cancer pts (31%) were identified to be in need for poi considering the results of both questionnaires. The number of identified pts in need of poi was lower when analyzing the results of the PO-Bado (n = 42, 21%) and the HSI (n = 39, 20%) separately. The degree of agreement between the results of PO-Bado and HSI was low (kappa = 0.3655). Several factors like gender, age and diagnosis were identified to have significant impact on the need for poi (p ≤ 0.05)., Conclusion: Our study underlines that different screening instruments for psychosocial distress may identify disparate populations of cancer pts. The study data also revealed significant characteristics that might be associated with elevated levels of psychosocial distress and a clear indication for poi. However, further analyses on larger populations of cancer pts are needed to provide information how to transfer positive screening to poi in clinical routine., (© 2023 S. Karger AG, Basel.)

Purpose: High pathologic complete response (pCR) rates and comparably good survival data were seen in a phase II trial combining perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy with trastuzumab for resectable, esophagogastric adenocarcinoma (EGA). The current trial evaluates the addition of trastuzumab and pertuzumab to FLOT as perioperative treatment for human epidermal growth factor receptor 2-positive resectable EGA., Methods: In this multicenter, randomized phase II/III trial, patients with human epidermal growth factor receptor 2-positive, resectable EGA (≥ clinical tumor 2 or clinical nodal-positive) were assigned to four pre- and postoperative cycles of either FLOT alone (arm A) or combined with trastuzumab and pertuzumab, followed by nine cycles of trastuzumab/pertuzumab (arm B). The primary end point for the phase II part was the rate of pCR., Results: The trial was closed prematurely, without transition into phase III, after results of the JACOB trial were reported. Eighty-one patients were randomly assigned (A: 41/B: 40) during the phase II part. The pCR rate was significantly improved with the trastuzumab/pertuzumab treatment (A: 12%/B: 35%; P = .02). Similarly, the rate of pathologic lymph node negativity was higher with trastuzumab/pertuzumab (A: 39%/B: 68%), whereas the R0 resection rate (A: 90%/B: 93%) and surgical morbidity (A: 43%/B: 44%) were comparable. Moreover, the inhouse mortality was equal in both arms (overall 2.5%). The median disease-free survival was 26 months in arm A and not yet reached in arm B (hazard ratio, 0.58; P = .14). After a median follow-up of 22 months, the median overall survival was not yet reached (hazard ratio, 0.56; P = .24). Disease-free survival and overall survival rates at 24 months were 54% (95% CI, 38 to 71) and 77% (95% CI, 63 to 90) in arm A and 70% (95% CI, 55 to 85) and 84% (95% CI, 72 to 96) in arm B, respectively. More ≥ grade 3 adverse events were reported with trastuzumab/pertuzumab, especially diarrhea (A: 5%/B: 41%) and leukopenia (A: 13%/B: 23%)., Conclusion: The addition of trastuzumab/pertuzumab to perioperative FLOT significantly improved pCR and nodal negativity rates at the price of higher rates of diarrhea and leukopenia.

Background: Immune checkpoint inhibitors (ICI) have been approved in uro-oncology for a few years. Real-world experience regarding benefits and risks with novel side effects are rare., Materials and Methods: In a retrospective analysis, all patients who received ICI therapy due to metastatic renal cell carcinoma (NCC) or urothelial carcinoma (UCA) were enrolled at two maximum care hospitals in Germany between July 2016 and May 2021. Radiologic response, progression-free survival (PFS), and adverse events leading to treatment interruption were collected. Oncologic response was compared to randomized controlled trials., Results: In all, 1185 ICI cycles were administered to 145 patients (111 men [77%] and 34 women [23%]): 64 (44.1 %) patients with NCC and 81 (55.9%) patients with UCA received ICI therapy. Of 141 patients with radiological follow-up, an objective response was observed in 21.3% (n = 13) of patients with NCC and 20.0% (n = 16) with UCA (median duration of response 14.9 months [3.0-51.3]). Median PFS was 5.3 months in patients with NCC and 4.8 months with UCA. ICI-associated adverse events requiring treatment interruption were observed in 17.2% patients with NCC and 20.9% with UCA. These were most commonly renal (5.5%: nephritis) and gastrointestinal (4.8%: colitis, diarrhea) adverse events. Hospitalization was required for 22 (15.1%) patients., Conclusion: This real-world experience may support patient-centered consultation in treatment decision-making. Further studies on prognostic factors are needed. Therapy interruptions are frequent and the spectrum of side effects requires interdisciplinary treatment., (© 2022. The Author(s).)

Perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) is a mainstay in the treatment of esophagogastric adenocarcinomas (EGA). Trastuzumab improved survival when added to chemotherapy in patients with HER-2-positive metastatic EGA. We investigated the combination of trastuzumab and FLOT as perioperative treatment in patients with locally advanced EGA. A multicenter phase II study evaluated the efficacy and toxicity of perioperative FLOT (24-hours 5-FU 2600 mg/m 2 , leucovorin 200 mg/m 2 , oxaliplatin 85 mg/mg 2 , docetaxel 50 mg/m 2 , trastuzumab 6 mg/kg then 4 mg/kg d1, repeated d15 for four cycles preoperatively and postoperatively followed by 9 cycles of trastuzumab monotherapy) in patients with HER-2 positive EGA. Patients had ≥cT2, any N, M0 EGA. The primary endpoint was the rate of centrally assessed pathological complete response (pCR). Secondary endpoints comprised disease-free (DFS) and overall survival (OS), R0 resection rate, toxicity and surgical morbidity. Fifty-six evaluable patients (median age 62 years) were included; n = 40 had tumors originating from the esophagogastric junction; T stage was (cT2/3/4/unknown): 4/42/8/2; n = 50 patients had cN+ disease. Main adverse events grades 3-4: leukopenia (17.9%), neutropenia (46.6%) and diarrhea (17.0%). All patients underwent tumor resections. R0 resection rate was 92.9%. Eight patients had anastomotic leakage. One postoperative death occurred. pCR was found in 12 patients (21.4%) and a further n = 14 patients (25.0%) had near complete response. Median DFS was 42.5 months and the 3-year OS rate was 82.1%. The primary endpoint of achieving a pCR >20% was reached. No unexpected safety issues were observed. Survival data are promising., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: Immune checkpoint inhibitors have shown efficacy in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) gastrointestinal (GI) cancers. However, depth and duration of clinical response is not uniform. We assessed tumor mutation burden (TMB) as a response marker in patients with GI cancers treated with immune checkpoint inhibitors., Methods: Detailed clinical and response data were collected from six patients with metastatic MSI-H/dMMR GI cancers treated with immune checkpoint inhibitors. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumors and matched normal tissue were profiled by targeted next generation sequencing (127 gene panel, size 0.8 Mb). Impact of included mutation types, germline filtering methodology and different variant allele frequency thresholds on TMB estimation was assessed., Results: Objective radiographic responses were observed in all six patients, and complete response was achieved in two of the six patients. Responses were durable (minimum 25 months). TMB estimates were clearly above the two recently reported cut-offs for metastatic colorectal cancer of 12 or 37 mutations per megabase for five of six patients, respectively, while one patient had borderline TMB elevation. TMB did not show an association with extent and duration of response but was influenced by included mutation types, germline filtering method and variant allele frequency threshold., Conclusion: Our case series confirms the clinical benefit of immune checkpoint blockade in patients with metastatic MSI-H/dMMR GI cancers and illustrates the vulnerability of TMB as predictive marker in a subset of patients.

Background: Music therapy or sound interventions were shown to confer beneficial effects in patients with cancer for instance in terms of pain or fear relief and improvement of other patient reported outcomes. Cardiovascular parameters, especially heart rate variability (HRV) were found to have prognostic implications in cancer patients. In this trial we aimed to investigate the effects of a sound intervention on cardiovascular parameters compared to rest in patients with cancer., Methods and Results: Using a randomized cross-over design, 52 patients (male 13, female 39) with cancer were recruited to receive both a 15-minute sound intervention and a 15-minute rest intervention within 4 weeks with at least a one-week blanking period. Cardiovascular parameters (among others HRV, aortic pulse wave velocity [PWV], augmentation index [Aix], aortic blood pressure [BP], heart rate [HR]) were assessed immediately before (pre) and after (post) the intervention had taken place. HRV (Root mean square of successive RR interval differences [RMSSD, ms]) significantly increased, during sound intervention (median RMSSD pre 24 [range 5-112] vs post 22 [range 9-141], P  = .03). Likewise, median PWV, as a direct marker of arterial stiffness, was significantly reduced by sound intervention ([m/s] pre 8.5 [range 5.6-19.6] vs post 8.3 [range 5.6-15.6], P  = .04). For both parameters no statistically significant change during rest was observed. HR was lowered by both, rest ( P  < .0001) and sound intervention ( P  = .02), with a more pronounced effect by rest. A significant increase in systolic aortic blood pressure was shown by rest ([mmHg] median 101 [range 78-150] vs post median 103 [range 71-152], P  = .04) but not during sound intervention ( P  = .59), while rest intervention led to a decrease in resistance index (pre median 33 [range 13-92] vs post median 32 [11-84], P  = .02)., Conclusion: In comparison with rest, a single sound intervention in patients with cancer improved cardiovascular parameters commonly associated with increased stress levels. Studies with longer follow-up and multiple interventions are warranted., Trial Registration: ISRCTN registry 70947363.

Acne-like skin reactions frequently occur in patients undergoing treatment with drugs inhibiting the epidermal growth factor receptor. Recently, the effects of vitamin K1 containing cream (Reconval K1) as prophylactic skin treatment in addition to doxycycline were explored in a double-blind randomized phase II trial (EVITA) in patients with metastatic colorectal cancer receiving cetuximab. EVITA demonstrated a trend towards less severe skin rash in Reconval K1-treated patients using the tripartite WoMo skin reaction grading score as a thorough tool for quantification of drug related skin reactions. This gender-specific analysis of the EVITA trial evaluated the application of the WoMo score for assessment of epidermal growth factor receptor (EGFR)-related skin toxicities according to treatment arm and gender. To show the robustness of results parametric and non-parametric statistical analyses were conducted. All three parts of the WoMo score independently demonstrated the superiority of the treatment arm (Reconval K1) regarding a significant reduction in acneiform skin reactions in women. Men did not benefit from Reconval K1 cream at any time point in none of the WoMo score analyses. The treatment effect in women was confirmed by the use of skin rash categories based on the final WoMo overall score and mixed effect longitudinal multiple linear regression analysis. The WoMo score represents a sensitive tool for studies exploiting treatments against EGFR mediated acne-like skin rash. Part C of the WoMo score seems to be sufficient for quantification of drug related skin toxicities in further studies. Standard WoMo skin reaction score values for future studies are provided., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background 5-Fluorouracil (5-FU) is frequently used for the treatment of gastrointestinal tumors. The pharmacological effect of 5-FU is influenced by genetic polymorphisms as well as differently dosed regimens. Currently, 5-FU is generally administered as a continuous infusion via an implanted port system using a body surface area (BSA)-based dose calculation. In order to optimize treatment, the area under the curve (AUC) can be estimated to allow for individual dose adjustment. A 5-FU AUC range between 20 and 30 [mg×h×L] is recommended. The aim of the current study was to assess if blood for AUC analysis could also be drawn at the side where the port system had been placed. Methods We collected EDTA blood samples of patients receiving infusional 5-FU simultaneously from different sampling points (right/left cubital vein). 5-FU concentrations were measured in a steady-state equilibrium based on nanoparticle immunoassay (My5-FU; Saladax). Results A total of 39 patients took part in this study. About half of the patients did not reach the target 5-FU concentration window (37% were under- and 16% of the patients were overdosed). Calculated median AUC was 23.3 for the right arm (range 5.8-59.4) and a median of 23.4 for the left arm (range 5.3-61.0). AUC values showed no difference between right compared to left arms (p=0.99). Conclusions In all, these results confirm that a high percentage of patients are not treated with 5-FU doses reaching suggested AUC levels of 20-30. The location of venepuncture, however, had no impact on the results of plasma 5-FU concentration.

Background: To investigate the importance of adjuvant chemotherapy in locally advanced rectal cancer (≥ cT3 or N+) staged ypT0-2 ypN0 on final histological work-up after neoadjuvant chemoradiation and radical resection., Methods: The clinical course of patients with rectal cancer and ypT0-2 ypN0 stages after neoadjuvant chemoradiation and radical resection was analyzed from 1999 to 2012. Patients were divided into two groups depending on whether adjuvant chemotherapy was administered or not. Overall survival, distant metastases, and local recurrence were compared between both groups., Results: Fifty-four patients with adjuvant (ACT) and 50 patients without adjuvant chemotherapy (NACT) after neoadjuvant chemoradiation followed by radical resection for rectal cancer were included in the analysis. Mean follow-up was 68 ± 33.7 months. One patient without adjuvant chemotherapy and none in the ACT group developed a local recurrence. Five patients in the NACT group and three patients in the ACT group had distant recurrences. Median disease-free survival for all patients was 65.5 ± 34.5 months. Multivariate analysis showed adjuvant chemotherapy to be the most relevant factor for disease-free and overall survival. Patients staged ypT2 ypN0 showed a significantly better disease-free survival after application of adjuvant chemotherapy. Disease-free survival in ypT0-1 ypN0 patients showed no correlation to the administration of adjuvant chemotherapy., Conclusion: Administration of adjuvant chemotherapy after neoadjuvant chemoradiation and radical resection in rectal cancer improved disease-free and overall survival of patients with ypT0-2 ypN0 tumor stages in our study. In particular, ypT2 ypN0 patients seem to profit from adjuvant treatment.

Dynamic post-translational modifications of histones regulate transcriptional gene expression in eukaryotes. Unique combinations of modifications, almost exclusively displayed at the flexible N-terminal tails on histones, create distributions of proteoforms that need to be characterized in order to understand the complexity of gene regulation and how aberrant modification patterns influence disease. Although mass spectrometry is a preferred method for the analysis of histone modifications, information is lost when using conventional trypsin-based histone methods. Newer "middle-down" protocols may retain a greater fraction of the full proteoform distribution. We describe a strategy for the simultaneous characterization of histones H3 and H4 with near-complete retention of proteoform distributions, using a conventional proteomics liquid chromatography-tandem mass spectrometry (LC-MS/MS) configuration. The selective prolyl endoprotease neprosin generates convenient peptide lengths for retention and dispersion of modified H3 and H4 peptides on reversed-phase chromatography, offering an alternative to the hydrophilic interaction liquid chromatography typically used in middle-down methods. No chemical derivatizations are required, presenting a significant advantage over the trypsin-based protocol. Over 200 proteoforms can be readily profiled in a single analysis of histones from HeLa S3 cells. An in-gel digestion protocol provides additional options for effective histone analysis.

Background: Combination chemotherapy has shown benefit in the treatment of biliary cancer and further improvements might be achieved by the addition of a biological agent. We report here the effect of chemotherapy with the monoclonal EGFR antibody panitumumab as therapy for KRAS wild-type biliary cancer., Patients and Methods: Patients with advanced biliary tract cancer were randomised (2:1) to receive cisplatin 25 mg/m 2 and gemcitabine 1000 mg/m 2 on day 1 and day 8/q3w with (arm A) or without panitumumab (arm B; 9 mg/kg BW, i.v q3w). The primary end-point was the evaluation of progression-free survival (PFS) at 6 months. Secondary end-points included objective response rate (ORR), overall survival (OS), and toxicity. In addition, a post hoc assessment of genetic alterations was performed. Finally, we performed a meta-analysis of trials with chemotherapy with and without EGFR antibodies., Results: Sixty-two patients were randomised in arm A and 28 patients in arm B. Patients received 7 treatment cycles in median (1-35) with a median treatment duration of 4.7 months (141 days, 8-765). PFS rate at 6 months was 54% in patients treated with cisplatin/gemcitabine and panitumumab but was 73% in patients treated with cisplatin/gemcitabine without antibody, respectively. Secondary end-points were an ORR of 45% in treatment arm A compared with 39% receiving treatment B and a median OS of 12.8 months (arm A) and of 20.1 months (arm B), respectively. In contrast to the p53-status, genetic alterations in IDH1/2 were linked to a high response after chemotherapy and prolonged survival. In accordance with our results, the meta-analysis of 12 trials did not reveal a survival advantage for patients treated with EGFR antibodies compared with chemotherapy alone., Conclusions: Panitumumab in combination with chemotherapy does not improve ORR, PFS and OS in patients with KRAS wild-type, advanced biliary cancer. Genetic profiling should be included in CCA trials to identify and validate predictive and prognostic biomarkers., Clinical Trials Number: The trial was registered with NCT01320254., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Studies investigating combinations of anti-epidermal growth factor receptor monoclonal antibodies such as panitumumab or cetuximab with standard chemoradiation therapy protocols in rectal cancer have yielded disappointing results. Because of the supposed negative interaction of epidermal growth factor receptor inhibition and chemoradiation therapy, we conducted a phase 2 study using single-agent panitumumab in combination with radiation therapy in patients with RAS wild-type locally advanced rectal cancer., Methods and Materials: Patients with RAS wild-type locally advanced (clinical stage II or III) rectal cancer localized 0 to 12 cm from the anus were eligible for study participation. The primary objective of the study was to determine pathologic complete response (pCR). Secondary objectives comprised assessing the safety, surgical morbidity, clinical response, tumor downstaging, and tumor regression grading according to Dworak., Results: A total of 54 patients with a median age of 58 years were treated. In 3.7% of patients, pCR was achieved. Downstaging of the primary tumor or lymph nodes was seen in 65% of patients. No grade ≥2 hematologic toxicity was seen. The most common grade ≥3 nonhematologic toxicities were skin toxicity (24%) and diarrhea (10%)., Conclusions: Panitumumab in combination with radiation therapy as neoadjuvant treatment for locally advanced rectal cancer showed a favorable toxicity profile but failed to meet the predefined pCR rate to justify further clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background/aim: The aim of this work was to evaluate the efficacy and safety of second-line treatment with weekly high-dose 5-fluorouracil (5-FU) as a 24-hour infusion (24-h inf.) combined with sodium folinic acid (FA) (AIO-regimen) plus irinotecan (Iri.) after pretreatment with AIO-regimen plus oxaliplatin (L-OHP)., Patients and Methods: Patients with non-resectable distant CRC metastases were enrolled in a prospective phase II study for palliative second-line treatment after previous progression of first-line treatment in accordance with the AIO-regimen plus oxaliplatin. On an outpatient basis, the patients received a treatment regimen comprising of weekly 80 mg/m 2 irinotecan in the form of a 1-hour i.v. infusion and 2,000 mg/m 2 5-FU combined with 500 mg/m 2 sodium folinic acid administered as a 24-h infusion i.v. once weekly., Results: During second-line treatment, a total of 59 patients received 520 chemotherapy applications. As the main higher-grade symptom of toxicity, diarrhea (NCI-CTC-toxicity grade 3) presented in 8 patients (13.6%, 95%CI=5.1-23.7), followed by leukocytopenia (CTC grade 3) in 3 patients (5.1%, 95%CI=0-11.9), followed by thrombocytopenia (CTC grade 3) in 1 patient (1.7%, 95%CI=0-5.1). Fifty-nine patients were evaluable for treatment response. The remission data can be summarized as follows: complete remission (CR); n=0; partial remission (PR); n=6 (10%; 95%CI=3.4-18.6); stable disease (SD); n=31 (53%; 95%CI=39.0-64.4); progressive disease (PD); n=19 (33%; 95%CI=20.3-44.1). The median progression-free survival (PFS) rate (n=59) was 4.2 months (range=3.8-5.8 months). The median survival time counted from the start of second-line treatment (n=59) 14.2 months (range 8.2-17.3 months) and the median survival time counted from the start of first-line therapy (n=59) 25 months (range 19-27 months)., Conclusion: Palliative second-line treatment according to the AIO regimen plus irinotecan offers both a favourable toxicity profile and promising efficacy in second-line and palliative sequential therapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Unlabelled: Due to its importance as a cereal crop worldwide, high interest in the determination of factors influencing barley grain quality exists. This study focusses on the elucidation of protein networks affecting early grain developmental processes. NanoLC-based separation coupled to label-free MS detection was applied to gain insights into biochemical processes during five different grain developmental phases (pre-storage until storage phase, 3days to 16days after flowering). Multivariate statistics revealed two distinct developmental patterns during the analysed grain developmental phases: proteins showed either highest abundance in the middle phase of development - in the transition phase - or at later developmental stages - within the storage phase. Verification of developmental patterns observed by proteomic analysis was done by applying hypothesis-driven approaches, namely Western Blot analysis and enzyme assays. High general metabolic activity of the grain with regard to protein synthesis, cell cycle regulation, defence against oxidative stress, and energy production via photosynthesis was observed in the transition phase. Proteins upregulated in the storage phase are related towards storage protein accumulation, and interestingly to the defence of storage reserves against pathogens. A mixed regulatory pattern for most enzymes detected in our study points to regulatory mechanisms at the level of protein isoforms., Biological Significance: In-depth understanding of early grain developmental processes of cereal caryopses is of high importance as they influence final grain weight and quality. Our knowledge about these processes is still limited, especially on proteome level. To identify key mechanisms in early barley grain development, a label-free data-independent proteomics acquisition approach has been applied. Our data clearly show, that proteins either exhibit highest expression during cellularization and the switch to the storage phase (transition phase, 5-7 DAF), or during storage product accumulation (10-16 DAF). The results highlight versatile cellular metabolic activity in the transition phase and strong convergence towards storage product accumulation in the storage phase. Notably, both phases are characterized by particular protective mechanism, such as scavenging of oxidative stress and defence against pathogens, during the transition and the storage phase, respectively., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background. No predictive or prognostic biomarker is available for patients with locally advanced rectal cancer (LARC) undergoing perioperative chemoradiotherapy (CRT). Members of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases EGFR (HER1, ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4) are therapeutic targets in several cancers. The analysis was performed to assess expression levels and study the potential prognostic impact for disease-free and overall survival in patients with LARC. Patients and Methods. ERBB1-4 mRNA expression and tumor proliferation using Ki-67 (MKI67) mRNA were evaluated using RT-quantitative PCR in paraffin-embedded tumor samples from 86 patients (median age: 63) treated with capecitabine or 5-fluorouracil-based CRT within a phase 3 clinical trial. Results. A positive correlation of HER4 and HER2, HER3 and HER2, and HER4 and HER3 with each other was observed. Patients with high mRNA expression of ERBB1 (EGFR, HER1) had significantly increased risk for recurrence and death. Patients with high mRNA expression of MKI67 had reduced risk for relapse. Conclusion. This analysis suggests a prognostic impact of both ERBB1 and MKi67 mRNA expression in LARC patients treated with capecitabine or fluorouracil-based chemoradiotherapy.

We analysed trends over time in palliative first-line chemotherapy in patients with locally advanced or metastatic esophagogastric cancer. Special focus was on frequency and quality of HER2-testing and trends in drug use in combination with trastuzumab. Earlier published data about patients treated outside clinical studies showed a relatively low rate of HER2-testing and insufficient test quality. A total of 2,808 patients retrospectively documented in Therapiemonitor (®) from 2006 to 2013 were analysed regarding treatment intensity and trends in used drugs. Data on HER2-testing and therapies were analysed in two cohorts documented in 2010 and 2011 (1) compared to 2012 and 2013 (2). Treatment intensity increased: 49.3% of patients received at least a triplet in 2013 compared to 10.1% in 2006. In cohort 2 HER2 expression was tested in 79.1% of the cases. Still, in 26.9% testing was not done as requested by guidelines. Good performance status, multiple metastases, age ≤ 65 years, the objective "to prevent progression," good cognitive capabilities, estimated good compliance, and social integration positively influenced the probability of HER2-testing; comorbidities negatively affected it. Usage of the combination of fluoropyrimidines and cisplatin with trastuzumab declined from 67% in cohort 1 to 50% in cohort 2.

Background: Improved cancer treatments have resulted in prolonged survival. Nevertheless, tumor symptoms and side effects still compromise physical activity and quality of life (QoL)., Patients and Methods: We conducted an anonymous survey among cancer patients undergoing chemotherapy using standardized questionnaires: the 'Freiburger Fragebogen zur körperlichen Aktivität' (Freiburg Questionnaire on Physical Activity) and European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. Two main questions were addressed: were there differences (1) in physical activity and QoL between patients who do not believe that sport could improve their QoL and those who believe it could (group A vs. B); and (2) in QoL between patients with a total activity (TA) < 18 metabolic equivalent of task (MET) h/week and those with a TA of ≥ 18 MET h/week (group C vs. D)?, Results: 276 of 400 questionnaires were completed. Groups A and B were balanced in terms of baseline characteristics. Group A suffered significantly more from fatigue and pain; group B reported higher levels of global health status (GHS) and TA. Groups C and D differed in gender distribution, age, and educational background. Group D had significantly higher levels of GHS, group C suffered more from fatigue, pain, and appetite loss., Conclusion: Physical activity correlates with a better QoL of cancer patients undergoing chemotherapy., (© 2015 S. Karger GmbH, Freiburg.)

Purpose: We conducted a multicenter phase II study to assess the toxicity and efficacy of a combination of mitomycin C (MMC) and capecitabine in pretreated patients with metastatic or locally advanced gastric cancer., Methods: Thirty-nine patients (77 % male) between 33 and 78 years (median 66) with pretreated locally advanced or metastatic esophagogastric adenocarcinoma and eastern cooperative oncology group performance status of ≤2, measurable lesions, and adequate organ functions were recruited into the study. Eight patients (21 %) had received more than one prior chemotherapy regimen. Treatment consisted of three-weekly MMC 10 mg/m(2) day 1 and capecitabine 2,000 mg/m(2) (day 1-14; repeated day 22)., Results: A median of three cycles of therapy was administered. Grade 3 toxicity occurred in 20 patients (54 %). Main grade 3 adverse events were thrombocytopenia (11 %, n = 4), fatigue (8 %, n = 3), and neuropathy (8 %, n = 3). Two events of grade 4 toxicity were reported (5 %) (dyspnea and elevation of alkaline phosphatase due to bone metastases). Partial remission was noticed in 10.3 % (n = 4), stable disease in 33.3 % (n = 13) adding to a tumor control rate of 43.6 %. The median progression-free and overall survival were 2.8 and 5.6 months, respectively., Conclusion: The combination of MMC and capecitabine exhibited a favorable tolerability profile in pretreated patients with gastric cancer. The disease control rate compares adequately with that of other phase II and phase III trials for second-line therapy in gastric cancer. This regimen may be considered as an alternative second-line treatment, especially for patients not suitable for or pretreated with taxanes and/or irinotecan.

The antiproliferative effects of the tyrosine kinase inhibitor imatinib mesylate were reported in single cases with polycythemia vera (PV). We, therefore, conducted a clinical phase II study to assess the rate and quality of response in patients with PV. Thirty-one patients, with a median age of 64 years (range, 45-84 years), were included. All but one patient were on phlebotomy; 14 (45%) had previously received cytoreductive therapy. Imatinib was started with 400 mg/day. In 26% of patients, dose escalation up to 800 mg was performed. After a median treatment duration of 8.3 months (range, 0.1-62.1 months), the overall response rate was 55%. No complete remission (normalization of all parameters: hematocrit, white blood cell (WBC) count, platelet count, and spleen size determined by ultrasound examination) was reached because the spleen remained enlarged in all patients. Thirteen patients (42%) achieved partial remission (≥25% reduction of at least one of the previously mentioned parameters); in 10 of these, the respective reduction was ≥50%. In four patients (13%) with minor response, the reduction was <25%. No change or progressive disease was seen in 14 patients (45%). The nonresponders had a longer previous disease duration and had received more antecedent cytoreductive therapy (p = 0.009). Compared to baseline characteristics, imatinib induced the reduction of phlebotomies (p = 0.003), of WBC count (p = 0.002), and of platelet count (p = 0.04). Three patients became free from phlebotomies. In six investigated patients, no significant reduction of the JAK2V617F burden was observed despite clinical improvement. The results show that imatinib has moderate cytoreductive effects in PV.