CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method.

BACKGROUND: Berzosertib (M6620) is a highly potent (IC50 = 19 nM) and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. This trial assessed the safety, preliminary efficacy, and tolerance of berzosertib in oesophageal cancer (A1 cohort) with RT and advanced solid tumours (A2 cohort) with cisplatin and capecitabine. METHODS: Single-arm, open-label dose-escalation (Time-to-Event Continual Reassessment Method) trial with 16 patients in A1 and 18 in A2. A1 tested six dose levels of berzosertib with RT (35 Gy over 15 fractions in 3 weeks). RESULTS: No dose-limiting toxicities (DLTs) in A1. Eight grade 3 treatment-related AEs occurred in five patients, with rash being the most common. The highest dose (240 mg/m2) was determined as the recommended phase II dose (RP2D) for A1. Seven DLTs in two patients in A2. The RP2D of berzosertib was 140 mg/m2 once weekly. The most common grade ≥3 treatment-related AEs were neutropenia and thrombocytopenia. No treatment-related deaths were reported. CONCLUSIONS: Berzosertib combined with RT is feasible and well tolerated in oesophageal cancer patients at high palliative doses. Berzosertib with cisplatin and capecitabine was well tolerated in advanced cancer. Further investigation is warranted in a phase 2 setting. CLINICAL TRIALS IDENTIFIER: EU Clinical Trials Register (EudraCT) - 2015-003965-27 ClinicalTrials.gov - NCT03641547.

Subchondral bone changes after joint distraction treatment for end stage knee osteoarthritis.

OBJECTIVE: Increased subchondral cortical bone plate thickness and trabecular bone density are characteristic of knee osteoarthritis (OA). Knee joint distraction (KJD) is a joint-preserving knee OA treatment where the joint is temporarily unloaded. It has previously shown clinical improvement and cartilage regeneration, indicating reversal of OA-related changes. The purpose of this research was to explore 3D subchondral bone changes after KJD treatment using CT imaging. DESIGN: Twenty patients were treated with KJD and included to undergo knee CT imaging before, one, and two years after treatment. Tibia and femur segmentation and registration to canonical surfaces were performed semi-automatically. Cortical bone thickness and trabecular bone density were determined using an automated algorithm. Statistical parametric mapping (SPM) with two-tailed F-tests was used to analyze whole-joint changes. RESULTS: Data was available of 16 patients. Subchondral cortical bone plate thickness and trabecular bone density were higher in the weight-bearing region of the most affected compartment (MAC; mostly medial). Especially the MAC showed a decrease in thickness and density in the first year after treatment, which was sustained towards the second year. CONCLUSIONS: KJD treatment results in bone changes that include thinning of the subchondral cortical bone plate and decrease of subchondral trabecular bone density in the first two years after treatment, potentially indicating a partial normalization of subchondral bone.

Significant variation in histopathological assessment of endoscopic resections for Barrett's neoplasia suggests need for consensus reporting: propositions for improvement.

Endoscopic resection (ER) is an important diagnostic step in management of patients with early Barrett's esophagus (BE) neoplasia. Based on ER specimens, an accurate histological diagnosis can be made, which guides further treatment. Based on depth of tumor invasion, differentiation grade, lymphovascular invasion, and margin status, the risk of lymph node metastases and local recurrence is judged to be low enough to justify endoscopic management, or high enough to warrant invasive surgical esophagectomy. Adequate assessment of these histological risk factors is therefore of the utmost importance. Aim of this study was to assess pathologist concordance on these histological features on ER specimens and evaluate causes of discrepancy. Of 62 challenging ER cases, one representative H&E slide and matching desmin and endothelial marker were digitalized and independently assessed by 13 dedicated GI pathologists from 8 Dutch BE expert centers, using an online assessment module. For each histological feature, concordance and discordance were calculated. Clinically relevant discordances were observed for all criteria. Grouping depth of invasion categories according to expanded endoscopic treatment criteria (T1a and T1sm1 vs. T1sm2/3), ≥1 pathologist was discrepant in 21% of cases, increasing to 45% when grouping diagnoses according to the traditional T1a versus T1b classification. For differentiation grade, lymphovascular invasion, and margin status, discordances were substantial with 27%, 42%, and 32% of cases having ≥1 discrepant pathologist, respectively. In conclusion, histological assessment of ER specimens of early BE cancer by dedicated GI pathologists shows significant discordances for all relevant histological features. We present propositions to improve definitions of diagnostic criteria.

[Diagnostic image (382). A man with a painful knee and black cartilage]. / Diagnose in beeld (382). Een man met een pijnlijke knie en zwart kraakbeen.

A 56-year-old man presented with a painful knee with black pigmentation of synovium and cartilage due to ochronosis caused by alkaptonuria.

A peptide derived from melanocytic protein gp100 and presented by HLA-B35 is recognized by autologous cytolytic T lymphocytes on melanoma cells.

A panel of autologous cytolytic T lymphocyte (CTL) clones have been isolated from blood lymphocytes of a melanoma patient after in vitro stimulation with autologous tumor cells. We previously reported the molecular definition of three distinct antigens recognized by some of these CTL clones. We describe here, the identification of a fourth antigenic peptide expressed by this melanoma line and recognized by a CTL clone restricted by HLA-B*3503. The antigenic peptide, which is nine-amino acid long, has the sequence LPHSSSHWL and is derived from melanocyte differentiation antigen gp100. As HLA-B35 is one of the most frequent HLA-B alleles, being present in 20% of the Caucasian individuals, this peptide may be a good target for peptide-based immunotherapy of melanoma.

A tyrosinase peptide presented by HLA-B35 is recognized on a human melanoma by autologous cytotoxic T lymphocytes.

We previously described different cytotoxic T lymphocyte (CTL) clones isolated from the blood lymphocytes of a melanoma patient after in vitro stimulation with autologous tumor cells. These CTL clones recognized at least 2 distinct antigens on the melanoma cells. Here, we show that one of them consists of a peptide derived from tyrosinase and presented by HLA-B35. The peptide is 9 amino acids long and has the sequence LPSSADVEF. It can be presented by the 2 major B35 allelic subtypes, B*3501 and B*3503. As HLA-B35 is one of the most frequent HLA-B specificities, being present in about 20% of Caucasian individuals, it may be a useful target for peptide-based immunotherapy of melanoma.