Background: PF-114 is a 4^th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR-ABL1 isoforms including BCR-ABL1^T315I. We present data from a phase-1 study in patients with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or with BCR-ABL1^T315I (NCT02885766) with ≥6 months therapy. Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic, and molecular criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 patients were enrolled. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given continuously. Median age was 50 years (range, 29-82 years). Median CML duration pre-study was 10 years (range, 0.3-23 years). All patients had baseline ECOG performance scores 0-1. Twelve patients had BCR-ABL1^T315I. Patients were heavily pre-treated: 25 received ≥3 prior TKIs; 5 patients with BCR-ABL1^T315I received 1 prior TKI. Interim analysis was conducted at follow-up of ≥6 months (cut-off date January 16^th 2019). Therapy was ongoing in 17 patients at doses 200 mg (n=4), 300 mg (n=9), 400 mg (n=3) and 600 mg (n=1) with median duration of exposure of 7,4 (range, 4,6-26), 9,2 (range, 7,4-26), 9,2 (range, 8,3-9,2) and 9,2 months. Other patients discontinued because of progression (n=18), adverse events (n=6), consent withdrawal (n=4), participation in another study (n=3) or other reasons (n=3). The MTD was 600 mg with the grade-3 psoriasis-like skin lesions the DLT, which occurred during the first 28 days of treatment. Reversible grade-3 skin toxicity occurred in 11 patients at doses ≥400 mg. There were no other drug-related non-hematologic grade-3 toxicities except 1 grade-3 toxic hepatitis at 400 mg and there were no detectable effects on ankle-brachial index or vascular occlusive events. The best safety/efficacy dose was 300 mg/d with 6 of 11 patients achieving a major cytogenetic response (MCyR) and 4 of them - a major molecular response (MMR). Higher doses were less effective probably because of toxicity-related therapy interruptions and discontinuations. Five of 12 patients with BCR-ABL1^T315I responded, 3 of which achieved a complete hematologic response and 4 achieved MCyR. Conclusion: PF-114 was safe and effective in patients with CML failing ≥2 TKIs or with BCR-ABL1^T315I. The most effective dose was 300 mg/d. Five of 12 patients with BCR-ABL1^T315I responded. A pivotal study is beginning.

Automatic layers recognition of the wall of the stomach and colon on whole slide images is an extremely urgent task in digital pathology as it can be used for automatic determining the depth of invasion of the digestive tract tumors. In this paper we propose a new CNN-based method of automatic tissue type recognition on whole slide histological images. We also describe an effective pipeline of training that uses 2 different training datasets. The proposed method of automatic tissue type recognition achieved 0.929 accuracy and 0.903 balanced accuracy on CRC-VAL-HE-7K dataset for 9-types classification and 0.98 accuracy and 0.926 balanced accuracy on the test subset of whole slide images from PATH-DT- MSU dataset for 5-types classification. The developed method makes it possible to classify the areas corresponding to the gastric own mucous glands in the lamina propria and also to distinguish the tubular structures of a highly differentiated gastric adenocarcinoma with normal glands.

Background: PF-114 mesylate is a 4^th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCRABL1 isoforms including those with a BCRABL1^T315I. We present data from a phase-1 study in subjects with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or who have BCRABL1^T315I (NCT02885766). Methods: 3+3 dose-escalation design to determine maximum tolerated dose (MTD) followed by expanded cohorts for doses ≤MTD. The primary objective was to determine the MTD and identify dose-limiting toxicities (DLTs) during cycle 1 (28 days). Secondary objectives included safety and anti-CML activity based on hematological, cytogenetic, and molecular criteria. Adverse events (AEs) were assessed and graded using NCI-CTCAE v4.03. Results: 51 subjects were enrolled as of June 26, 2018. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given on a continuous QD schedule. Median age was 50 years (range, 29-82 years). Median interval from diagnosis to study-entry was 10 years (range, 0-23 years). Subjects had baseline ECOG performance scores <2. 13 subjects were reported to have BCRABL1^T315I. Subjects were heavily pre-treated: 25 had received ≥3 prior TKIs; 5 subjects with BCRABL1^T315I received 1 prior TKI. 600 mg was identified as the MTD with 1 of 6 subjects experiencing a DLT at this dose (Gr 3 psoriasis-like skin lesion). Similar grade-3 skin lesions were also identified at the dose of 750 mg in 2 subjects and at 400 mg in 1 subject. Therapy is ongoing in 23 subjects at doses 200, 300 and 400 mg with median duration of exposure of 5 (range, 1-21), 3 (range, 1-12) and 4 (range, 1-19) cycles. Other subjects discontinued because of progression (n=16), AEs (n=6) or other reasons (n=6). The most common of non-hematologic toxicity was skin toxicity, which was common at doses of ≥400 mg. Grade-3 skin toxicity occurred in 3 subjects on daily dose 750 mg, 4 subjects on dose 600 mg, 1 patient on dose 500 mg and 3 subjects on dose 400 mg. Skin lesions resolved rapidly upon drug discontinuation and topical therapy. No other drug related non-hematologic grade-3 toxicities except a single case of grade-3 hepatitis on dose 400 mg were observed. No deterioration of ankle-brachial index or vascular occlusive events were observed. A complete hematologic response was achieved in 8 of 19 evaluable subjects including 3 of 8 with BCRABL1^T315I. Major cytogenetic response was achieved in 6 of 21 evaluable subjects including 3 of 7 with BCRABL1^T315I. Major molecular response was achieved in 2 of 18 subjects completing ≥13 cycles. Most cytogenetic and molecular responses were achieved at doses 200 and 300 mg which were well-tolerated and will be considered for the phase-2 study. Conclusion: MTD of PF-114 is 600 mg with skin toxicity as the DLT. The best safety/efficacy ratio was seen at doses of 200 and 300 mg which are being studied in expanded cohorts and soon in a phase-2 study.

Carcinogenesis and tumor progression are not caused not only by malignant epithelial cells, but also by the tumor stroma around cancer stem cells which performs regulatory, nutritional and 'framework' functions. It is represented by mesenchymal cells of various types predominantly by cancer-associated fibroblasts (CAF). αSMA, FAP-1, desmin, podoplanin, neuron-glial antigen 2 (NG2), PDGFR-α and -β are used for CAF identification but there is no universal markers due to the plasticity of the cell population that underlies the subpopulation division CAF. CAF subpopulations are not described for many tumor types. Recently, evidence has accumulated that CAFs mediate many adverse processes in the tumor, including can support stromal inflammation and cause fibrosis. By forming a niche in cancer stem cells, CAFs mediate chemoresistance and the appearance of dormant metastases. The study of the role of CAF will allow not only to form a fundamentally new understanding of the mechanisms of carcinogenesis, but also to create new diagnostic and therapeutic targets for treating tumors.

Mucous glands is an important diagnostic element in digestive pathology. The first step of differential diagnosis of colon polyps in order to assess their malignant potential is gland segmentation. The process of mucous glands segmentation is challenging as the glands not only needed to be separated from a background but also individually identified to obtain reliable morphometric criteria for quantitative diagnostic methods. We propose a new convolutional neural network for mucous gland segmentation that takes into account glands’ contours and can be used for gland instance segmentation. Training and evaluation of the network was performed on a standard Warwick-QU dataset as well as on the collected PATH-DT-MSU dataset of histological images obtained from hematoxylin and eosin staining of paraffin sections of colon biopsy material collected by our Pathology department. The collected PATH-DT-MSU dataset will be available at http://imaging.cs.msu.ru/en/research/histology.

The use of modern approaches based on convolutional neural networks (CNNs) for segmentation of whole slide images (WSIs) helps pathologists obtain more stable and quantitative analysis results and improve diagnosis objectivity. But working with WSIs is extremely difficult due to their resolution and size. To solve this problem in this paper we for the first time present PathScribe – a new universal cross-platform cloud-based tool for comfortable viewing and manipulating large collections of WSIs on almost any device, including tablets and smartphones. We also consider the important problem of automatic tissue type recognition on WSIs and present the WSS1 and WSS2 subsets of PATH-DT-MSU dataset representing a collection of high-quality WSIs of digestive tract tumors with tissue type area annotations. We also propose a new CNN-based method of automatic tissue type recognition on WSIs. It achieved 0.929 accuracy on CRC-VAL-HE-7K dataset (9 classes) and 0.97 accuracy on PATH-DT-MSU-WSS1, WSS2 datasets (5 classes). The developed method allows classifying the areas corresponding to the gastric own mucous glands in the lamina propria and distinguishing the tubular structures of a highly differentiated gastric adenocarcinoma with normal glands.