CUB Domain-Containing Protein 1 (CDCP1) is a rational target for the development of imaging tracers and antibody-drug conjugates for cancer detection and therapy.

Rationale: An antibody-drug conjugate (ADC) is a targeted therapy consisting of a cytotoxic payload that is linked to an antibody which targets a protein enriched on malignant cells. Multiple ADCs are currently used clinically as anti-cancer agents significantly improving patient survival. Herein, we evaluated the rationale of targeting the cell surface oncoreceptor CUB domain-containing protein 1 (CDCP1) using ADCs and assessed the efficacy of CDCP1-directed ADCs against a range of malignant tumors. Methods: CDCP1 mRNA expression was evaluated using large transcriptomic datasets of normal/tumor samples for 23 types of cancer and 15 other normal organs, and CDCP1 protein expression was examined in 34 normal tissues, >300 samples from six types of cancer, and in 49 cancer cell lines. A recombinant human/mouse chimeric anti-CDCP1 antibody (ch10D7) was labelled with 89Zirconium or monomethyl auristatin E (MMAE) and tested in multiple pre-clinical cancer models including 36 cancer cell lines and three mouse xenograft models. Results: Analysis of CDCP1 expression indicates elevated CDCP1 expression in the majority of the cancers and restricted expression in normal human tissues. Antibody ch10D7 demonstrates a high affinity and specificity for CDCP1 inducing cell signalling via Src accompanied by rapid internalization of ch10D7/CDCP1 complexes in cancer cells. 89Zirconium-labelled ch10D7 accumulates in CDCP1 expressing cells enabling detection of pancreatic cancer xenografts in mice by PET imaging. Cytotoxicity of MMAE-labelled ch10D7 against kidney, colorectal, lung, ovarian, pancreatic and prostate cancer cells in vitro, correlates with the level of CDCP1 on the plasma membrane. ch10D7-MMAE displays robust anti-tumor effects against mouse xenograft models of pancreatic, colorectal and ovarian cancer. Conclusion: CDCP1 directed imaging agents will be useful for selecting cancer patients for personalized treatment with cytotoxin-loaded CDCP1 targeting agents including antibody-drug conjugates.

Diminishing lengths of subsequent bowel resections in the surgical management of ileal Crohn's disease.

BACKGROUND: Crohn's disease is a chronic inflammatory bowel disease that most commonly affects the ileum. As a result, it is associated with a high lifetime risk of one or more surgical resections. The surgical paradigm is to preserve intestinal length. This study aims to assess the length of ileum resected at the index operation and at subsequent ileocolic resections for Crohn's disease. METHODS: This is a retrospective study assessing the clinical and pathological data of patients undergoing ileocolic resection for the management of Crohn's disease over the period 01/01/2002 to 31/07/2020 in two metropolitan Australian hospitals. RESULTS: One hundred and seventy-six patients were analysed: 130 underwent a single resection; 31 underwent two resections; and 15 underwent three resections. The median age at the first operation was 37.2 years (range 18-69) with 60% of patients female. The median length resected at the first surgery was 17.8 cm (IQR 12.0) for small bowel, and 5.0 cm (IQR 1.0) for large bowel. The length of ileum resected at the first surgery was significantly greater than that of the second (P = 0.0001), without significant differences between the second and third resections (P = 0.49). The time interval from diagnosis to the first surgery had no significant impact on the length of intestine resected at the index ileocolic resection. CONCLUSION: In Crohn's disease, the length of ileum removed at first resection is the greatest, with subsequent resection lengths less than the first.

Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy in the world, with 22% of patients presenting with metastatic disease and a further 50% destined to develop metastasis. Molecular imaging uses antigen-specific ligands conjugated to radionuclides to detect and characterise primary cancer and metastases. Expression of the cell surface protein CDCP1 is increased in CRC, and here we sought to assess whether it is a suitable molecular imaging target for the detection of this cancer. CDCP1 expression was assessed in CRC cell lines and a patient-derived xenograft to identify models suitable for evaluation of radio-labelled 10D7, a CDCP1-targeted, high-affinity monoclonal antibody, for preclinical molecular imaging. Positron emission tomography-computed tomography was used to compare zirconium-89 (89Zr)-10D7 avidity to a nonspecific, isotype control 89Zr-labelled IgGκ1 antibody. The specificity of CDCP1-avidity was further confirmed using CDCP1 silencing and blocking models. Our data indicate high avidity and specificity for of 89Zr-10D7 in CDCP1 expressing tumors at. Significantly higher levels than normal organs and blood, with greatest tumor avidity observed at late imaging time points. Furthermore, relatively high avidity is detected in high CDCP1 expressing tumors, with reduced avidity where CDCP1 expression was knocked down or blocked. The study supports CDCP1 as a molecular imaging target for CRC in preclinical PET-CT models using the radioligand 89Zr-10D7.

PET Imaging Quantifying 68Ga-PSMA-11 Uptake in Metastatic Colorectal Cancer.

At diagnosis, 22% of colorectal cancer (CRC) patients have metastases, and 50% later develop metastasis. Peptide receptor radionuclide therapy (PRRT), such as 177Lu-PSMA-617, is used to treat metastatic prostate cancer. 177Lu-PSMA-617 targets prostate-specific membrane antigen (PSMA), a cell-surface protein enriched in prostate cancer and the neovasculature of other solid tumors, including CRC. We performed 68Ga-PSMA-11 PET/CT imaging of 10 patients with metastatic CRC to assess metastasis avidity. Eight patients had lesions lacking avidity, and 2 had solitary metastases exhibiting very low avidity. Despite expression of PSMA in CRC neovasculature, none of the patients exhibited tumor avidity sufficient to be considered for 177Lu-PSMA-617 PRRT.

Transanal total mesorectal excision for rectal cancer: state of the art.

Achieving a high-quality total mesorectal excision (TME) resection specimen is a central tenet of curative rectal cancer management. However, operating at the caudal extremity of the pelvis is inherently challenging and a number of patient- and tumour-related factors may increase the risk of obtaining a poor TME specimen and positive resection margins. Transanal TME (TaTME) is an advanced surgical technique developed to overcome the limitations in pelvic exposure and instrumentation of transabdominal surgery. This up-to-date narrative review describes the evolution of TME surgery, the indications for TaTME, current published outcomes, its limitations and future developments.

Indocyanine green fluorescence angiography (ICGFA) during laparoscopic and robotic colorectal surgery- a video vignette.

Anastomotic leaks are a dreaded complication of all colorectal surgery with the main factors contributing to it being tension on the anastomosis, intra-abdominal or systemic sepsis, distal obstruction, inadequate blood supply and improper surgical techniques. The leak rate of left-sided high colorectal resections can have a clinically significant leak rate from as low as 1-5% in high anterior resections to 7.9% in low anastomoses. This article is protected by copyright. All rights reserved.