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Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
Vismodegib, an inhibitor of the Hedgehog signaling pathway, is an approved drug for monotherapy in locally advanced or metastatic basal cell carcinoma (BCC). Data on combined modality treatment by vismodegib and radiation therapy, however, are rare. In the present study, we examined the radiation sensitizing effects of vismodegib by analyzing viability, cell cycle distribution, cell death, DNA damage repair and clonogenic survival in three-dimensional cultures of a BCC and a head and neck squamous cell carcinoma (HNSCC) cell line. We found that vismodegib decreases expression of the Hedgehog target genes glioma-associated oncogene homologue (GLI1) and the inhibitor of apoptosis protein (IAP) Survivin in a cell line- and irradiation-dependent manner, most pronounced in squamous cell carcinoma (SCC) cells. Furthermore, vismodegib significantly reduced proliferation in both cell lines, while additional irradiation only slightly further impacted on viability. Analyses of cell cycle distribution and cell death induction indicated a G1 arrest in BCC and a G2 arrest in HNSCC cells and an increased fraction of cells in SubG1 phase following combined treatment. Moreover, a significant rise in the number of phosphorylated histone-2AX/p53-binding protein 1 (γH2AX/53BP1) foci in vismodegib- and radiation-treated cells was associated with a significant radiosensitization of both cell lines. In summary, these findings indicate that inhibition of the Hedgehog signaling pathway may increase cellular radiation response in BCC and HNSCC cells.
Purpose: Recent advances in the treatment algorithm of locally advanced rectal cancer (LARC) have significantly improved complete response (CR) rates and disease-free survival (DFS), but therapy resistance, with its substantial impact on outcomes and survival, remains a major challenge. Our group has recently unraveled a critical role of interleukin-1α (IL-1α) signaling in activating inflammatory cancer-associated fibroblasts (iCAFs) and mediating radiation-induced senescence, extracellular matrix (ECM) accumulation, and ultimately therapy resistance. We here summarize the recently initiated ACO/ARO/AIO-21 phase I trial, testing the IL-1 receptor antagonist (IL-1 RA) anakinra in combination with fluoropyrimidine-based chemoradiotherapy (CRT) for advanced rectal cancer.
Methods/Design: The ACO/ARO/AIO-21 is an investigator-driven, prospective, open-labeled phase I drug-repurposing trial assessing the maximum tolerated dose (MTD) of capecitabine administered concurrently to standard preoperative radiotherapy (45 Gy in 25 fractions followed by 9 Gy boost in 5 fractions) in combination with fixed doses of the IL-1RA anakinra (100 mg, days −10 to 40). Capecitabine will be administered using a 3 + 3 dose-escalation design (500 mg/m2 bid; 650 mg/m2 bid; 825 mg/m2 bid, respectively) from day 1 to day 40. Response assessment including digital rectal examination (DRE), endoscopy and pelvic magnetic resonance imaging (MRI) is scheduled 10 weeks after completion of CRT. For patients achieving clinical complete response (cCR), primary non-operative management is provided. In case of non-cCR immediate total mesorectal excision (TME) will be performed. Primary endpoint of this phase I trial is the MTD of capecitabine.
Discussion: Based on extensive preclinical research, the ACO/ARO/AIO-21 phase I trial will assess whether the IL-1RA anakinra can be safely combined with fluoropyrimidine-based CRT in rectal cancer. It will further explore the potential of IL-1 inhibition to overcome therapy resistance and improve response rates. A comprehensive translational research program will expand our understanding from a clinical perspective and may help translate the results into a randomized phase II trial.
Background: Preoperative radiochemotherapy (RCT) with 5-FU or capecitabine is the standard of care for patients with locally advanced rectal cancer (LARC). Preoperative RCT achieves pathological complete response rates (pCR) of 10-15%. We conducted a single arm phase II study to investigate the feasibility and efficacy of addition of bevacizumab and oxaliplatin to preoperative standard RCT with capecitabine.
Methods: Eligible patients had LARC (cT3-4; N0/1/2, M0/1) and were treated with preoperative RCT prior to planned surgery. Patients received conventionally fractionated radiotherapy (50.4 Gy in 1.8 Gy fractions) and simultaneous chemotherapy with capecitabine 825 mg/m2 bid (d1-14, d22-35) and oxaliplatin 50 mg/m2 (d1, d8, d22, d29). Bevacizumab 5 mg/kg was added on days 1, 15, and 29. The primary study objective was the pCR rate.
Results: 70 patients with LARC (cT3-4; N0/1, M0/1), ECOG < 2, were enrolled at 6 sites from 07/2008 through 02/2010 (median age 61 years [range 39–89], 68% male). At initial diagnosis, 84% of patients had clinical stage T3, 62% of patients had nodal involvement and 83% of patients were M0. Mean tumor distance from anal verge was 5.92 cm (± 3.68). 58 patients received the complete RCT (full dose RT and full dose of all chemotherapy). During preoperative treatment, grade 3 or 4 toxicities were experienced by 6 and 2 patients, respectively: grade 4 diarrhea and nausea in one patient (1.4%), respectively, grade 3 diarrhea in 2 patients (3%), grade 3 obstipation, anal abscess, anaphylactic reaction, leucopenia and neutropenia in one patient (1.4%), respectively. In total, 30 patients (46%) developed postoperative complications of any grade including one gastrointestinal perforation in one patient (2%), wound-healing problems in 7 patients (11%) and bleedings in 2 patients (3%). pCR was observed in 12/69 (17.4%) patients. Pathological downstaging (ypT < cT and ypN ≤ cN) was achieved in 31 of 69 patients (44.9%). All of the 66 operated patients had a R0 resection. 47 patients (68.1%) underwent sphincter preserving surgery.
Conclusions: The addition of bevacizumab and oxaliplatin to RCT with capecitabine was well tolerated and did not increase perioperative morbidity or mortality. However, the pCR rate was not improved in comparison to other trials that used capecitabine or capecitabine/oxaliplatin in preoperative radiochemotherapy.
Background: With the current study, we aimed to determine the prevalence of back pain in employees of a German chemical company. We put a specific focus on disabling back pain and its association with sociodemographic, lifestyle- and work-related characteristics.
Methods: We used cross-sectional data, surveyed in health check-ups between 2011 and 2014 in Ludwigshafen am Rhein (Germany). A blood sample, physical examination and anamnesis by an occupational health physician as well as a written questionnaire were part of the check-up. A modified version of the Standardised Nordic Musculoskeletal Questionnaire was utilized to survey the back-pain specific information. Disabling back pain was defined as presence of any back pain in the past 12 months which prevented employees from carrying out their usual working tasks. We used multinomial logistic regression analysis to assess the association between (categorical) duration of disabling back pain and sociodemographic, lifestyle-, and work-related characteristics.
Results: Overall, 17,351 employees participated in the health check-up, information on 16,792 persons could be used for analyses. Participants were on average 43.7 (SD: 9.7) years old and mainly male (79.1%). Lifetime-, 12-months-, and 7-days-prevalence of any type and duration of back pain were 72.5, 66.1, and 27.1% respectively. About one third (33.5%) had suffered from an episode of disabling back pain, 16.7% 1–7 days, 10.3% 8–30 days, and 6.5% more than 30 days. Multinomial regression analysis yielded that 8–30 days or more than 30 days of disabling back pain (relative to 0 days) were more likely with older age, female gender, being married, former or current smoking, lower occupational status, higher work-related stress score, history of a spinal injury, and diagnosed dorsopathy.
Conclusions: There is a great need for action regarding multifaceted preventive measures and early interventions, especially for manual workers, older employees and women, where occupational medicine can play a decisive role.
NIMA (never-in-mitosis gene A)-related kinase 1 (Nek1) is shown to impact on different cellular pathways such as DNA repair, checkpoint activation, and apoptosis. Its role as a molecular target for radiation sensitization of malignant cells, however, remains elusive. Stably transduced doxycycline (Dox)-inducible Nek1 shRNA HeLa cervix and siRNA-transfected HCT-15 colorectal carcinoma cells were irradiated in vitro and 3D clonogenic radiation survival, residual DNA damage, cell cycle distribution, and apoptosis were analyzed. Nek1 knockdown (KD) sensitized both cell lines to ionizing radiation following a single dose irradiation and more pronounced in combination with a 6 h fractionation (3 × 2 Gy) regime. For preclinical analyses we focused on cervical cancer. Nek1 shRNA HeLa cells were grafted into NOD/SCID/IL-2Rγc−/− (NSG) mice and Nek1 KD was induced by Dox-infused drinking water resulting in a significant cytostatic effect if combined with a 6 h fractionation (3 × 2 Gy) regime. In addition, we correlated Nek1 expression in biopsies of patients with cervical cancer with histopathological parameters and clinical follow-up. Our results indicate that elevated levels of Nek1 were associated with an increased rate of local or distant failure, as well as with impaired cancer-specific and overall survival in univariate analyses and for most endpoints in multivariable analyses. Finally, findings from The Cancer Genome Atlas (TCGA) validation cohort confirmed a significant association of high Nek1 expression with a reduced disease-free survival. In conclusion, we consider Nek1 to represent a novel biomarker and potential therapeutic target for drug development in the context of optimized fractionation intervals.
Background: With the aging population and a rising incidence of squamous cell carcinoma of the head and neck (SCCHN), there is an emerging need for developing strategies to treat elderly patients.
Patients and Methods: We retrospectively analyzed 158 patients treated with definitive, concurrent chemoradiotherapy (CRT) for SCCHN. Clinicopathological characteristics, acute toxicities, and oncological outcomes were compared between patients younger and older than (or of age equal to) 65, 70, and 75 years.
Results: RT dose, chemotherapy regimen, and total chemotherapy dose were balanced between the groups. After a median follow-up of 29 months, overall survival (OS), progression-free survival (PFS), local control rate, and distant metastasis-free survival stratified by age of ≥65, ≥70, or ≥75 years revealed no differences. The rate of acute toxicities was also not higher for older patients. Worse ECOG performance score (ECOG 2-3) was associated with impaired OS () and PFS ().
Conclusion: Definitive treatment with CRT for SCCHN is feasible and effective; even in advanced age treatment decisions should be made according to general condition and comorbidity, rather than calendar age alone.
Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.
Background: Breast cancer (BC) is the most frequent female cancer and preferentially metastasizes to bone. The transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism. However, it is not yet known whether TGIF is associated with BC bone metastasis or patient outcome and thus of potential interest. Methods: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue samples from BC patients treated in the GAIN (German Adjuvant Intergroup Node-Positive) study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining. Endpoints were disease-free survival (DFS), overall survival (OS) and time to primary bone metastasis as first site of relapse (TTPBM). Results: We found associations of higher TGIF protein expression with smaller tumor size (p= 0.015), well differentiated phenotype (p< 0.001) and estrogen receptor (ER)-positive BC (p< 0.001). Patients with higher TGIF expression levels showed a significantly longer disease-free (DFS: HR 0.75 [95%CI 0.59–0.95], log-rank p=0.019) and overall survival (OS: HR 0.69 [95%CI 0.50–0.94], log-rank p= 0.019), but no association with TTPBM (HR 0.77 [95%CI 0.51–1.16]; p= 0.213). Univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: HR 0.68 [95%CI 0.51–0.91]; log-rank p= 0.009, interaction p= 0.130; OS: HR 0.60 [95%CI 0.41–0.88], log-rank p= 0.008, interaction p= 0.107) and in the HER2-negative subgroup (DFS:HR 0.67 [95%CI 0.50–0.88], log-rank p= 0.004, interaction p= 0.034; OS: HR 0.57 [95%CI 0.40–0.81], log-rank p= 0.002, interaction p= 0.015). Conclusions: Our results suggest that moderate to high TGIF expression is a common feature of breast cancer cells and that this is not associated with bone metastases as first site of relapse. However, a reduced expression is linked to tumor progression, especially in HER2-negative breast cancer.
Following publication of the original article, the authors noticed an incorrect affiliation for Christine Stürken and Udo Schumacher. The correct affiliations are as follows: Christine Stürken: Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Udo Schumacher: Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. The affiliations have been correctly published in this correction and the original article has been updated.