High survivin expression as a risk factor in patients with anal carcinoma treated with concurrent chemoradiotherapy

Purpose: To investigate the prognostic value of survivin expression in pretreatment specimens from patients with anal cancer treated with concurrent 5-FU and mitomycin C-based chemoradiation (CRT). Material and methods: Immunohistochemical staining for survivin was performed in pretreatment biopsies of 62 patients with anal carcinoma. Survivin expression was correlated with clinical and histopathological characteristics as well as local failure free- (LFFS), distant metastases free- (DMFS), cancer specific- (CSS), and overall survival (OS). Results: Survivin staining intensity was weak in 10%, intermediate in 48% and intense in 42% of the patients. No association between survivin expression and clinicopathologic factors (tumor stage, age and HIV status) could be shown. In univariate analysis, the level of survivin staining was significantly correlated with DMFS (low survivin vs. high survivin: 94% vs. 74%, p=0.04). T-stage, N-stage and the tumor grading were significantly associated with OS and CSS and with DMFS and LFFS, respectively. In multivariate analysis, survivin was confirmed as independent prognostic parameter for DMFS (RR, 0.04; p=0.02) and for OS (RR, 0.27; p=0.04). Conclusion: Our results demonstrated that the level of pretreatment survivin is correlated with the clinical outcome in patients with anal carcinoma treated with concurrent CRT. Further studies are warranted to elucidate the complex role of survivin for the oncologic treatment and to exploit the protein as a therapeutic target in combined modality treatment of anal cancer

Feasibility of a 12-month-exercise intervention during and after radiation and chemotherapy in cancer patients: impact on quality of life, peak oxygen consumption, and body composition

Background Accumulating evidence suggests that exercise is effective in treating many of the acute and chronic side effects of anti-cancer therapy. A recent meta-analysis supported the use of exercise to prevent or treat fatigue and lymphoedema and to improve functional status in breast cancer patients. Patients and methods This trial was intended as a controlled, prospective feasibility study evaluating the impact of physical exercise (PE) in cancer patients during and after treatment with radio- and chemotherapy. Inclusion criteria were previous or ongoing treatment for cancer, motivation for PE of 0.5-1hour duration at least twice weekly for at least 3 months. Continuation of PE was encouraged thereafter. Every three months the following endpoints were assessed: Peak oxygen consumption as measured by supervised cardiopulmonary exercise test, body composition and quality of life. Results A total of 45 patients were included with a median age of 49 years. Forty were female and five male. Cancer types were: Breast cancer (n = 30/67 %), gastrointestinal cancer (n = 5/12 %), other types (n = 10/22 %). Thirty-eight (84 %) of the patients were included during curative treatment of their disease. Seven (16 %) were considered palliative. Adherence to the PE-programme longer than 6 months was noted for 41/45 (91 %) of the patients. Intensity of PE was thrice weekly in 32/45 (71 %), twice weekly in 11/45 (24 %). Two of 45 patients (5 %) had no PE. Mean peak oxygen consumption increased from 18.8 ± 5.6 ml/min/kg to 20.5 ± 3 ml/min/kg and 19.9 ± 4.7 ml/min/kg at 3 months (p = 0.005) and 12 months (p = 0.003), respectively. Median fat mass decreased from 30.7 ± 15 kg to 28.9 ± 15 kg and 29.5 ± 13 kg at 3 months (p = 0.001) and 12 months (p = 0.017), respectively. Global health status scores increased from a median baseline value of 54.9 ± 16.3 to 66.4 ± 14 % and 68.0 ± 20.3 % at 3 months (p = 0.001) and 12 months (p = 0.002), respectively. Conclusion This exercise programme in cancer patients with 2–3 weekly supervised sessions over three months was well feasible and demonstrated measurable improvement of oxygen consumption, body composition and quality of life. In addition, a 90 %-adherence rate to the PE-programme beyond 6 months was encouraging. Further randomized prospective data in a larger patient population will be collected comparing the impact of two versus four months supervision

CD8+ and Regulatory T cells Differentiate Tumor Immune Phenotypes and Predict Survival in Locally Advanced Head and Neck Cancer

Background: The tumor immune status “inflamed”, “immune excluded”, and “desert” might serve as a predictive parameter. We studied these three cancer immune phenotypes while using a simple immunohistochemical algorithm. Methods: Pre-treatment tissue samples of 280 patients with locally advanced HNSCC treated with radiochemotherapy were analyzed. A double staining of CD8+ cytotoxic T cells (CTL) and FoxP3+ (Treg) was performed and the cell density was evaluated in the intraepithelial and stromal compartment of the tumor. Results: The classification of tumors as “immune desert” when stromal CTL were ≤ 50 cells/mm2, “inflamed” when intraepithelial CTL were > 500 cells/mm2, and as “excluded” when neither of these definitions met these cut off values allowed the best discrimination regarding overall survival. These groups had median OS periods of 37, 61, and 85 months, respectively. In “immune desert” and “immune excluded” tumors high Treg tended to worsen OS, but in “inflamed” tumors high Treg clearly improved OS. Conclusions: We propose that, in locally advanced HNSCC, the tumor immune state “inflamed”, “immune excluded”, and “immune desert” can be defined by intraepithelial and stromal CTL. Tregs can further subdivide these groups. The opposing effects of Tregs in the different groups might be the reason for the inconsistency of Tregs prognostic values published earlier

Ex Vivo Apoptosis in CD8+ Lymphocytes Predicts Rectal Cancer Patient Outcome

Background. Apoptotic rates in peripheral blood lymphocytes can predict radiation induced normal tissue toxicity. We studied whether apoptosis in lymphocytes has a prognostic value for therapy outcome. Methods. Lymphocytes of 87 rectal cancer patients were ex vivo irradiated with 2 Gy, 8 Gy, or a combination of 2 Gy ionizing radiation and Oxaliplatin. Cells were stained with Annexin V and 7-Aminoactinomycin D and apoptotic and necrotic rates were analyzed by multicolor flow cytometry. Results. After treatment, apoptotic and necrotic rates in CD8+ cells are consistently higher than in CD4+ cells, with lower corresponding necrotic rates. Apoptotic and necrotic rates of CD4+ cells and CD8+ cells correlated well within the 2 Gy, 8 Gy, and 2 Gy and Oxaliplatin arrangements (p≤0.009). High apoptotic CD8+ rates after 2 Gy, 8 Gy, and 2 Gy + Oxaliplatin treatment were prognostically favorable for metastasis-free survival (p=0.009, p=0.038, and p=0.009) and disease-free survival (p=0.013, p=0.098, and p=0.013). Conclusions. Ex vivo CD8+ apoptotic rates are able to predict the patient outcome in regard to metastasis-free or disease-free survival. Patients with higher CD8+ apoptotic rates in the peripheral blood have a more favorable prognosis. In addition to the prediction of late-toxicity by utilization of CD4+ apoptotic rates, the therapy outcome can be predicted by CD8+ apoptotic rates

Deep learning for brain metastasis detection and segmentation in longitudinal MRI data

Brain metastases occur frequently in patients with metastatic cancer. Early and accurate detection of brain metastases is very essential for treatment planning and prognosis in radiation therapy. To improve brain metastasis detection performance with deep learning, a custom detection loss called volume-level sensitivity-specificity (VSS) is proposed, which rates individual metastasis detection sensitivity and specificity in (sub-)volume levels. As sensitivity and precision are always a trade-off in a metastasis level, either a high sensitivity or a high precision can be achieved by adjusting the weights in the VSS loss without decline in dice score coefficient for segmented metastases. To reduce metastasis-like structures being detected as false positive metastases, a temporal prior volume is proposed as an additional input of DeepMedic. The modified network is called DeepMedic+ for distinction. Our proposed VSS loss improves the sensitivity of brain metastasis detection for DeepMedic, increasing the sensitivity from 85.3% to 97.5%. Alternatively, it improves the precision from 69.1% to 98.7%. Comparing DeepMedic+ with DeepMedic with the same VSS loss, 44.4% of the false positive metastases are reduced in the high sensitivity model and the precision reaches 99.6% for the high specificity model. The mean dice coefficient for all metastases is about 0.81. With the ensemble of the high sensitivity and high specificity models, on average only 1.5 false positive metastases per patient needs further check, while the majority of true positive metastases are confirmed. The ensemble learning is able to distinguish high confidence true positive metastases from metastases candidates that require special expert review or further follow-up, being particularly well-fit to the requirements of expert support in real clinical practice.Comment: Implementation is available to public at https://github.com/YixingHuang/DeepMedicPlu

Benchmarking ChatGPT-4 on ACR Radiation Oncology In-Training (TXIT) Exam and Red Journal Gray Zone Cases: Potentials and Challenges for AI-Assisted Medical Education and Decision Making in Radiation Oncology

The potential of large language models in medicine for education and decision making purposes has been demonstrated as they achieve decent scores on medical exams such as the United States Medical Licensing Exam (USMLE) and the MedQA exam. In this work, we evaluate the performance of ChatGPT-4 in the specialized field of radiation oncology using the 38th American College of Radiology (ACR) radiation oncology in-training (TXIT) exam and the 2022 Red Journal gray zone cases. For the TXIT exam, ChatGPT-3.5 and ChatGPT-4 have achieved the scores of 63.65% and 74.57%, respectively, highlighting the advantage of the latest ChatGPT-4 model. Based on the TXIT exam, ChatGPT-4's strong and weak areas in radiation oncology are identified to some extent. Specifically, ChatGPT-4 demonstrates good knowledge of statistics, CNS & eye, pediatrics, biology, and physics but has limitations in bone & soft tissue and gynecology, as per the ACR knowledge domain. Regarding clinical care paths, ChatGPT-4 performs well in diagnosis, prognosis, and toxicity but lacks proficiency in topics related to brachytherapy and dosimetry, as well as in-depth questions from clinical trials. For the gray zone cases, ChatGPT-4 is able to suggest a personalized treatment approach to each case with high correctness and comprehensiveness. Most importantly, it provides novel treatment aspects for many cases, which are not suggested by any human experts. Both evaluations demonstrate the potential of ChatGPT-4 in medical education for the general public and cancer patients, as well as the potential to aid clinical decision-making, while acknowledging its limitations in certain domains. Because of the risk of hallucination, facts provided by ChatGPT always need to be verified

Non-professional phagocytosis: a general feature of normal tissue cells

Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells

Benchmarking ChatGPT-4 on a radiation oncology in-training exam and Red Journal Gray Zone cases: potentials and challenges for ai-assisted medical education and decision making in radiation oncology

PurposeThe potential of large language models in medicine for education and decision-making purposes has been demonstrated as they have achieved decent scores on medical exams such as the United States Medical Licensing Exam (USMLE) and the MedQA exam. This work aims to evaluate the performance of ChatGPT-4 in the specialized field of radiation oncology.MethodsThe 38th American College of Radiology (ACR) radiation oncology in-training (TXIT) exam and the 2022 Red Journal Gray Zone cases are used to benchmark the performance of ChatGPT-4. The TXIT exam contains 300 questions covering various topics of radiation oncology. The 2022 Gray Zone collection contains 15 complex clinical cases.ResultsFor the TXIT exam, ChatGPT-3.5 and ChatGPT-4 have achieved the scores of 62.05% and 78.77%, respectively, highlighting the advantage of the latest ChatGPT-4 model. Based on the TXIT exam, ChatGPT-4’s strong and weak areas in radiation oncology are identified to some extent. Specifically, ChatGPT-4 demonstrates better knowledge of statistics, CNS & eye, pediatrics, biology, and physics than knowledge of bone & soft tissue and gynecology, as per the ACR knowledge domain. Regarding clinical care paths, ChatGPT-4 performs better in diagnosis, prognosis, and toxicity than brachytherapy and dosimetry. It lacks proficiency in in-depth details of clinical trials. For the Gray Zone cases, ChatGPT-4 is able to suggest a personalized treatment approach to each case with high correctness and comprehensiveness. Importantly, it provides novel treatment aspects for many cases, which are not suggested by any human experts.ConclusionBoth evaluations demonstrate the potential of ChatGPT-4 in medical education for the general public and cancer patients, as well as the potential to aid clinical decision-making, while acknowledging its limitations in certain domains. Owing to the risk of hallucinations, it is essential to verify the content generated by models such as ChatGPT for accuracy

Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia

<p>Abstract</p> <p>Background</p> <p>Recent evidence suggests that CD4⁺CD25⁺FoxP3⁺regulatory T-cells (Treg) may be responsible for the failure of host anti-tumour immunity by suppressing cytotoxic T- cells. We assessed the prognostic significance of tumour infiltrating lymphocytes (TIL) in intestinal-type gastric cardiac cancer.</p> <p>Methods</p> <p>Tumour infiltrating lymphocyte (TIL) subsets and tumour infiltrating macrophages (TIM) were investigated in 52 cases using tissue microarrays. The interrelationship between the cell populations (CD3+, CD8+, CD20+, CD68+, GranzymeB+, FoxP3+) in different compartments and NED-survival was investigated (median follow-up time: 61 months).</p> <p>Results</p> <p>Intraepithelial infiltration with TIL and TIM including Treg was generally low and not related to NED-survival. However, patients with large numbers of FoxP3⁺Treg in the tumour stroma (>125.9 FoxP3⁺TILs/mm²) had a median survival time of 58 months while those with low FoxP3⁺TIL counts (<125.9 FoxP3⁺TILs/mm²) had a median survival time of 32 months (p = 0.006). Patients with high versus low stromal CD68⁺/FoxP3⁺cell ratios in primary tumour displayed median survivals of 32 and 55 months, respectively (p = 0.008).</p> <p>Conclusion</p> <p>Our results suggest that inflammatory processes within the tumour stroma of gastric intestinal-type adenocarcinomas located at the gastric cardia may affect outcome in two ways. Tumour-infiltrating macrophages are likely to promote carcinogenesis while large numbers of Treg are associated with improved outcome probably by inhibiting local inflammatory processes promoting carcinogenesis. Thus, inhibition of Treg may not be a feasible treatment option in gastric adenocarcinoma.</p