Integrated Clinical, Molecular and Immunological Characterization of Pulmonary Sarcomatoid Carcinomas Reveals an Immune Escape Mechanism That May Influence Therapeutic Strategies.

Pulmonary sarcomatoid carcinoma (PSC) has highly aggressive biological behaviour and poor clinical outcomes, raising expectations for new therapeutic strategies. We characterized 179 PSC by immunohistochemistry, next-generation sequencing and in silico analysis using a deep learning algorithm with respect to clinical, immunological and molecular features. PSC was more common in men, older ages and smokers.

Daratumumab in first-line treatment of patients with light chain amyloidosis and Mayo stage IIIb improves treatment response and overall survival.

Treatment of patients with Mayo stage IIIb light chain (AL) amyloidosis is still challenging, and the prognosis remains very poor. Mayo stage IIIb patients were excluded from the pivotal trial leading to the approval of daratumumab in combination with bortezomib-cyclophosphamide-dexamethasone. This retrospective, multicenter study evaluates the addition of daratumumab to first-line therapy in patients with newly diagnosed stage IIIb AL amyloidosis.

Accuracy of nodal staging by 18F-FDG-PET/CT in limited disease small-cell lung cancer.

Background: Small-cell lung cancer (SCLC) is highly aggressive with a nearly incurable disease in most cases. The most important prognostic factor is the status of the mediastinal lymph nodes. Only a small proportion of patients can be diagnosed at early stages and directed to curative multimodal treatment.

The p38/MK2 Pathway Functions as Chk1-Backup Downstream of ATM/ATR in G-Checkpoint Activation in Cells Exposed to Ionizing Radiation.

We have recently reported that in G-phase cells (but not S-phase cells) sustaining low loads of DNA double-strand break (DSBs), ATM and ATR regulate the G-checkpoint epistatically, with ATR at the output-node, interfacing with the cell cycle through Chk1. However, although inhibition of ATR nearly completely abrogated the checkpoint, inhibition of Chk1 using UCN-01 generated only partial responses. This suggested that additional kinases downstream of ATR were involved in the transmission of the signal to the cell cycle engine.

SUV Above 20 in F-FDG PET/CT at Initial Diagnostic Workup Associates with Favorable Survival in Patients with Cancer of Unknown Primary.

Cancer of unknown primary (CUP) is a heterogeneous entity with a limited prognosis. Novel prognostic markers are needed for patient stratification in prospective clinical trials exploring innovative therapies. In CUP patients treated at the West German Cancer Center Essen, the prognostic value of F-FDG PET/CT at the initial diagnostic workup was analyzed by comparing overall survival (OS) in patients who underwent F-FDG PET/CT with those who did not.

Location of Recurrences after Trimodality Treatment for Glioblastoma with Respect to the Delivered Radiation Dose Distribution and Its Influence on Prognosis.

Background: While prognosis of glioblastoma after trimodality treatment is well examined, recurrence pattern with respect to the delivered dose distribution is less well described. Therefore, here we examine the gain of additional margins around the resection cavity and gross-residual-tumor.

Methods: All recurrent glioblastomas initially treated with radiochemotherapy after neurosurgery were included.

Low CDK Activity and Enhanced Degradation by APC/C Abolishes CtIP Activity and Alt-EJ in Quiescent Cells.

Alt-EJ is an error-prone DNA double-strand break (DSBs) repair pathway coming to the fore when first-line repair pathways, c-NHEJ and HR, are defective or fail. It is thought to benefit from DNA end-resection-a process whereby 3' single-stranded DNA-tails are generated-initiated by the CtIP/MRE11-RAD50-NBS1 (MRN) complex and extended by EXO1 or the BLM/DNA2 complex. The connection between alt-EJ and resection remains incompletely characterized.

Identification of a ΔNp63-Dependent Basal-Like A Subtype-Specific Transcribed Enhancer Program (B-STEP) in Aggressive Pancreatic Ductal Adenocarcinoma.

Unlabelled: A major hurdle to the application of precision oncology in pancreatic cancer is the lack of molecular stratification approaches and targeted therapy for defined molecular subtypes. In this work, we sought to gain further insight and identify molecular and epigenetic signatures of the Basal-like A pancreatic ductal adenocarcinoma (PDAC) subgroup that can be applied to clinical samples for patient stratification and/or therapy monitoring. We generated and integrated global gene expression and epigenome mapping data from patient-derived xenograft models to identify subtype-specific enhancer regions that were validated in patient-derived samples.

Non-lethal outcomes of engaging regulated cell death pathways in cancer.

Regulated cell death (RCD) is essential for successful systemic cancer therapy. Yet, the engagement of RCD pathways does not inevitably result in cell death. Instead, RCD pathways can take part in diverse biological processes if the cells survive.

Ga-FAPI PET/CT Interobserver Agreement on Tumor Assessment: An International Multicenter Prospective Study.

Ga-fibroblast activation protein inhibitors (FAPIs) are promising radiotracers for cancer imaging, with emerging data in the recent years. Nonetheless, the interobserver agreement on Ga-FAPI PET/CT study interpretations in cancer patients remains poorly understood. Ga-FAPI PET/CT was performed on 50 patients with various tumor entities (sarcoma [ = 10], colorectal cancer [ = 10], pancreatic adenocarcinoma [ = 10], genitourinary cancer [ = 10], and other types of cancer [ = 10]).

Favorable survival outcomes in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer sequentially treated with a tyrosine kinase inhibitor and osimertinib in a real-world setting.

Purpose: EGFR tyrosine kinase inhibitor (TKI) therapy in EGFR-mutated lung cancer is limited by acquired resistance. In half of the patients treated with first/second-generation (1st/2nd gen) TKI, resistance is associated with EGFR p.T790M mutation.

Smaller panel, similar results: genomic profiling and molecularly informed therapy in pancreatic cancer.

Background: Pancreatic cancer has a dismal prognosis. One reason is resistance to cytotoxic drugs. Molecularly matched therapies might overcome this resistance but the best approach to identify those patients who may benefit is unknown.

Respiration-controlled radiotherapy in lung cancer: Systematic evaluation of the optimal application practice.

Background And Purpose: Definitive radiochemotherapy (RCT) for non-small cell lung cancer (NSCLC) in UICC/TNM I-IVA (singular, oligometastatic) is one of the treatment methods with a potentially curative concept. However, tumour respiratory motion during RT requires exact pre-planning. There are various techniques of motion management like creating internal target volume (ITV), gating, inspiration breath-hold and tracking.

Fibroblast Activation Protein Inhibitor (FAPI)-PET Imaging in Sarcoma.

Advances in histopathologic and molecular genetic subtyping of sarcoma will potentially allow identification of novel diagnostic and therapeutic targets for specific subtypes, but a "pan-sarcoma" target is needed. This article provides an overview on expression of one potential candidate, fibroblast activation protein alpha in soft tissue and bone sarcoma, and the resulting application of 68Ga-FAPI as novel imaging probes in these rare tumor entities. Current preclinical and clinical data on 68Ga-FAPI-PET/CT in sarcomas are summarized.

Superior Tumor Detection for Ga-FAPI-46 Versus F-FDG PET/CT and Conventional CT in Patients with Cholangiocarcinoma.

Management of cholangiocarcinoma is among other factors critically determined by accurate staging. Here, we aimed to assess the accuracy of PET/CT with the novel cancer fibroblast-directed Ga-fibroblast activation protein (FAP) inhibitor (FAPI)-46 tracer for cholangiocarcinoma staging and management guidance. Patients with cholangiocarcinoma from a prospective observational trial were analyzed.

Comparison of Online-Onboard Adaptive Intensity-Modulated Radiation Therapy or Volumetric-Modulated Arc Radiotherapy With Image-Guided Radiotherapy for Patients With Gynecologic Tumors in Dependence on Fractionation and the Planning Target Volume Margin.

Importance: Patients with newly diagnosed locally advanced cervical carcinomas or recurrences after surgery undergoing radiochemotherapy whose tumor is unsuited for a brachytherapy boost need high-dose percutaneous radiotherapy with small margins to compensate for clinical target volume deformations and set-up errors. Cone-beam computed tomography-based online adaptive radiotherapy (ART) has the potential to reduce planning target volume (PTV) margins below 5 mm for these tumors.

Objective: To compare online ART technologies with image-guided radiotherapy (IGRT) for gynecologic tumors.

Decrypting drug actions and protein modifications by dose- and time-resolved proteomics.

Although most cancer drugs modulate the activities of cellular pathways by changing posttranslational modifications (PTMs), little is known regarding the extent and the time- and dose-response characteristics of drug-regulated PTMs. In this work, we introduce a proteomic assay called decryptM that quantifies drug-PTM modulation for thousands of PTMs in cells to shed light on target engagement and drug mechanism of action. Examples range from detecting DNA damage by chemotherapeutics, to identifying drug-specific PTM signatures of kinase inhibitors, to demonstrating that rituximab kills CD20-positive B cells by overactivating B cell receptor signaling.

Clinical Outcome and Treatment Sequences of Patients with Advanced Pancreatic Cancer Treated with Contemporary Chemotherapy Protocols.

Introduction: Systemic therapy is firmly established in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Clinical efficacy is still modest and options are limited. Combination therapy protocols such as FOLFIRINOX and gemcitabine/nab-paclitaxel (Gem/NP) define standard-of-care.

Machine-learning-based prediction of the effectiveness of the delivered dose by exhale-gated radiotherapy for locally advanced lung cancer: The additional value of geometric over dosimetric parameters alone.

Purpose: This study aimed to assess interfraction stability of the delivered dose distribution by exhale-gated volumetric modulated arc therapy (VMAT) or intensity-modulated arc therapy (IMAT) for lung cancer and to determine dominant prognostic dosimetric and geometric factors.

Methods: Clinical target volume (CTV) from the planning CT was deformed to the exhale-gated daily CBCT scans to determine CTV, treated by the respective dose fraction. The equivalent uniform dose of the CTV was determined by the power law (EUD) and cell survival model (EUD) as effectiveness measure for the delivered dose distribution.

Neurofeedback Treatment Affects Affective Symptoms, But Not Perceived Cognitive Impairment in Cancer Patients: Results of an Explorative Randomized Controlled Trial.

Background: EEG biofeedback (NF) is an established therapy to enable individuals to influence their own cognitive-emotional state by addressing changes in brainwaves. Psycho-oncological approaches of NF in cancer patients are rare and effects are hardly studied.

Objective: The aim of this explorative, randomized controlled trial was to test the effectiveness of an alpha and theta NF training protocol, compared to mindfulness based therapy as an established psycho-oncological treatment.

A post hoc analysis of the EPAZ trial: The role of geriatric variables in elderly soft tissue sarcoma patients on toxicity and outcome.

Objective: The EPAZ study (NCT01861951) showed recently that pazopanib was non-inferior to doxorubicin in patients ≥60 years treated in first line for advanced soft tissue sarcoma . The current post-hoc analysis aimed to assess the prognostic impact of frailty.

Methods: Geriatric assessments were evaluated at baseline.

A Phase II Study of Nab-Paclitaxel and Gemcitabine as First-Line Therapy in Patients with Cholangiocarcinoma Ineligible for Cisplatin-Based Chemotherapy (NACHO).

Introduction: Gemcitabine and cisplatin is the standard first-line systemic treatment in patients with advanced cholangiocarcinoma (CCA). However, a substantial number of patients do not qualify for cisplatin due to comorbidities or poor performance status. The phase II pilot study NACHO evaluated the efficacy of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) given on days 1, 8, and 15 every 4 weeks as first-line therapy in patients with advanced CCA ineligible for cisplatin-based chemotherapy.

Preoperative PET-SUVmax and volume based PET parameters of the primary tumor fail to predict nodal upstaging in early-stage lung cancer.

Objectives: Accurate nodal staging is of utmost importance in patients with lung cancer. FDG-PET/CT imaging is now part of the routine staging. Despite thorough preoperative staging nodal upstaging still occurs in early-stage lung cancer.

LAMC2 Regulates Key Transcriptional and Targetable Effectors to Support Pancreatic Cancer Growth.

Purpose: The identification of pancreatic ductal adenocarcinoma (PDAC) dysregulated genes may unveil novel molecular targets entering inhibitory strategies. Laminins are emerging as potential targets in PDAC given their role as diagnostic and prognostic markers. Here, we investigated the cellular, functional, and clinical relevance of LAMC2 and its regulated network, with the ultimate goal of identifying potential therapies.