Precision medicine applied to metastatic colorectal cancer using tumor-derived organoids and in-vitro sensitivity testing: a phase 2, single-center, open-label, and non-comparative study.

BACKGROUND: Patients with colorectal metastatic disease have a poor prognosis, limited therapeutic options, and frequent development of resistance. Strategies based on tumor-derived organoids are a powerful tool to assess drug sensitivity at an individual level and to suggest new treatment options or re-challenge. Here, we evaluated the method's feasibility and clinical outcome as applied to patients with no satisfactory treatment options. METHODS: In this phase 2, single-center, open-label, non-comparative study (ClinicalTrials.gov, register NCT03251612), we enrolled 90 patients with metastatic colorectal cancer following progression on or after standard therapy. Participants were 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, adequate organ function, and metastasis available for biopsy. Biopsies from the metastatic site were cultured using organoids model. Sensitivity testing was performed with a panel of drugs with proven activity in phase II or III trials. At the discretion of the investigator considering toxicity, the drug with the highest relative activity was offered. The primary endpoint was the proportion of patients alive without disease progression at two months per local assessment. RESULTS: Biopsies available from 82 to 90 patients were processed for cell culture, of which 44 successfully generated organoids with at least one treatment suggested. The precision cohort of 34 patients started treatment and the primary endpoint, progression-free survival (PFS) at two months was met in 17 patients (50%, 95% CI 32-68), exceeding the pre-defined level (14 of 45; 31%). The median PFS was 67 days (95% CI 51-108), and the median overall survival was 189 days (95% CI 103-277). CONCLUSIONS: Patient-derived organoids and in-vitro sensitivity testing were feasible in a cohort of metastatic colorectal cancer. The primary endpoint was met, as half of the patients were without progression at two months. Cancer patients may benefit from functional testing using tumor-derived organoids. TRIAL REGISTRATION: ClinicalTrials.gov, register NCT03251612.

Intra- and Interobserver Variability of Shear Wave Elastography in Rectal Cancer.

BACKGROUND: Endorectal ultrasound (ERUS) is an important tool when evaluating complex rectal adenomas and rectal cancer, and the accuracy is improved by adding elastography measurements. A high interobserver agreement is imperative in clinical practice. Therefore, the aim of this study was to evaluate interobserver agreement assessed on real-time images. Additionally, we investigated the intra- and interobserver agreement between experienced and inexperienced observers. MATERIALS AND METHODS: We prospectively included patients referred to an ERUS at the Department of Radiology with a complex rectal polyp or suspected rectal malignancy. Two operators independently scanned each patient in turn. Furthermore, four observers assessed previously obtained images using three different methods for placing the region of interest (ROI). Three months later, the four observers reassessed the images to assess intraobserver variability. RESULTS: A total of 19 patients were included for live assessment. Agreement of tumor classification was substantial for T stage (kappa: 0.86) and fair for N stage (kappa: 0.73), with an absolute agreement for T and N stages of 84% and 89%, respectively. Agreement of SWE was good for Emean (ICC 0.94, 95% CI 0.86-0.98) and fair for Emax (ICC 0.85, 95% CI 0.66-0.94). Intra- and interobserver agreement between inexperienced and experienced observers showed good to excellent agreement with all ROI methods. CONCLUSION: Interobserver agreement is high in SWE when performed in a clinical setting. We found the best agreement using the mean value of several ROIs. Intra- and interobserver agreement was high regardless of operator experience.

Diffusion-Weighted MRI in Patients with Testicular Tumors-Intra- and Interobserver Variability.

In general, magnetic resonance (MR) diffusion-weighted imaging (DWI) has shown potential in clinical settings. In testicles parenchyma, the DW imaging helps differentiate and characterize benign from malignant lesions. Placement and size of the region of interest (ROI) may affect the ADC value. Therefore, the aim of this study was to investigate the intra- and interobserver variability in testicular tumors when measuring ADC using various types of regions of interest (ROI). Two observers performed the ADC measurements in testicular lesions based on three ROI methods: (1) whole volume, (2) round, and (3) small sample groups. Intra- and interobserver variability was analyzed for all ROI methods using intraclass correlation coefficients (ICC) and bland-altman plots. The two observers performed the measurements twice, three months apart. A total of 26 malignant testicle tumors were included. Interobserver agreement was excellent in tumor length (ICC = 0.98) and tumor width (ICC = 0.98). In addition, intraobserver agreement was excellent in tumor length (ICC = 0.98) and tumor width (ICC = 0.99). The whole volume interobserver agreement in the first reading was excellent (ICC = 0.93). Round ADC had an excellent (ICC = 0.93) and fair (ICC = 0.58) interobserver agreement, in the first and second reading, respectively. Interobserver agreement in ADC small ROIs was good (ICC = 0.87), and good (ICC = 0.78), in the first and second reading, respectively. Intraobserver agreement varied from fair, good to excellent agreement. The ROI method showed varying inter- and intraobserver agreement in ADC measurement. Using multiple small ROI conceded the highest interobserver variability, and, thus, the whole volume or round seem to be the preferable methods.

CT and 3 Tesla MRI in the TN Staging of Colon Cancer: A Prospective, Blind Study.

(1) Background: Computer tomography (CT) scanning is currently the standard method for staging of colon cancer; however, the CT based preoperative local staging is far from optimal. The purpose of this study was to investigate the sensitivity and specificity of magnetic resonance imaging (MRI) compared to CT in the T- and N-staging of colon cancer. (2) Methods: Patients underwent a standard contrast-enhanced CT examination. For the abdominal MRI scan, a 3 Tesla unit was used, including diffusion weighted imaging (DWI). Experienced radiologists reported the CT and MRI scans blinded to each other and the endpoint of the pathological report. (3) Results: From 2018 to 2021, 134 patients received CT and MRI scans. CT identified 118 of the 134 tumors, whereas MRI identified all tumors. For discriminating between stage T3ab and T3cd, the sensitivity of CT was 51.1% and of MRI 80.0% (p = 0.02). CT and MRI showed a sensitivity of 21.4% and 46.4% in detecting pT4 tumors and a specificity of 79.0% and 85.0%, respectively. (4) Conclusion: Compared to CT, the sensitivity of MRI was statistically significantly higher in staging advanced T3cd and T4 tumors. MRI has the potential to be used in the treatment planning of colon cancer.

Intra- and Interobserver Variability in Magnetic Resonance Imaging Measurements in Rectal Cancer Patients.

Colorectal cancer is the second most common cancer in Europe, and accurate lymph node staging in rectal cancer patients is essential for the selection of their treatment. MRI lymph node staging is complex, and few studies have been published regarding its reproducibility. This study assesses the inter- and intraobserver variability in lymph node size, apparent diffusion coefficient (ADC) measurements, and morphological characterization among inexperienced and experienced radiologists. Four radiologists with different levels of experience in MRI rectal cancer staging analyzed 36 MRI scans of 36 patients with rectal adenocarcinoma. Inter- and intraobserver variation was calculated using interclass correlation coefficients and Cohens-kappa statistics, respectively. Inter- and intraobserver agreement for the length and width measurements was good to excellent, and for that of ADC it was fair to good. Interobserver agreement for the assessment of irregular border was moderate, heterogeneous signal was fair, round shape was fair to moderate, and extramesorectal lymph node location was moderate to almost perfect. Intraobserver agreement for the assessment of irregular border was fair to substantial, heterogeneous signal was fair to moderate, round shape was fair to moderate, and extramesorectal lymph node location was substantial to almost perfect. Our data indicate that subjective variables such as morphological characteristics are less reproducible than numerical variables, regardless of the level of experience of the observers.

Reporting colon cancer staging using a template.

PURPOSE: The purpose of this study was to evaluate the effect of completeness of the radiological reports in primary local staging colon cancer when using a template. METHODS: The study used primary staging reports retrieved from the departments RIS/PACS. Five key tumour descriptors were evaluated within each report: tumour morphology (polypoid or annular), information on tumour breach of the colon wall (≥ T3), tumour out-growth in mm, nodal status and TNM in conclusion. The failure to provide a description of the presence or absence of a feature in a report counted as 'not reported'. To allow comparisons between reporting styles, the template or free-text style of reporting was also recorded. RESULTS: During a two year period, a total of 666 patients CT reports were evaluated at the colorectal center multidisciplinary team (MDT) conference. In 200 of these reports a template was used. Information on tumour morphology (polypoid or annular) was present in 81% of the template reports vs 9% in free-text style. The figures in percentage for information on tumour breach of the colon wall (≥ T3) were 93% vs 48 %, tumour out-growth in mm: 51% vs 17%, nodal status: 99% vs 86% and TNM in conclusion: 98% vs 51%. P < 0.0001. CONCLUSION: The present study provides additional support for the routine use of template reports to improve imaging reporting standards in colonic cancer.

Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis.

BACKGROUND & AIMS: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis. METHODS: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint. RESULTS: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02-2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA. CONCLUSION: This study suggests that TSA >83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. LAY SUMMARY: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.

Perforated adenocarcinoma of the colon within a scrotal hernia imaged by CT: case report and literature review.

Colorectal cancer is one of the most common cancers in the developed countries, and colon cancer is well documented. However, it is very rare for a primary colon cancer to exist in a scrotal hernia, and even rarer for the scrotal hernia to perforate. Here, we describe an unusual case where a 75-year-old patient with a colon tumor that perforated in a scrotal hernia. The teaching point is to highlight the computed tomography scan imaging characteristics of this rare finding in patients with both abdominal and scrotal pain.

Local staging of sigmoid colon cancer using MRI.

BACKGROUND: An accurate radiological staging of colon cancer is crucial to select patients who may benefit from neoadjuvant chemotherapy. PURPOSE: To evaluate the diagnostic accuracy of preoperative magnetic resonance imaging (MRI) in identifying locally advanced sigmoid colon cancer, poor prognostic factors, and the inter-observer variation of the tumor apparent diffusion coefficient (ADC) values of diffusion-weighted imaging (DWI). MATERIAL AND METHODS: Using 1.5 T MRI with high resolution T2-weighted (T2W) imaging, DWI, and no contrast enhancement, 35 patients with sigmoid colon cancer were assessed. T-stage, N-stage, extramural vascular invasion (EMVI), and ADC values of the tumors were assessed and blindly compared by two observers using postoperative histopathological examination as the gold standard. Early tumors were defined as T1 to T3ab, and advanced tumors as T3cd or T4. RESULTS: The accuracy of the two radiologists in staging early versus advanced tumors, N-stage, and identification of EMVI was 94%/89%, 60%/66%, and 77%/60% with an inter-observer agreement of к = 0.86 (95% confidence interval [CI] = 0.67-1.00), к = 0.64 (95% CI = 0.39-0.90), and к = 0.52 (95% CI = 0.23-0.80). All the measured mean ADC values were below 1.0 × 10-3 mm2/s with an intra-class correlation coefficient in T3cd-T4 tumors of 0.85. CONCLUSION: Preoperative MRI can identify locally advanced sigmoid colon cancer and has potential as the imaging of choice to select patients for neoadjuvant chemotherapy. Initial experience with ADC measurement was achieved with an excellent inter-observer agreement in advanced tumors.

Computed tomography assessment of early response to neoadjuvant therapy in colon cancer.

INTRODUCTION: Using multidetector computed tomography, we aimed to assess the early response of neoadjuvant drug therapy for locally advanced colon cancer. METHODS: Computed tomography with IV contrast was acquired from 67 patients before and after up to three cycles of preoperative treatment. All patients had histologically confirmed colon cancer, a T4 or T3 tumour with extramural invasion ≥ 5 mm and no distant metastases or peritoneal nodules. The patients were treated with oxaliplatin and capecitabine. In addition, those with no mutations in the KRAS, BRAF and PIK3CA genes were also treated with panitumumab. Before and after treatment, we measured the tumour diameter in two different planes, the extension of the extramural tumour invasion, and the number and size of enlarged lymph nodes. RESULTS: The mean tumour length was 7.8 cm (95% confidence interval (CI): 5.3-10.4) at baseline and 4.34 cm (95% CI: 4.0-4.9) after treatment. The mean extramural tumour invasion was 10.6 mm (95% CI: 9.5-11.8) at baseline and 5.7 mm (95% CI: 4.7-6.7) after treatment. The mean number of enlarged lymph nodes was 4.1 (95% CI: 3.4-4.9) at baseline and 2.1 (95% CI: 1.4-2.7) after treatment. According to RECIST 1.1, 45% (95% CI: 34-57) of the patients had a response and 55% (95% CI: 43-67) had stable disease. None of the patients showed progressive disease. CONCLUSION: Using CT, we demonstrated a significant reduction in tumour size, extramural tumour invasion, number and size of enlarged lymph nodes following neoadjuvant treatment. FUNDING: not relevant. TRIAL REGISTRATION: Registered with ClinicalTrials.gov (NCT 01108107).

Selection of colon cancer patients for neoadjuvant chemotherapy by preoperative CT scan.

OBJECTIVE: Preoperative staging is essential to plan correct treatment of colon cancer and calls for objective, accurate methods for the introduction of neoadjuvant chemotherapy, which represents a new treatment option. PURPOSE: To evaluate the diagnostic accuracy of multislice computed tomography (CT) in local staging of colon cancer correlated with histopathological parameters, including criteria for adjuvant chemotherapy. MATERIAL AND METHODS: A total of 74 included patients had preoperative CT scans and surgical resection of their colon tumors. Tumor stage (T-stage), extramural tumor invasion (ETI), nodal stage (N-stage), extramural venous invasion (EVI) and the distance from tumor to nearest retroperitoneal fascia (DRF) were retrospectively assessed on the CT scan and compared blindly with the results of the pathological examination, including evaluation of the criteria for adjuvant chemotherapy. Advanced tumors were defined as T3 with ETI ≥5 mm or T4. RESULTS: Sixty-nine percent of the tumors were correctly T-staged by CT, 7% were overstaged and 24% were understaged. As to correct recognition of ETI on the CT scan, the observer was 73% accurate compared with histology (70% sensitivity (95% CI: 53-82%), 78% specificity (95% CI: 60-90%), 81% positive predictive value (PPV) (95% CI: 63-91%) and 66% negative predictive value (NPV) (95% CI: 49-80%). N-stage, EVI and DRF had poor accuracy: 53%, 53% and 64%. All patients with advanced tumors on CT fulfilled the criteria for adjuvant chemotherapy. Positive predictive value: 100% (95% CI: 88-100%). CONCLUSION: CT has a potential in the preoperative selection of advanced tumors suitable for neoadjuvant chemotherapy without overtreatment of low-risk patients.

Ultrasound follow-up for gallbladder polyps less than 6 mm may not be necessary.

INTRODUCTION: The management of ultrasound (US) detected gallbladder (GB) polyps remains a dilemma. The aim of this study was to assess the size distribution and the outcome of US follow-up of GB polyps. MATERIAL AND METHODS: The study was approved by the Danish Data Protection Agency. US reports from patients examined with abdominal US in our department from January 2008 to the end of December 2009 were reviewed with a view to including all patients with GB polyps. Patients with GB polyps are routinely recommended a 2-year follow-up with US every six months. The GB polyp size was recorded at baseline and at subsequent US reports. Pathology reports were finally reviewed for all patients with GB polyps to check who underwent cholecystectomy and to register the histological diagnosis. RESULTS: A total of 203 patients (median age 54 years; range 19-95 years) with GB polyps were included; 89 (44%) men and 114 (56%) women. The mean polyp size was 5 mm (range 2-40 mm). In 143 patients (70%) the GB polyp diameter was less than 6 mm. The first US follow-up was performed in 120 patients (59%), and only 31 (15%) completed the full 2-year US follow-up programme. Polyp size was stable in 100 patients, decreased in five patients, increased in eight and resolved in 15 patients. A total of 13 patients (6%) underwent cholecystectomy. Of the 203 patients, none showed neoplastic or malignant GB polyps. CONCLUSION: We recommend that follow-up US of patients with GB polyps < 6 mm is avoided. Alternatively, the intervals between US follow-up of GB polyps < 6 mm may be extended. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

[MRI of rectal stromal tumour]. / MR-skanning ved rektal stromal tumor.

A 39-year-old man was referred to hospital with a rectal tumour and underwent gastrointestinal endoscopy and diagnostic imaging. The tumour had immunohistochemical characteristics for gastrointestinal stromal tumour (GIST). The differential diagnosis of GIST to adenocarcinoma is important to be aware of for the rectal multidisciplinary team. On suspicion of GIST, patients should be referred to a sarcoma centre. The diagnosis of rectal GIST can be suggested on MRI by the presence of a well-defined heterogeneously large mass with a necrotic center associated with a prominent extra-luminal component and hyperechoic appearance on ultrasound.

[Erythropoietic protoporphyria. A rare inherited metabolic disorder with skin symptoms]. / Erytropoietisk protoporfyri. En sjaelden arvelig metabolisk sygdom med hudmanifestationer.

Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder, resulting from a deficiency of a specific enzyme, ferrochelatase, in the haem biosynthesis pathway. Early and late skin symptoms in EPP are demonstrated by three case stories. Diagnosis depends on characteristic skin symptoms and raised level of protoporphyrin in erythrocytes. The cases illustrate the aspect of inheritance, prophylaxis and recommended follow-up in EPP.