Development and validation of machine learning models to predict the need for haemostatic therapy in acute upper gastrointestinal bleeding.

Background: Acute upper gastrointestinal bleeding (AUGIB) is a major cause of morbidity and mortality. This presentation however is not universally high risk as only 20-30% of bleeds require urgent haemostatic therapy. Nevertheless, the current standard of care is for all patients admitted to an inpatient bed to undergo endoscopy within 24 h for risk stratification which is invasive, costly and difficult to achieve in routine clinical practice. Objectives: To develop novel non-endoscopic machine learning models for AUGIB to predict the need for haemostatic therapy by endoscopic, radiological or surgical intervention. Design: A retrospective cohort study. Method: We analysed data from patients admitted with AUGIB to hospitals from 2015 to 2020 (n = 970). Machine learning models were internally validated to predict the need for haemostatic therapy. The performance of the models was compared to the Glasgow-Blatchford score (GBS) using the area under receiver operating characteristic (AUROC) curves. Results: The random forest classifier [AUROC 0.84 (0.80-0.87)] had the best performance and was superior to the GBS [AUROC 0.75 (0.72-0.78), p < 0.001] in predicting the need for haemostatic therapy in patients with AUGIB. A GBS cut-off of ⩾12 was associated with an accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 0.74, 0.49, 0.81, 0.41 and 0.85, respectively. The Random Forrest model performed better with an accuracy, sensitivity, specificity, PPV and NPV of 0.82, 0.54, 0.90, 0.60 and 0.88, respectively. Conclusion: We developed and validated a machine learning algorithm with high accuracy and specificity in predicting the need for haemostatic therapy in AUGIB. This could be used to risk stratify high-risk patients to urgent endoscopy.

Derivation and validation of a novel risk score to predict need for haemostatic intervention in acute upper gastrointestinal bleeding (London Haemostat Score).

BACKGROUND: Acute upper gastrointestinal bleeding (AUGIB) is a common medical emergency, which takes up considerable healthcare resources. However, only approximately 20%-30% of bleeds require urgent haemostatic intervention. Current standard of care is for all patients admitted to hospital to undergo endoscopy within 24 hours for risk stratification, but this is difficult to achieve in practice, invasive and costly. AIM: To develop a novel non-endoscopic risk stratification tool for AUGIB to predict the need for haemostatic intervention by endoscopic, radiological or surgical treatments. We compared this with the Glasgow-Blatchford Score (GBS). DESIGN: Model development was carried out using a derivation (n=466) and prospectively collected validation cohort (n=404) of patients who were admitted with AUGIB to three large hospitals in London, UK (2015-2020). Univariable and multivariable logistic regression analysis was used to identify variables that were associated with increased or decreased chances of requiring haemostatic intervention. This model was converted into a risk scoring system, the London Haemostat Score (LHS). RESULTS: The LHS was more accurate at predicting need for haemostatic intervention than the GBS, in the derivation cohort (area under the receiver operating curve (AUROC) 0.82; 95% CI 0.78 to 0.86 vs 0.72; 95% CI 0.67 to 0.77; p<0.001) and validation cohort (AUROC 0.80; 95% CI 0.75 to 0.85 vs 0.72; 95% CI 0.67 to 0.78; p<0.001). At cut-off scores at which LHS and GBS identified patients who required haemostatic intervention with 98% sensitivity, the specificity of the LHS was 41% vs 18% with the GBS (p<0.001). This could translate to 32% of inpatient endoscopies for AUGIB being avoided at a cost of only a 0.5% false negative rate. CONCLUSIONS: The LHS is accurate at predicting the need for haemostatic intervention in AUGIB and could be used to identify a proportion of low-risk patients who can undergo delayed or outpatient endoscopy. Validation in other geographical settings is required before routine clinical use.

Does computer-aided diagnostic endoscopy improve the detection of commonly missed polyps? A meta-analysis.

BACKGROUND/AIMS: Colonoscopy is the gold standard diagnostic method for colorectal neoplasia, allowing detection and resection of adenomatous polyps; however, significant proportions of adenomas are missed. Computer-aided detection (CADe) systems in endoscopy are currently available to help identify lesions. Diminutive (≤5 mm) and nonpedunculated polyps are most commonly missed. This meta-analysis aimed to assess whether CADe systems can improve the real-time detection of these commonly missed lesions. METHODS: A comprehensive literature search was performed. Randomized controlled trials evaluating CADe systems categorized by morphology and lesion size were included. The mean number of polyps and adenomas per patient was derived. Independent proportions and their differences were calculated using DerSimonian and Laird random-effects modeling. RESULTS: Seven studies, including 2,595 CADe-assisted colonoscopies and 2,622 conventional colonoscopies, were analyzed. CADe-assisted colonoscopy demonstrated an 80% increase in the mean number of diminutive adenomas detected per patient compared with conventional colonoscopy (0.31 vs. 0.17; effect size, 0.13; 95% confidence interval [CI], 0.09-0.18); it also demonstrated a 91.7% increase in the mean number of nonpedunculated adenomas detected per patient (0.32 vs. 0.19; effect size, 0.05; 95% CI, 0.02-0.07). CONCLUSION: CADe-assisted endoscopy significantly improved the detection of most commonly missed adenomas. Although this method is a potentially exciting technology, limitations still apply to current data, prompting the need for further real-time studies.

Endoscopic submucosal dissection: an update on tools and accessories.

Endoscopic submucosal dissection (ESD) is a minimally invasive therapeutic procedure to remove larger polyps or early non-metastatic lesions. It has long been used in Asia, but is now fast growing in popularity in the West. There are multiple challenges faced by ESD practitioners. While the practice of ESD in gastric lesions is relatively well established, the oesophagus with its narrow lumen and challenging workspace, and the colon with its tortuous course and folds are more challenging frontiers. The nature of performing a procedure endoscopically means that conventional methods offer no mechanism for providing counter-traction while performing dissection, impeding visibility and increasing the rate of complications. There are a multitude of tools available to those performing ESD for the different stages of the procedure. This article reviews the accessories currently used in regular ESD practice including the knives used to cut and dissect lesions, the cap and hood devices used to improve visibility and safety, injection fluids to lift the submucosal plane, haemostatic devices, generators, and finally, emerging traction apparatus. There is some evidence behind the use of these tools, however, ESD remains the domain of a small number of practitioners and the practice relies heavily on expert experience. Evolution of the ESD toolbox will make the procedure more accessible to more endoscopists, which in turn will drive the development of a more substantial evidence base to evaluate efficacy and safety of the multitude of tools.

The evolution of lower gastrointestinal endoscopy: where are we now?

Lower gastrointestinal endoscopy has evolved over time, fulfilling a widening diagnostic and therapeutic remit. As our understanding of colorectal cancer and its prevention has improved, endoscopy has progressed with improved diagnostic technologies and advancing endoscopic therapies. Despite this, the fundamental design of the endoscope has remained similar since its inception. This review presents the important role lower gastrointestinal endoscopy serves in the prevention of colorectal cancer and the desirable characteristics of the endoscope that would enhance this. A brief history of the endoscope is presented. Current and future robotic endoscopic platforms, which may fulfil these desirable characteristics, are discussed. The incorporation of new technologies from allied scientific disciplines will help the endoscope fulfil its maximum potential in preventing the increasing global burden of colorectal cancer. There are a number of endoscopic platforms under development, which show significant promise.

Discharge of patients with an acute upper gastrointestinal bleed from the emergency department using an extended Glasgow-Blatchford Score.

OBJECTIVE: To use an extended Glasgow-Blatchford Score (GBS) cut-off of ≤1 to aid discharge of patients presenting with acute upper gastrointestinal bleeding (AUGIB) from emergency departments. BACKGROUND: The GBS accurately predicts the need for intervention and death in AUGIB, and a cut-off of 0 is recommended to identify patients for discharge without endoscopy. However, this cut-off is limited by identifying a low percentage of low-risk patients. Extension of the cut-off to ≤1 or ≤2 has been proposed to increase this proportion, but there is controversy as to the optimal cut-off and little data on performance in routine clinical practice. METHODS: Dual-centre study in which patients with AUGIB and GBS ≤1 were discharged from the emergency department without endoscopy unless there was another reason for admission. Retrospective analysis of associated adverse outcome defined as a 30-day combined endpoint of blood transfusion, intervention or death. RESULTS: 569 patients presented with AUGIB from 2015 to 2018. 146 (25.7%) had a GBS ≤1 (70, GBS=0; 76, GBS=1). Of these, 103 (70.5%) were managed as outpatients, and none had an adverse outcome. GBS ≤1 had a negative predictive value=100% and the GBS had an area under receiver operator characteristic​​ (AUROC)=0.89 (95% CI 0.86 to 0.91) in predicting adverse outcomes. In 2008-2009, prior to risk scoring (n=432), 6.5% of patients presenting with AUGIB were discharged safely from the emergency department in comparison with 18.1% (p<0.001) in this cohort. A GBS cut-off ≤2 was associated with an adverse outcome in 8% of cases. CONCLUSION: GBS of ≤1 is the optimal cut-off for the discharge of patients with an AUGIB from the emergency department.

Derivation and validation of a novel risk score for safe discharge after acute lower gastrointestinal bleeding: a modelling study.

BACKGROUND: Acute lower gastrointestinal bleeding is a common reason for emergency hospital admission, and identification of patients at low risk of harm, who are therefore suitable for outpatient investigation, is a clinical and research priority. We aimed to develop and externally validate a simple risk score to identify patients with lower gastrointestinal bleeding who could safely avoid hospital admission. METHODS: We undertook model development with data from the National Comparative Audit of Lower Gastrointestinal Bleeding from 143 hospitals in the UK in 2015. Multivariable logistic regression modelling was used to identify predictors of safe discharge, defined as the absence of rebleeding, blood transfusion, therapeutic intervention, 28 day readmission, or death. The model was converted into a simplified risk scoring system and was externally validated in 288 patients admitted with lower gastrointestinal bleeding (184 safely discharged) from two UK hospitals (Charing Cross Hospital, London, and Hammersmith Hospital, London) that had not contributed data to the development cohort. We calculated C statistics for the new model and did a comparative assessment with six previously developed risk scores. FINDINGS: Of 2336 prospectively identified admissions in the development cohort, 1599 (68%) were safely discharged. Age, sex, previous admission for lower gastrointestinal bleeding, rectal examination findings, heart rate, systolic blood pressure, and haemoglobin concentration strongly discriminated safe discharge in the development cohort (C statistic 0·84, 95% CI 0·82-0·86) and in the validation cohort (0·79, 0·73-0·84). Calibration plots showed the new risk score to have good calibration in the validation cohort. The score was better than the Rockall, Blatchford, Strate, BLEED, AIMS65, and NOBLADS scores in predicting safe discharge. A score of 8 or less predicts a 95% probability of safe discharge. INTERPRETATION: We developed and validated a novel clinical prediction model with good discriminative performance to identify patients with lower gastrointestinal bleeding who are suitable for safe outpatient management, which has important economic and resource implications. FUNDING: Bowel Disease Research Foundation and National Health Service Blood and Transplant.

Prediction of Outcome in Acute Lower Gastrointestinal Bleeding Using Gradient Boosting.

BACKGROUND: There are no widely used models in clinical care to predict outcome in acute lower gastro-intestinal bleeding (ALGIB). If available these could help triage patients at presentation to appropriate levels of care/intervention and improve medical resource utilisation. We aimed to apply a state-of-the-art machine learning classifier, gradient boosting (GB), to predict outcome in ALGIB using non-endoscopic measurements as predictors. METHODS: Non-endoscopic variables from patients with ALGIB attending the emergency departments of two teaching hospitals were analysed retrospectively for training/internal validation (n=170) and external validation (n=130) of the GB model. The performance of the GB algorithm in predicting recurrent bleeding, clinical intervention and severe bleeding was compared to a multiple logic regression (MLR) model and two published MLR-based prediction algorithms (BLEED and Strate prediction rule). RESULTS: The GB algorithm had the best negative predictive values for the chosen outcomes (>88%). On internal validation the accuracy of the GB algorithm for predicting recurrent bleeding, therapeutic intervention and severe bleeding were (88%, 88% and 78% respectively) and superior to the BLEED classification (64%, 68% and 63%), Strate prediction rule (78%, 78%, 67%) and conventional MLR (74%, 74% 62%). On external validation the accuracy was similar to conventional MLR for recurrent bleeding (88% vs. 83%) and therapeutic intervention (91% vs. 87%) but superior for severe bleeding (83% vs. 71%). CONCLUSION: The gradient boosting algorithm accurately predicts outcome in patients with acute lower gastrointestinal bleeding and outperforms multiple logistic regression based models. These may be useful for risk stratification of patients on presentation to the emergency department.

Fluorescence lifetime spectroscopy of tissue autofluorescence in normal and diseased colon measured ex vivo using a fiber-optic probe.

We present an ex vivo study of temporally and spectrally resolved autofluorescence in a total of 47 endoscopic excision biopsy/resection specimens from colon, using pulsed excitation laser sources operating at wavelengths of 375 nm and 435 nm. A paired analysis of normal and neoplastic (adenomatous polyp) tissue specimens obtained from the same patient yielded a significant difference in the mean spectrally averaged autofluorescence lifetime -570 ± 740 ps (p = 0.021, n = 12). We also investigated the fluorescence signature of non-neoplastic polyps (n = 6) and inflammatory bowel disease (n = 4) compared to normal tissue in a small number of specimens.

Expansion of anti-mesothelin specific CD4+ and CD8+ T cell responses in patients with pancreatic carcinoma.

We aimed to assess the status of naturally occurring CD4(+) and CD8(+) T cell responses to a tumour associated antigen, Mesothelin, in patients with pancreatic carcinoma and study the effects of elevated IL-10 on Mesothelin-specific T cell responses. For that sake, short term T cell lines were generated from PBMCs of 16 healthy controls, 15 patients with benign pancreatic diseases and 25 patients with pancreatic carcinoma and Mesothelin-specific CD4(+) and CD8(+) T cell responses were analysed using intracellular cytokine assays for IFN-γ. Plasma levels of IL-10 and Mesothelin were measured using cytometric bead array and ELISA assay, respectively. The blocking assays were performed to assess the effects of IL-10 on Mesothelin-specific T cell responses. Here, we demonstrate that the plasma levels of Mesothelin and IL-10 are significantly increased in patients with pancreatic carcinoma. Additionally, we found that (a) Mesothelin-specific T cell responses are significantly expanded in cancer patients (p = 0.0053), (b) the multifunctional CD4(+) T cell response is directed toward a broad repertoire of epitopes within the Mesothelin protein. (c) Mesothelin-specific CD4+ T cell response is directly inhibited by elevated IL-10 in cancer patients. These data provides evidence for the use of Mesothelin as an immunogen for tumour-specific T cell response.

R0 but not R1/R2 resection is associated with better survival than palliative photodynamic therapy in biliary tract cancer.

BACKGROUND: There is a need for better management strategies to improve the survival and quality of life in patients with biliary tract cancer (BTC). AIM: To assess prognostic factors for survival in a large, non-selective cohort of patients with BTC. METHOD: We compared outcomes in 321 patients with a final diagnosis of BTC (cholangiocarcinoma n = 237, gallbladder cancer n = 84) seen in a tertiary referral cancer centre between 1998 and 2007. Survival according to disease stage and treatment category was compared using log-rank testing. Cox's regression analysis was used to determine independent prognostic factors. RESULTS: Eighty-nine (28%) patients underwent a surgical intervention with curative intent, of whom 38% had R0 resections. Among the 321 patients, 34% were given chemo- and/or radiotherapy, 14% were palliated with photodynamic therapy (PDT) and 37% with biliary drainage procedures alone. The overall median survival was 9 months (3-year survival, 14%). R0-resective surgery conferred the most favourable outcome (3-year survival, 57%). Although patients palliated with PDT had more advanced clinical T-stages, their survival was similar to those treated with attempted curative surgery but who had positive resection margins. On multivariable analysis, treatment modality, serum carbohydrate-associated antigen 19-9, distant metastases and vascular involvement were independent prognostic indicators of survival. CONCLUSION: In this large UK series of BTC, palliative PDT resulted in survival similar to those with curatively intended R1/R2 resections. Surgery conferred a survival advantage only in patients with R0 resection margins, emphasising the need for accurate pre-operative staging.

Analysis of risk scoring for the outpatient management of acute upper gastrointestinal bleeding.

OBJECTIVE: To determine whether the Glasgow-Blatchford bleeding score (GBS) or pre-endoscopy Rockall score was better at accurately identifying patients with acute upper gastrointestinal bleeding (AUGIB) who were at low risk of the need for clinical intervention and death and therefore suitable for outpatient management. DESIGN: Retrospective database and case note review of all patients admitted to the emergency departments with AUGIB from 1 January 2008 to 31 December 2009. SETTING: Two tertiary centre teaching hospitals. PATIENTS: 432 patients met the inclusion criteria. INTERVENTION: None. MAIN OUTCOME MEASURE: Clinical interventions (blood transfusion, endoscopic therapy and surgery) and death. RESULTS: Of 432 patients, 40 (9.3%) had a GBS of 0 and none required intervention or died. In contrast, 13/104 patients (12.5%) who had a pre-endoscopy Rockall score of 0 and 23/125 patients (18.4%) who had a complete Rockall score <3, required clinical intervention. The performance of the scores at these cut-offs were: GBS (sensitivity 100%, specificity 16.1%, positive predictive value (PPV) 37.8%, negative predictive value (NPV) 100%, accuracy 82.3%), pre-endoscopy Rockall (sensitivity 91.2%, specificity 32.0%, PPV 41.2%, NPV 87.5%, accuracy 70.9%) and complete Rockall (sensitivity 84.5%, specificity 50.7%, PPV 55.8%, NPV 81.6%, accuracy 76.2%). For prediction of the need for intervention or death, the accuracy of the GBS (0.82; 95% CI 0.78 to 0.86) was superior to the pre-endoscopy Rockall score (0.71; 95% CI 0.67 to 0.76). CONCLUSION: The GBS but not the pre-endoscopy Rockall score identifies patients with upper gastrointestinal bleeding who may be suitable for outpatient management, therefore potentially allowing for more efficient use of hospital resources.

Human CD4(+) T cells recognize an epitope within alpha-fetoprotein sequence and develop into TGF-beta-producing CD4(+) T cells.

There is limited information on the influence of tumor growth on the expansion of tumor-specific TGF-beta-producing CD4(+) T cells in humans. alpha-Fetoprotein (AFP) is an oncofetal Ag and has intrinsic immunoregulatory properties. In this study, we report the identification and characterization of subsets of CD4(+) T cells that recognize an epitope within the AFP sequence (AFP(46-55)) and develop into TGF-beta-producing CD4(+) T cells. In a peptide-specific and dose-dependent manner, AFP(46-55) CD4(+) T cells produce TGF-beta, GM-CSF, and IL-2 but not Th1-, Th2-, Th17-, or Tr1-type cytokines. These cells express CTLA-4 and glucocorticoid-induced TNR receptor and inhibit T cell proliferation in a contact-dependent manner. In this study, we show that the frequency of AFP(46-55) CD4(+) T cells is significantly higher (p = 001) in patients with hepatocellular carcinoma than in healthy donors, suggesting that these cells are expanded in response to tumor Ag. In contrast, tumor necrosis-inducing treatments that are shown to improve survival rate can shift the Th1/TGF-beta-producing CD4(+) T cell balance in favor of Th1 responses. Our data demonstrate that tumor Ags may contain epitopes which activate the expansion of inducible regulatory T cells, leading to evasion of tumor control.

Complications and diagnostic difficulties arising from biliary self-expanding metal stent insertion before definitive histological diagnosis.

BACKGROUND: Self-expanding metal bile duct stents provide good palliation for inoperable malignant disease. However, problems may arise if metal stents are inserted before definitive histological diagnosis. The aim of this study was to evaluate the outcome of such patients. METHODS: A retrospective case note review was conducted of patients referred to a tertiary pancreaticobiliary center between 1992 and 2004 in whom a metal bile duct stent was inserted for presumed unresectable malignant disease before definitive histological diagnosis. RESULTS: There were 21 patients identified. Final diagnoses were: group 1, benign disease (n = 3); group 2, resectable malignancy (n = 2); group 3, unresectable malignancy (n = 12); and group 4, diagnosis remains uncertain (n = 4). During a follow-up of 22, 38 and 111 months, the patients in group 1 had one, eight and five episodes of stent occlusion. In group 2, both patients underwent pancreaticoduodenectomy for ampullary carcinoma, 2 and 6 months after presentation. In group 3, the median time to a confirmed malignant diagnosis was 2 months (range 1-27 months). In group 4, a median of two biopsies (range 1-4) were negative for malignancy, during a median follow up of 13 months (range 3-46). Overall in eight patients, the metal stents caused artifacts on computed tomography and/or were associated with tissue in-growth making the differentiation between benign and malignant disease difficult. CONCLUSION: These cases indicate that metal bile duct stent insertion before definitive histological diagnosis can be problematic. A proportion of cases will have benign strictures and in others the confirmation of malignancy may be made more difficult.

Photodynamic therapy of malignant biliary strictures using meso-tetrahydroxyphenylchlorin.

OBJECTIVES: The palliation of patients with malignant bile duct obstruction using metal or plastic biliary stents may be limited by stent occlusion. The aim of this study was to determine the safety and efficacy of endoscopically delivered meso-tetrahydroxyphenyl chlorin photodynamic therapy in the treatment of irresectable malignant biliary strictures and recurrent stent occlusion. METHODS: Thirteen patients with malignant biliary obstruction owing to carcinoma of the biliary tract (n=9), pancreas (n=3) or stomach (n=1), were studied. All had been initially palliated with metal (n=10) or polyethylene (n=3) biliary stents, but presented with recurrent obstructive jaundice because of local tumour progression. Patients received meso-tetrahydroxyphenyl chlorin 0.15 mg/kg intravenously 72 h before endoluminal light activation with an endoscopically placed optical fibre, followed by polyethylene stent insertion. RESULTS: Before photodynamic therapy, patients had a median of three (range 0-5) stent occlusions in the preceding 11 (2-22) months, with a median patency of plastic stents placed inside metal bile duct stents for recurrent stent occlusion of 3.5 (0.5-13) months. After photodynamic treatment, tumour necrosis and/or metal stent recanalization was seen in all patients, with a median of 0 (0-3) stent occlusions during 7 (1-43) months follow-up. The median patency of plastic stents placed inside metal stents after photodynamic therapy was 5 (1-43) months. The median survival after diagnosis and photodynamic therapy administration was 21 (10-56) and 8 (1-43) months, respectively. Photodynamic therapy was generally well tolerated but two patients developed cholangitis within the first week, complicated in one by a fatal liver abscess and two developed haemobilia within 4 weeks of treatment, one of whom died with a gall bladder empyema. CONCLUSION: In patients with malignant biliary obstruction, endoscopically delivered meso-tetrahydroxyphenyl chlorin photodynamic therapy causes efficient tumour necrosis and recanalization of blocked metal stents, but there is a significant risk of complications.

Photodynamic therapy using verteporfin photosensitization in the pancreas and surrounding tissues in the Syrian golden hamster.

BACKGROUND/AIM: Photodynamic therapy (PDT) is a potential treatment for locally advanced pancreatic cancer. We aimed to assess the safety of interstitial PDT using verteporfin (benzoporphyrin derivative monoacid A - a novel photosensitizer with a short drug-light interval and limited cutaneous photosensitivity) in the Syrian golden hamster, and compare it to meso-tetrahydroxyphenylchlorin (mTHPC) which we have previously evaluated in preclinical and clinical studies. METHODS: Verteporfin (2 mg/kg) was administered at laparotomy by inferior vena caval injection (n = 57), with plasma levels quantified at 5, 15, 30, 60 and 240 min, and 24 h. 15 min after photosensitization, tissues (liver, pancreas, duodenum, colon, aorta) were illuminated with 690 nm red laser light (150 mW), at a range of light doses (1-100 J/cm(2)). The PDT effects on the targeted organ and adjacent structures were assessed at post-mortem on days 3 and 21, or at the time of death. RESULTS: The elimination half-life of verteporfin was 4-5 h. Light doses of 10, 25 and 50 J/cm(2) were safe in the hamster pancreas, liver and colon, respectively, and produced coagulative necrotic lesions of 3 (range 3-4), 10 (9-10) and 7 (7-8) mm diameter. Collagen was resistant to damage and lesions healed mainly by regeneration of normal tissue. At higher light doses, necrosis extended to the edge of organs, sometimes causing sealed duodenal perforations as seen with mTHPC. CONCLUSION: The safety profile of verteporfin is very similar to mTHPC, with the advantages of a shorter drug-light interval and drug elimination time. Phase I clinical studies using this photosensitizer in pancreatic cancer should be feasible.

Unmasking of alpha-fetoprotein-specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization.

Necrosis of tumor cells can activate both innate and adaptive antitumor immunity. However, there is little information on the effects of necrosis-inducing cancer treatments on tumor-specific T cell immune responses in humans. We studied the effects of a necrosis-inducing treatment (embolization) on anti-alpha-fetoprotein (AFP)-specific CD4(+) T cell responses in hepatocellular carcinoma (HCC) patients and controls using an array of AFP-derived peptides. In this study, we show that AFP-specific CD4(+) T cell responses to three immunodominant epitopes in HCC patients were significantly expanded during (p < 0.0001) and after embolization (p < 0.002). The development of higher frequencies of AFP-specific CD4(+) T cells after treatment were significantly associated with the induction of >50% necrosis of tumor and an improved clinical outcome (p < 0.007). In addition, we identified two novel HLA-DR-restricted AFP-derived CD4(+) T cell epitopes (AFP(137-145) and AFP(249-258)) and showed that the CD4(+) T cells recognizing these epitopes produce Th1 (IFN-gamma and TNF-alpha) but not Th2 (IL-5)-type cytokines. AFP(137-145)-, AFP(249-258)-, and AFP(364-373)-specific CD4(+) T cells were detected in HCC patients but not in patients with chronic liver diseases or healthy donors. In conclusion; our study shows that induction of tumor necrosis by a conventional cancer treatment can unmask tumor rejection Ag cell-mediated immunity and provides a rationale for combining embolization with immunotherapy in HCC patients.

Photodynamic therapy for pancreatic and biliary tract carcinoma.

The prognosis of patients with pancreatic and biliary tract cancer treated with conventional therapies such as stent insertion or chemotherapy is often poor, and new approaches are urgently needed. Surgery is the only curative treatment but is appropriate in less than 20% of cases, and even then it is associated with a 5-yr survival of less than 30% in selected series. Photodynamic therapy represents a novel treatment for pancreaticobiliary malignancy. It is a way of producing localized tissue necrosis with light, most conveniently from a low-power, red laser, after prior administration of a photosensitizing agent, thereby initiating a non-thermal cytotoxic effect and tissue necrosis. This review outlines the mechanisms of action of photodynamic therapy including direct cell death, vascular injury, and immune system activation, and summarizes the results of preclinical and clinical studies of photodynamic therapy for pancreaticobiliary malignancy.

Photodynamic therapy for pancreatic carcinoma: experimental and clinical studies.

Pancreatic carcinoma is the sixth leading cause of cancer-related mortality in the United Kingdom, with an overall 5-year survival of less than 5%. Attempted curative surgery is possible in less than 20% of cases and is associated with a 5-year survival of just 10-20%. Palliative radio-chemotherapy improves symptoms of pancreatic cancer but rarely extends median survival beyond 12 months. There is a need to develop novel therapies that improve outcome. Photodynamic therapy, which is a way of producing localised non-thermal tissue necrosis with light, is currently under evaluation as a treatment for pancreatic cancer. This review will examine some of the mechanisms underlying photodynamic therapy, and the preclinical work, which has led to this treatment being piloted in human studies.