Use of patient-derived explants as a preclinical model for precision medicine in colorectal cancer: A scoping review.

PURPOSE: Whilst the treatment paradigm for colorectal cancer has evolved significantly over time, there is still a lack of reliable biomarkers of treatment response. Treatment decisions are based on high-risk features such as advanced TNM stage and histology. The role of the tumour microenvironment, which can influence tumour progression and treatment response, has generated considerable interest. Patient-derived explant cultures allow preservation of native tissue architecture and tumour microenvironment. The aim of the scoping review is to evaluate the utility of patient-derived explant cultures as a preclinical model in colorectal cancer. METHODS: A search was conducted using Ovid MEDLINE, EMBASE, Web of Science, and Cochrane databases from start of database records to September 1, 2022. We included all peer-reviewed human studies in English language which used patient-derived explants as a preclinical model in primary colorectal cancer. Eligible studies were grouped into the following categories: assessing model feasibility; exploring tumour microenvironment; assessing ex vivo drug responses; discovering and validating biomarkers. RESULTS: A total of 60 studies were eligible. Fourteen studies demonstrated feasibility of using patient-derived explants as a preclinical model. Ten studies explored the tumour microenvironment. Thirty-eight studies assessed ex vivo drug responses of chemotherapy agents and targeted therapies. Twenty-four studies identified potential biomarkers of treatment response. CONCLUSIONS: Given the preservation of tumour microenvironment and tumour heterogeneity, patient-derived explants has the potential to identify reliable biomarkers, treatment resistance mechanisms, and novel therapeutic agents. Further validation studies are required to characterise, refine and standardise this preclinical model before it can become a part of precision medicine in colorectal cancer.

Retrospective audit: Utility of PET scan in routine preoperative rectal cancer staging.

BACKGROUND: Accurate staging for rectal cancer is pertinent with recent introduction of rectum-sparing approaches for patients showing complete clinical response on restaging. Positron emission tomography(PET) is used in detection of recurrence or metastasis, but its value in routine preoperative rectal cancer staging remains unclear. Studies report that preoperative PET altered the stage in 39% and changed the management in 17-27% of patients. Our study aims to look at the utility of PET in routine preoperative staging of rectal cancer within 2 two colorectal units, and to determine if PET did result in a change in management. METHODS: Patients in Nepean Hospital (NSW) and Peter MacCallum Cancer Centre (VIC) who were diagnosed with rectal cancer between 1 January 2017 and 31 December 2021 were included in this retrospective study. All patients who did not have a PET scan were excluded. PET scan results were then compared with MRI and CT results. RESULTS: Three hundred and fifty-seven patients were included in the study. 30.3% of the patients had Stage 3 rectal cancer. 71.7% received neoadjuvant therapy. PET scan provided additional information in 55.5% of patients when compared with CT and MRI alone; 18.2% of the PET findings resulted in an altered management for the patient. CONCLUSION: PET scan can be a valuable tool in accurate staging, especially for ambiguous or equivocal lesions on CT. Our study demonstrated that additional information from PET scan resulted in an altered management plan in 18.2% of the patients. PET/MRI as a newer modality may be more accurate with reduced radiation exposure.

Patients' perspective on bowel resection for inflammatory bowel disease.

PURPOSE: The study aimed to determine whether patients are receiving adequate counselling about elective bowel resection and timely surgery for inflammatory bowel disease (IBD). METHODS: Patients with IBD who underwent an elective bowel resection in a tertiary referral centre between April 2012 and Dec 2014 were identified from a prospective database. Patients under the age of 16 years were excluded from the study. Patients were contacted over the phone to complete a questionnaire regarding their perspective on their surgery, including the consultations that took place, preparedness and timing of surgery, as well as patient attitude towards bowel resection and satisfaction with post-operative outcomes. Demographic details were recorded. RESULTS: Thirty-one patients participated in the study. Twenty-one (68%) patients were diagnosed with Crohn's disease, nine (29%) were diagnosed with ulcerative colitis, and one (3%) had indeterminate colitis. Twenty-seven (87%) patients reported that the timing of the initial consultation regarding the option of bowel resection was appropriate. Twenty-five (81%) patients felt prepared after a consultation with the surgical team with regard to perioperative issues and potential complications. Fourteen (45%) patients reported that the timing of bowel resection was appropriate, while 15 (48%) reported that it should have been earlier. A significant improvement in patient's pre- and post-operative attitudes towards bowel resection was demonstrated (p = 0.004). Thirty (97%) patients were either happy or very happy with their results and symptom improvement post-bowel resection. CONCLUSION: Most patients are receiving adequate counselling about elective bowel resection for IBD, although there is room for improvement for preoperative education and optimising timing of surgery.

Detection of incidental colorectal pathology on positron emission tomography/computed tomography.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) is an important modality in cancer imaging. With its increasing availability and use, it is not uncommon to detect incidental focal colorectal 18 F-FDG uptake which poses a diagnostic challenge, as they may be associated with malignant or pre-malignant colorectal lesions. The aim of our study is to determine the proportion of these findings which represents true pathology. METHODS: Patients with incidental focal colorectal 18 F-FDG uptake on PET/CT who subsequently underwent colonoscopy between January 2002 to September 2013 were identified from a prospective database in a tertiary referral centre. PET/CT results were correlated with colonoscopy and pathology results in these patients. Positive predictive values (PPVs) and 95% confidence intervals (CIs) of PET/CT in the detection of incidental colorectal pathology were calculated. RESULTS: A total of 148 patients (92 men and 56 women), with a mean age 73 years (range of 36 to 93 years) were included in the study. A total of 170 foci of colorectal 18 F-FDG uptake were detected on PET/CT. Of these, 101 foci corresponded to a malignant or pre-malignant lesion (PPV 59%; 95% CI: 52-67%). On a per-patient analysis, 93 patients had at least one focus of colorectal 18 F-FDG uptake which corresponded to a pre-malignant or malignant lesion (PPV 63%; 95% CI: 54-71%). CONCLUSION: Focal colorectal 18 F-FDG uptake on PET/CT is associated with a significant proportion of malignant or pre-malignant lesions. Further evaluation with colonoscopy is recommended.

Maternal Supplementation with LGG Reduces Vaccine-Specific Immune Responses in Infants at High-Risk of Developing Allergic Disease.

Probiotics are defined as live micro-organisms that when administered in adequate amounts confer a health benefit on the host. Among their pleiotropic effects, inhibition of pathogen colonization at the mucosal surface as well as modulation of immune responses are widely recognized as the principal biological activities of probiotic bacteria. In recent times, the immune effects of probiotics have led to their application as vaccine adjuvants, offering a novel strategy for enhancing the efficacy of current vaccines. Such an approach is particularly relevant in regions where infectious disease burden is greatest and where access to complete vaccination programs is limited. In this study, we report the effects of the probiotic, Lactobacillus rhamnosus GG (LGG) on immune responses to tetanus, Haemophilus influenzae type b (Hib) and pneumococcal conjugate (PCV7) vaccines in infants. This study was conducted as part of a larger clinical trial assessing the impact of maternal LGG supplementation in preventing the development of atopic eczema in infants at high-risk for developing allergic disease. Maternal LGG supplementation was associated with reduced antibody responses against tetanus, Hib, and pneumococcal serotypes contained in PCV7 (N = 31) compared to placebo treatment (N = 30) but not total IgG levels. Maternal LGG supplementation was also associated with a trend to increased number of tetanus toxoid-specific T regulatory in the peripheral blood compared to placebo-treated infants. These findings suggest that maternal LGG supplementation may not be beneficial in terms of improving vaccine-specific immunity in infants. Further clinical studies are needed to confirm these findings. As probiotic immune effects can be species/strain specific, our findings do not exclude the potential use of other probiotic bacteria to modulate infant immune responses to vaccines.

Non-specific effect of Bacille Calmette-Guérin vaccine on the immune response to routine immunisations.

Bacille Calmette-Guérin (BCG) is one of the most commonly administered vaccines worldwide. In addition to protection against tuberculosis (TB), evidence suggests that BCG immunisation has a number of additional beneficial non-specific immunological effects. These include a reduction in overall infant and child mortality attributable to causes other than TB in high-mortality regions. The antibody response to immunisations provides an opportunity to investigate the influence of BCG on the immune response to unrelated antigens. This study compared the antibody response to routine immunisations in BCG-immunised and non-BCG-immunised infants. BCG-immunised infants were recruited from a related study in which BCG was given at birth and non-BCG-immunised infants were recruited from immunisation clinics. All infants received their routine immunisations according to the Australian National Immunisation Program. Concentrations of antibodies against pneumococcal (anti-Pn Ps), Haemophilus influenzae type B (anti-Hib), tetanus toxoid (anti-TT) and hepatitis B surface (anti-HBs) antigen were measured four weeks after the last (six month) set of infant immunisations. A total of 127 parents agreed for their infants to take part in the study of which 108 were included in the final analysis (56 BCG-immunised and 52 non-BCG-immunised). The geometric mean concentration (GMC) of anti-Pn Ps IgG for all serotypes, anti-Hib IgG and anti-TT IgG were higher in the BCG-immunised group than the non-BCG-immunised group. This difference reached statistical significance for serotype 9V (p<0.01) and 18C (p=0.04). The GMC of anti-HBs IgG was lower in the BCG-immunised group than the non-BCG-immunised group (p=0.03). The majority of participants in both groups had antibody levels above the protective threshold. BCG immunisation at birth influences the antibody response to routine immunisations administered later in infancy. This has important implications for the introduction of both pneumococcal conjugate and novel TB vaccines in resource-limited countries.