Risk of bowel obstruction in patients with colon cancer responding to immunotherapy: an international case series.

BACKGROUND: Immunotherapy is used routinely for treating deficient mismatch repair (dMMR) colon cancer (CC). This case series highlights an emerging safety issue, where patients develop bowel obstruction associated with immunotherapy response. PATIENTS AND METHODS: Patients with dMMR CC who developed bowel obstruction while responding to immunotherapy were retrospectively identified. Data on patient, disease, treatment, and response-specific factors were explored for potential risk factors. Overall treatment numbers were used to estimate incidence. RESULTS: Nine patients from eight European centres were included. Common features were hepatic flexure location (5/9), T4 radiological staging (6/9), annular shape (8/9), radiological stricturing (5/9), and endoscopic obstruction (6/9). All received pembrolizumab and obstructed between 45 and 652 days after starting treatment. Seven patients underwent surgical resection; one was managed with a defunctioning stoma; and one was managed conservatively. One patient died from obstruction. Radiological response was seen in eight patients, including two complete responses. Pathological response was seen in all seven who underwent resection, including four complete responses. The overall incidence of immunotherapy response-related obstruction in these centres was 1.51%. CONCLUSIONS: Bowel obstruction associated with immunotherapy response may represent a rare treatment-related complication in dMMR CC. Clinicians must recognise this safety signal and share experience to maintain patient safety.

Best-Practice Biomarker Testing of Oesophago-Gastric Cancer in the UK: Expert Consensus Recommendations Developed Using a Modified Delphi.

AIMS: Oesophago-gastric cancers (OGCs) are amongst the most commonly diagnosed malignancies worldwide and are associated with high disease-related mortality. Predictive biomarkers are molecules that can be objectively measured and used to indicate a likely response to therapeutic intervention, thus facilitating individualised cancer therapy. However, there remains variation in uptake and implementation of biomarker testing across the UK. MATERIALS AND METHODS: We conducted a modified Delphi study to formulate consensus recommendations for best-practice biomarker testing of OGC in the UK. We employed two rounds of online questionnaires followed by a virtual consensus meeting. Biomarkers for discussion included HER2, MSI/MMR, and PD-L1. Topics comprised the overall biomarker pathway, pre-analytical, analytical, and post-analytical considerations, including challenges in current practice. RESULTS: Twenty-six and eighteen participants completed the first and second round Delphi questionnaire, respectively, with an even split of pathologists and oncologists from across the UK. There was consensus (>80% agreement) across several topics, including the requirements for standardisation of the pathway, which must include coordination throughout the tissue journey, requirements for a quality-assured process to ensure accuracy and validity of testing, plus the need for clear, detailed information on the pathology report to support treatment decisions. There was consensus amongst oncologists regarding reflex testing of all biomarkers depending on histology; however, concerns over capacity in relation to workload and availability of pathologists were evident among the pathologists. Overall, participants were in the opinion that reflex testing improves the speed of treatment decisions and improves patient care. CONCLUSION: The recommendations reflect best-practices and should be implemented to support rapid multidisciplinary team decision-making within oesophago-gastric cancer. Results reflect the need for standardisation and demonstrate the challenges faced in clinical practice by those requesting and testing biomarkers for oesophago-gastric cancer, suggesting significant concerns relating to pathologist capacity.

Stroma AReactive Invasion Front Areas (SARIFA): a novel histopathologic biomarker in colorectal cancer patients and its association with the luminal tumour proportion.

BACKGROUND: Stroma AReactive Invasion Front Areas (SARIFA) is a novel prognostic histopathologic biomarker measured at the invasive front in haematoxylin & eosin (H&E) stained colon and gastric cancer resection specimens. The aim of the current study was to validate the prognostic relevance of SARIFA-status in colorectal cancer (CRC) patients and investigate its association with the luminal proportion of tumour (PoT). METHODS: We established the SARIFA-status in 164 CRC resection specimens. The relationship between SARIFA-status, clinicopathological characteristics, recurrence-free survival (RFS), cancer-specific survival (CSS), and PoT was investigated. RESULTS: SARIFA-status was positive in 22.6% of all CRCs. SARIFA-positivity was related to higher pT, pN, pTNM stage and high grade of differentiation. SARIFA-positivity was associated with shorter RFS independent of known prognostic factors analysing all CRCs (RFS: hazard ratio (HR) 2.6, p = 0.032, CSS: HR 2.4, p = 0.05) and shorter RFS and CSS analysing only rectal cancers. SARIFA-positivity, which was measured at the invasive front, was associated with PoT-low (p = 0.009), e.g., higher stroma content, and lower vessel density (p = 0.0059) measured at the luminal tumour surface. CONCLUSION: Here, we validated the relationship between SARIFA-status and prognosis in CRC patients and provided first evidence for a potential prognostic relevance in the subgroup of rectal cancer patients. Interestingly, CRCs with different SARIFA-status also showed histological differences measurable at the luminal tumour surface. Further studies to better understand the relationship between high luminal intratumoural stroma content and absence of a stroma reaction at the invasive front (SARIFA-positivity) are warranted and may inform future treatment decisions in CRC patients.

SF-CORNER (splenic flexure colorectal cancer): an international survey of operative approaches and outcomes for cancers of the splenic flexure.

AIM: The optimum surgical approach to splenic flexure cancers (SFCs) remains uncertain. The aim of this survey was to explore the opinions of an international surgical community on the management and outcomes of SFC. METHOD: A questionnaire was constructed comprising five sections (information about respondents; definition and prognosis of SFC; operative approach; approach in specific scenarios; outcomes) and circulated through an international dissemination committee and social media. RESULTS: The survey received 576 responses over 4 weeks across 50 countries. There was no consensus regarding the definition of the splenic flexure, whilst the proportion of respondents who did and did not think that patients with SFC had a worse outcome was equal. The overall preferred operative approach was left hemicolectomy [203 (35.2%)], followed by segmental resection [167 (29%)], extended right hemicolectomy [126 (21.9%)] and subtotal colectomy [7 (12%)]. The stated pedicles for ligation varied between resection types and also within the same resection. One hundred and sixty-six (28.8%) respondents thought a segmental resection was associated with the worst survival and 190 (33%) thought it was associated with the best quality of life. CONCLUSION: This survey confirms a lack of consensus across all aspects SFC treatment. The differing approaches described are likely to represent different beliefs around the variable anatomy of this region and the associated lymphatic drainage. Future studies are required to address such inconsistencies and identify the optimum surgical strategy, whilst also incorporating quality-of-life metrics and patient-reported outcomes. A one-size-fits-all approach is probably not appropriate with SFC, and a more bespoke approach is required.

Extra-mandibular Osteoradionecrosis after the Treatment of Head and Neck Cancer.

AIMS: Osteoradionecrosis (ORN) is a serious toxicity of head and neck radiotherapy. It predominantly affects the mandible. Extra-mandibular ORN is rare. The aim of this study was to report the incidence and outcomes of extra-mandibular ORNs from a large institutional database. MATERIALS AND METHODS: In total, 2303 head and neck cancer patients were treated with radical or adjuvant radiotherapy. Of these, extra-mandibular ORN developed in 13 patients (0.5%). RESULTS: Maxillary ORNs (n = 8) were a consequence of the treatment of various primaries (oropharynx = 3, sinonasal = 2, maxilla = 2, parotid = 1). The median interval from the end of radiotherapy to the development of ORN was 7.5 months (range 3-42 months). The median radiotherapy dose in the centre of the ORN was 48.5 Gy (range 22-66.5 Gy). Four patients (50%) healed in 7, 14, 20 and 41 months. All temporal bone ORNs (n = 5) developed after treatment to the parotid gland (of a total of 115 patients who received radiotherapy for parotid gland malignancy). The median interval from the end of radiotherapy to the development of ORN was 41 months (range 20-68 months). The median total dose in the centre of the ORN was 63.5 Gy (range 60.2-65.3 Gy). ORN healed in only one patient after 32 months of treatment with repeated debridement and topical betamethasone cream. CONCLUSION: Extra-mandibular ORN is a rare late toxicity and this current study provides useful information on its incidence and outcome. The risk of temporal bone ORN should be considered in the treatment of parotid malignancies and patients should be counselled. More research is required to determine the optimal management of extra-mandibular ORN, particularly on the role of the PENTOCLO regimen.

Antipseudomonal treatment decisions during CF exacerbation management.

BACKGROUND: Cystic fibrosis (CF) pulmonary exacerbation (PEx) treatment guidelines suggest that Pseudomonas aeruginosa (Pa) airway infection be treated with two antipseudomonal agents. METHODS: We retrospectively studied treatment responses for STOP2 PEx treatment trial (NCT02781610) participants with a history of Pa infection. Mean lung function and symptom changes from intravenous (IV) antimicrobial treatment start to Visit 2 (7 to 10 days later) were compared between those receiving one, two, and three+ antipseudomonal classes before Visit 2 by ANCOVA. Odds of PEx retreatment with IV antimicrobials within 30 days and future IV-treated PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively. Sensitivity analyses limited to the most common one-, two-, and three-class regimens, to only IV/oral antipseudomonal treatments, and with more stringent Pa infection definitions were conducted. RESULTS: Among 751 participants, 50 (6.7%) were treated with one antipseudomonal class before Visit 2, while 552 (73.5%) and 149 (19.8%) were treated with two and with three+ classes, respectively. Females and participants with a negative Pa culture in the prior month were more likely to be treated with a single class. The most common single, double, and triple class regimens were beta-lactam (BL; n = 42), BL/aminoglycoside (AG; n = 459), and BL/AG/fluoroquinolone (FQ; n = 73). No lung function or symptom response, odds of retreatment, or future PEx hazard differences were observed by number of antipseudomonal classes administered in primary or sensitivity analyses. CONCLUSIONS: We were unable to identify additional benefit when multiple antipseudomonal classes are used to treat PEx in people with CF and Pa.

Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

C-reactive protein (CRP) as a biomarker of pulmonary exacerbation presentation and treatment response.

BACKGROUND: C-reactive protein (CRP) has been proposed as a biomarker for pulmonary exacerbation (PEx) diagnosis and treatment response. CRP >75mg/L has been associated with increased risk of PEx treatment failure. We have analyzed CRP measures as biomarkers for clinical response during the STOP2 PEx study (NCT02781610). METHODS: CRP measures were collected at antimicrobial treatment start (V1), seven to 10 days later (V2), and two weeks after treatment end (V3). V1 log10CRP concentrations and log10CRP change from V1 to V3 correlations with clinical responses (changes in lung function and symptom score) were assessed by least squares regression. Odds of intravenous (IV) antimicrobial retreatment within 30 days and future PEx hazard associated with V1 and V3 CRP concentrations and V1 CRP >75 mg/L were studied by adjusted logistic regression and proportional hazards modeling, respectively. RESULTS: In all, 951 of 982 STOP2 subjects (92.7%) had CRP measures at V1. V1 log10CRP varied significantly by V1 lung function subgroup, symptom score quartile, and sex, but not by age subgroup. V1 log10CRP correlated moderately with log10CRP change at V3 (r2=0.255) but less so with lung function (r2=0.016) or symptom (r2=0.031) changes at V3. Higher V1 CRP was associated with greater response. CRP changes from V1 to V3 only weakly correlated with lung function (r2=0.061) and symptom (r2=0.066) changes. However, V3 log10CRP was associated with increased odds of retreatment (P = .0081) and future PEx hazard (P = .0114). DISCUSSION: Despite consistent trends, log10CRP change was highly variable with only limited utility as a biomarker of PEx treatment response.

Association of site of treatment with clinical outcomes following intravenous antimicrobial treatment of a pulmonary exacerbation.

BACKGROUND: In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital. METHODS: Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location. RESULTS: In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV1 improvement was significantly (p < 0.05) lower for those treated at home only, 5.0 (3.5, 6.5), compared with at home and in the hospital, 7.0 (5.9, 8.1), and in the hospital only, 8.0 (6.7, 9.4). Mean weight (p < 0.001) and symptom (p < 0.05) changes were significantly smaller for those treated at home only compared to those treated in the hospital only. CONCLUSIONS: Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. The limitations of home IV therapy should be addressed in order to optimize outcomes for adults with CF treated at home.

Interobserver variation in the classification of tumor deposits in rectal cancer-is the use of histopathological characteristics the way to go?

The focus on lymph node metastases (LNM) as the most important prognostic marker in colorectal cancer (CRC) has been challenged by the finding that other types of locoregional spread, including tumor deposits (TDs), extramural venous invasion (EMVI), and perineural invasion (PNI), also have significant impact. However, there are concerns about interobserver variation when differentiating between these features. Therefore, this study analyzed interobserver agreement between pathologists when assessing routine tumor nodules based on TNM 8. Electronic slides of 50 tumor nodules that were not treated with neoadjuvant therapy were reviewed by 8 gastrointestinal pathologists. They were asked to classify each nodule as TD, LNM, EMVI, or PNI, and to list which histological discriminatory features were present. There was overall agreement of 73.5% (κ 0.38, 95%-CI 0.33-0.43) if a nodal versus non-nodal classification was used, and 52.2% (κ 0.27, 95%-CI 0.23-0.31) if EMVI and PNI were classified separately. The interobserver agreement varied significantly between discriminatory features from κ 0.64 (95%-CI 0.58-0.70) for roundness to κ 0.26 (95%-CI 0.12-0.41) for a lone arteriole sign, and the presence of discriminatory features did not always correlate with the final classification. Since extranodal pathways of spread are prognostically relevant, classification of tumor nodules is important. There is currently no evidence for the prognostic relevance of the origin of TD, and although some histopathological characteristics showed good interobserver agreement, these are often non-specific. To optimize interobserver agreement, we recommend a binary classification of nodal versus extranodal tumor nodules which is based on prognostic evidence and yields good overall agreement.

Robotic complete mesocolic excision with central vascular ligation for right colonic tumours - a propensity score-matching study comparing with standard laparoscopy.

BACKGROUND: Laparoscopic complete mesocolic excision (CME) of the right colon with central vascular ligation (CVL) is a technically demanding procedure. This study retrospectively evaluated the feasibility, safety and oncological outcomes of the procedure when performed using the da Vinci® robotic system. METHODS: A prospective case series was collected over 3 years for patients with right colonic cancers treated by standardized robotic CME with CVL using the superior mesenteric vessels first approach. The CME group was compared to a 2 : 1 propensity score-matched non-CME group who had conventional laparoscopic right colectomy with D2 nodal dissection. Primary outcomes were total lymph node harvest and length of specimen. Secondary outcomes were operative time, postoperative complications, and disease-free and overall survival. RESULTS: The study included 120 patients (40 in the CME group and 80 in the non-CME group). Lymph node yield was higher (29 versus 18, P = 0.006), the specimen length longer (322 versus 260 mm, P = 0.001) and median operative time was significantly longer (180 versus 130 min, P < 0.001) with robotic CME versus laparoscopy, respectively. Duration of hospital stay was longer with robotic CME, although not significantly (median 6 versus 5 days, P = 0.088). There were no significant differences in R0 resection rate, complications, readmission rates and local recurrence. A trend in survival benefit with robotic CME for disease-free (P = 0.0581) and overall survival (P = 0.0454) at 3 years was documented. CONCLUSION: Robotic CME with CVL is feasible and, although currently associated with a longer operation time, it provides good specimen quality, higher lymph node yield and acceptable morbidity, with a disease-free survival advantage.

Changes in symptom scores as a potential clinical endpoint for studies of cystic fibrosis pulmonary exacerbation treatment.

INTRODUCTION: Symptom improvement was assessed as changes in the Chronic Respiratory Infection Symptom Score (CRISS) during intravenous antimicrobial exacerbation treatments among subjects from study NCT02109822. METHODS: Median daily CRISS reduction (i.e., improvement) and covariates associated with CRISS reduction by Day 14 were assessed by logistic regression. RESULTS: Among 173 subjects, median baseline CRISS was 49 [IQR 41, 56]; 93.6% had a CRISS reduction of ≥11 (minimal clinically important difference); median time to -11 reduction was 2 days [95% CI 2, 3]. The greatest median CRISS difference from baseline, on Day 17, was -26 [-29, -23]. Odds of -26 CRISS change by Day 14 were greater in subjects with higher baseline CRISS (P=.006) and younger ages (P=.041). CONCLUSIONS: CRISS response has good dynamic range and may be a useful efficacy endpoint for PEx interventional trials. The optimal use of CRISS change as an endpoint remains uncharacterized.

Dynamics of picosecond laser ablation for surgical treatment of colorectal cancer.

Endoluminal surgery for the treatment of colorectal neoplasia is typically carried out using electrocautery tools which imply limited precision and the risk of harm through collateral thermal damage to the adjacent healthy tissue. As a potential alternative, we present the successful colonic epithelial laser ablation by means of picosecond laser pulses. Laser ablation studies performed in ex-vivo colon tissue result in cavities with comparable thickness to early stage colorectal cancers. The corresponding histology sections exhibit only minimal collateral damage to the surrounding tissue and the depth of the ablation can be controlled precisely by means of the pulse energy. High-speed imaging has been used for the first time to visualize picosecond laser ablation of cancerous tissue in a clinically relevant model. This information was correlated with histopathology and optical surface profilometry revealing the dynamic nature of the laser tissue interaction and the need for temporal or spatial separation of pulses for optimum efficacy with regards to tissue removal. Overall, the application of picosecond laser pulses to ablate endoluminal bowel lesions demonstrates significantly improved precision and reduced thermal damage to the adjacent tissue in comparison to conventional procedures and hence will enable more precise surgical treatment of cancers.

Ex vivo specimen MRI and pathology confirm a rectosigmoid mesenteric waist at the junction of the mesorectum and mesocolon.

AIM: Continuity of the mesentery has recently been established and may provide an anatomical basis for optimal colorectal resectional surgery. Preliminary data from operative specimen measurements suggest there is a tapering in the mesentery of the distal sigmoid. A mesenteric waist in this area may be a risk factor for local recurrence of colorectal cancer. This study aimed to investigate the anatomical characteristics of the mesentery at the colorectal junction. METHOD: In this cross-sectional study, 20 patients were recruited. After planned colorectal resection, the surgical specimens were scanned in a MRI system and subsequently dissected and photographed as per national pathology guidelines. Mesenteric surface area and linear measurements were compared between MRI and pathology to establish the presence and location of a mesenteric waist. RESULTS: Specimen analysis confirmed that a narrowing in the mesenteric surface area was consistently apparent at the rectosigmoid junction. Above the anterior peritoneal reflection, the surface area and posterior distance of the mesentery of the upper rectum initially decreased before increasing as the mesentery of the sigmoid colon. These anatomical properties created the appearance of a mesenteric 'waist' at the rectosigmoid junction. Using the anterior reflection as a reference landmark, the rectosigmoid waist occurred at a mean height of 23.6 and 21.7 mm on MRI and pathology, respectively. CONCLUSION: A rectosigmoid waist occurs at the junction of the mesorectum and mesocolon, and is a mesenteric landmark for the rectum that is present on both radiology and pathology.

Current concepts in imaging for local staging of advanced rectal cancer.

Imaging of rectal cancer has an increasingly pivotal role in the diagnosis, staging, and treatment stratification of patients with the disease. This is particularly true for advanced rectal cancers where magnetic resonance imaging (MRI) findings provide essential information that can change treatment. In this review we describe the rationale for the current imaging standards in advanced rectal cancer for both morphological and functional imaging on the baseline staging and reassessment studies. In addition the clinical implications and future methods by which radiologists may improve these are outlined relative to TNM8.

Radiologist and multidisciplinary team clinician opinions on the quality of MRI rectal cancer staging reports: how are we doing?

AIM: To evaluate the current opinion of magnetic resonance imaging (MRI) reports amongst specialist clinicians involved in colorectal cancer multidisciplinary teams (CRC MDTs). MATERIALS AND METHODS: Active participants at 16 UK CRC MDTs across a population of 5.7 million were invited to complete a questionnaire, this included 22 closed and three open questions. Closed questions used ordinal (Likert) scales to judge the subjective inclusion of tumour descriptors and impressions on the clarity and consistency of the MRI report. Open (free-text) questions allowed overall feedback and suggestions. RESULTS: A total of 69 participants completed the survey (21 radiologists and 48 other CRC MDT clinicians). Both groups highlighted that reports commonly omit the status of the circumferential resection margin (CRM; 83% versus 81% inclusion, other clinicians and radiologists, respectively, p>0.05), presence or absence of extra-mural venous invasion (EMVI; 67% versus 57% inclusion, p>0.05), and lymph node status (90% inclusion in both groups). Intra-radiologist agreement across MRI examinations is reported as 75% by other clinicians. Free-text comments included suggestions for template-style reports. CONCLUSION: Both groups recognise a proportion of MRI reports are suboptimal with key tumour descriptors omitted. There are also concerns around the presentation style of MRI reports and inter- and intra-radiologist report variability. The widespread implementation of standardised report templates may improve completeness and clarity of MRI reports for rectal cancer and thus clinical management and outcomes in rectal cancer.