Synchronous colorectal cancer using CT colonography vs. other means: a systematic review and meta-analysis

Objectives

The objective of our study was to systematically review the evidence about synchronous colorectal cancer diagnosed with or without computed tomography colonography (CTC).

Materials and methods

Two systematic searches were performed (PubMed and EMBASE) for studies reporting the prevalence of synchronous colorectal cancer (CRC): one considering patients who underwent CTC and the another one considering patients who did not undergo CTC. A three-level analysis was performed to determine the prevalence of patients with synchronous CRC in both groups of studies. Heterogeneity was explored for multiple variables. Pooled prevalence and 95% confidence interval (CI) were calculated. A quality assessment (STROBE) was done for the studies.

Results

For CTC studies, among 2645 articles initially found, 21 including 1673 patients, published from 1997 to 2018, met the inclusion criteria. For non-CTC studies, among 6192 articles initially found, 27 including 111,873 patients published from 1974 to 2015 met the inclusion criteria. The pooled synchronous CRC prevalence was 5.7% (95% CI 4.7%–7.1%) for CTC studies, and 3.9% (95% CI 3.3%–4.4%) for non-CTC studies, with a significant difference (p = 0.004). A low heterogeneity was found for the CTC group (I² = 10.3%), whereas a high heterogeneity was found in the non-CTC group of studies (I² = 93.5%), and no significant explanatory variables were found. Of the 22 STROBE items, a mean of 18 (82%) was fulfilled by CTC studies, and a mean of 16 (73%) by non-CTC studies.

Conclusions

The prevalence of synchronous CRC was about 4–6%. The introduction of CTC is associated with a significant increase of the prevalence of synchronous CRCs.

     

Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction

Novel Ab-based immunotherapeutic strategies have exploited T-cell receptor-like chimeric immune receptors (CIR) expressed on the surface of transduced human peripheral blood mononuclear cell (PBMC) to redirect potent non-major histocompatibility complex-dependent cytotoxicity to tumor cells expressing a tumor-associated antigens. We transduced human PBMC with 2 fully human CIRs that trigger through the zeta-chain of CD3 and contain either one of two human scFv specific for the same epitope on the extracellular domain of HER2 but with distinctly different affinities (KD 1616 and 1 nM) for this antigen. Potent direct CIR-mediated killing and in vitro tumor growth inhibition mediated by transduced PBMC were observed against targets expressing different levels of HER2. High-affinity CIR showed stronger ability to bind Ag and retain binding than low-affinity CIR. When lytic potential of the 2 CIRs was evaluated, their efficiency was comparable under conditions of high CIR and Ag expression, whereas low-affinity CIR was more efficient than high-affinity CIR in conditions of limiting Ag and CIR expression levels. When tumor growth inhibition was evaluated, Ag and CIR levels, rather than CIR affinity appeared relevant. Ag-driven CIR activation resulted in the production of soluble factors mediating efficient bystander effect. By carefully defining CIR surface expression and increasing affinity for a specific target antigen, it may be possible to selectively exclude CIR-mediated activity against targets expressing low levels of antigen, as normal cells. On the contrary, low antigen-expressing tumor variants could be eliminated by decreasing CIR affinity. Tuning CIR expression and affinity might help in discriminating different biologic contexts.     

Bispecific antibodies and retargeted cellular cytotoxicity: novel approaches to cancer therapy.

We have used a relatively new technology to increase the number of human lymphocytes that will react with human ovarian carcinoma cells. This technology, often called "retargeting of the immune system," can temporarily redirect the activity of immune cells that were originally committed to react with foreign substances other than cancer cells. In the example presented here, the antitumor effects of retargeted human T lymphocytes, collected from normal donors, were tested in immunodeficient mice with a human ovarian carcinoma line growing intraperitoneally. We retargeted T cells in vitro with a bispecific antibody that reacted with the T cell receptor complex and with a cell-surface antigen expressed by the ovarian carcinoma cells. Retargeted lymphocytes, injected intraperitoneally into mice 4 days after intraperitoneal injection of the tumor cells, impeded tumor growth and doubled the host survival time. These findings provide support for the concept that treatment of ovarian cancer patients with retargeted T cells could prove beneficial.     

Impact of contrast-enhanced computed tomography colonography on laparoscopic surgical planning of colorectal cancer

Aim

To evaluate the impact of contrast-enhanced computed tomography colonography (CE-CTC) on laparoscopic surgery planning in patient with stenosing colorectal cancer.

Materials and methods

Sixty-nine patients with endoscopically proven colorectal cancer underwent CE-CTC, after incomplete conventional colonoscopy. Two experienced radiologists evaluated site, length, and TNM staging of colorectal cancers on three-dimensional double contrast enema-like views, 2D axial and multiplanar reconstructions. All the patients underwent colorectal resection and surgery bulletin, pathology of surgical specimens, and radiological follow-up at about 8 months were used as reference standard.

Results

The detection rate of colorectal cancer was 100 % (75/75); CE-CTC allowed for a diagnosis of a synchronous colorectal cancer in five patients (7 %). CE-CTC correctly judged the site of the lesions in all the cases; clinically significant localization errors at conventional colonoscopy were noted in 3 out of 69 patients (4 %). Additional colonic polyps greater than 6 mm in diameter were found in 21 out of 69 patients (30 %); in two patients (3 %) the surgeon performed an enlarged colectomy to include synchronous polyps proximal to colorectal cancer. Sensitivity, specificity, PPV, NPV, and accuracy were for T1–T2 vs. T3–T4: 96 %, 71 %, 92 %, 87 %, and 91 %, respectively; for N: 94 %, 42 %, 64 %, 86 %, and 70 %; for M: 100 %, 100 %, 83 %, 100 %, and 97 %. There were no complications associated with CE-CTC.

Conclusion

Information given by CE-CTC concerning colorectal cancer location and synchronous colonic cancers and polyps changed the laparoscopic surgical strategy in almost 14 % of patients.     

Human ovarian carcinoma lysis by cytotoxic T cells targeted by bispecific monoclonal antibodies: analysis of the antibody components

In the perspective of in vivo therapeutic applications, the monoclonal antibody (MAb) MOv18 was selected for its restricted reactivity with human ovarian carcinoma. Using the pH 2.8 desorption assay, we found that the antigen recognized by MOv18 had a high stability on the cell membrane and poor internalization. Therefore, a therapeutic approach which does not require internalization, i.e., the re-targeting of cytotoxic T lymphocytes (CTL) by bispecific MAbs, was investigated. MOv18 and anti-CD3 MAbs were used to produce bispecific reagents, obtained either by chemical cross-linkage (hetero-conjugates) or by somatic hybridization techniques (hybrid MAbs). The maintenance of the binding reactivity and specificity of the bispecific MAbs was analyzed by solid-phase radioimmunoassay, immunofluorescence and cross-competition tests on the relevant target cells (ovarian carcinoma cell line OVCA 432 for MOv18 and PHA-stimulated peripheral blood mononuclear cells for anti-CD3 MAbs), and on 2 irrelevant tumor cell lines. Bv a 51Cr-release assay the bispecific MAbs were found to efficiently promote, at picomolar concentration, cell lysis by CTL clones, but the specificity pattern was wider than that predicted by the binding studies. The F(ab')2 fragment of one hybrid MAb mediated a lysis which was just as efficient as the entire MAb on the relevant target cells and allowed specific lysis to be distinguished from Fc-receptor-mediated lysis. Human immunoglobulins were unable to compete with the Fc receptor binding of the hybrid MAbs and therefore, in the perspective of in vivo applications, Fc fragment removal seems to be an essential step. Analysis of the bispecific reagents indicated that hybrid MAbs are superior to the heteroconjugate as far as storage stability is concerned.     

Characterisation of in vivo ovarian cancer models by quantitative 1H magnetic resonance spectroscopy and diffusion-weighted imaging

Magnetic resonance imaging (MRI) and spectroscopy (MRS) offer powerful approaches for detecting physiological and metabolic alterations in malignancies and help investigate underlying molecular mechanisms. Research on epithelial ovarian carcinoma (EOC), the gynaecological malignancy with the highest death rate characterised by frequent relapse and onset of drug resistance, could benefit from application of these molecular imaging approaches. In this study, MRI/MRS were used to characterise solid tumour models obtained by subcutaneous (s.c.) or intraperitoneal (i.p.) implantation of human SKOV3.ip cells in severe combined immunodeficiency (SCID) mice. In vivo MRI/MRS, ex vivo magic-angle-spinning (MAS), and in vitro (1)H-NMR measurements were carried out at 4.7 T, 9.4 T, and 9.4/16.5 T, respectively. MRI evaluation was performed by T1-, T2-, and diffusion-weighted (DW) multislice spin-echo imaging. The in vivo (1)H spectra of all tumour models showed a prominent resonance of total choline-containing metabolites (tCho). Quantitative in vivo MRS of both i.p. and s.c. SKOV3.ip xenografts showed that the mean tCho content was in the 2.9-4.5 mM range, with a mean PCho/tCho ratio of 0.99 ± 0.01 [23 examinations, 14-34 days post injection (dpi)], in good agreement with ex vivo and in vitro analyses. Myo-inositol ranged between 11.7 and 17.0 mM, with a trend towards higher values in i.p. xenografts at 14-16 dpi. The average apparent diffusion coefficient (ADC) values of SKOV3.ip xenografts [1.64 ± 0.11 (n = 9, i.p.) and 1.58 ± 0.03 x10(-3) mm(2)/s (n = 7, s.c.)] were in agreement with values reported for tumours from patients with EOC, while the mean vascular signal fraction (VSF) was lower (≤ 4%), probably due to the more rapid growth of preclinical models. Both s.c. and i.p. xenografts are valuable preclinical models for monitoring biochemical and physiopathological changes associated with in vivo EOC tumour growth and response to therapy, which may serve as the basis for further clinical development of noninvasive MR approaches.     

Targeting of anti-tumor responses with bispecific antibodies.

T cells can be induced to specifically lyse tumor cells with bispecific antibodies containing anti-T cell receptor mAbs crosslinked to anti-tumor mAbs. Such "targeted cytolysis" requires that the target cell be bound directly to the cytotoxic cell. In addition, targeted T cells mediate a second activity, the secretion of factors that can block the growth of both tumor target cells and bystander tumor cells. When given to nude mice bearing intraperitoneal human ovarian carcinoma, targeted human T cells cause the rapid removal of most tumor cells from the peritoneum, and markedly prolong the times of survival of treated mice. The efficacy of targeted T cells for treating human cancer is currently being tested in clinical trials.     

Analysis of production,purification, and cytolytic potential of bi-specific antibodies reactive with ovarian-carcinoma-associated antigens and the T-cell antigen CD3

OV-TL 3 and MOvl8 MAbs, due to their restricted specificity, have been successfully used to visualize ovarian cancer in patients and might therefore be used to develop therapies for ovarian cancer. The bi-specific MAbs αT3/OC2 and αOC/TR (both being combinations of MOvl8 and aCD3) have been shown to lyse ovarian tumor cells in vitro. To evaluate the relative merits of MOvl8/CD3 and OV-TL 3/CD3, the present study was undertaken in which the bi-specific MAbs αT3/OC2 and αOC/TR, and a newly developed bi-specific MAb, OV-TL 3/CD3, were highly purified and compared for specificity, stability, purification and cytolytic potential. The dual specificity of the hybrid-hybridoma supernatants was analyzed by immunohistochemistry, and by testing bi-specific MAb-mediated cytotoxicity against relevant target cells in the presence of effector cells. Stability testing of bi-specific MAb-producing hybrid-hybridomas showed that, after sub-cloning, clones stably produced up to 40% bi-specific MAb even after prolonged in vitro culture. The purification of the bi-specific fractions was performed with protein A and by ion-exchange high-pressure liquid chromatography, depending on the sub-class combination of the bi-specific MAb. The purified bi-specific MAbs were tested for their ability to mediate target-cell lysis with the use of cytotoxic T-cell clones and activated peripheral-blood lymphocytes. The purified αT3/OC2, αOC/TR, and OV-TL 3/CD3 were all able to mediate highly specific lysis of various ovarian-carcinoma cell lines. No correlation was found between the level of antigen expression and bi-specific MAb-mediated cytolysis. © 1993 Wiley-Liss, Inc.