Cutting Edge: CCR8 Signaling Regulates IL-25- and IL-33-Responsive Skin Group 2 Innate Lymphoid Cell Migration and Function.

Group 2 innate lymphoid cells (ILC2s) are sentinels of barrier immunity, and their activation by the epithelial alarmins IL-25 and IL-33 is a defining trait. In this study, we identified a role for the chemokine receptor CCR8 in modulating skin ILC2 abundance and activation. CCR8 signaling facilitated IL-25-induced increases in skin and lung ILC2s, ILC2 activation and systemic IL-13 production, and ligand-directed ILC2 entry into skin and lung. CCR8 controlled ILC2 tissue entry in IL-25-treated naive mice, but only transferred bone marrow ILC2 progenitors were equipped to enter the skin, whereas multiple tissue-sourced ILC2s entered the lung. CCR8 selectively regulated IL-33-induced increases in skin ILC2s, their proliferation, and production of IL-13/IL-5, as well as IL-33-responsive transferred ILC2 trafficking only to the skin. Collectively, we illuminate (to our knowledge) novel aspects of CCR8 signaling-regulated ILC2 motility and function, especially in the skin, in response to two hallmark ILC2-activating alarmins.

A Novel Allogeneic Rituximab-Conjugated Gamma Delta T Cell Therapy for the Treatment of Relapsed/Refractory B-Cell Lymphoma.

Chimeric antigen receptor T cell (CAR-T) therapy has been applied in the treatment of B-cell lymphoma; however, CAR-T manufacturing requires virus- or non-virus-based genetic modification, which causes high manufacturing costs and potential safety concerns. Antibody-cell conjugation (ACC) technology, which originated from bio-orthogonal click chemistry, provides an efficient approach for arming immune cells with cancer-targeting antibodies without genetic modification. Here, we applied ACC technology in Vγ9Vδ2 T (γδ2 T) cells to generate a novel off-the-shelf CD20-targeting cell therapy ACE1831 (rituximab-conjugated γδ2 T cells) against relapsed/refractory B-cell lymphoma. ACE1831 exhibited superior cytotoxicity against B-cell lymphoma cells and rituximab-resistant cells compared to γδ2 T cells without rituximab conjugation. The in vivo xenograft study demonstrated that ACE1831 treatment strongly suppressed the aggressive proliferation of B-cell lymphoma and prolonged the survival of tumor-bearing mice with no observed toxicity. Mass spectrometry analysis indicated that cell activation receptors including the TCR complex, integrins and cytokine receptors were conjugated with rituximab. Intriguingly, the antigen recognition of the ACC-linked antibody/receptor complex stimulated NFAT activation and contributed to ACE1831-mediated cytotoxicity against CD20-expressing cancer cells. This study elucidates the role of the ACC-linked antibody/receptor complex in cytotoxicity and supports the potential of ACE1831 as an off-the-shelf γδ2 cell therapy against relapsed/refractory B-cell lymphoma.

A phase II study of bevacizumab in non-squamous, non-small-cell lung cancer patients with malignant pleural effusion.

Aim: To investigate the efficacy, safety and optimal dosage of bevacizumab in non-squamous, non-small-cell lung cancer (NSCLC) patients with malignant pleural effusion (MPE). Methods: 20 patients were enrolled and received intrapleural injection of bevacizumab (group A: 2.5 mg/kg d1, d8; group B: 5 mg/kg d1, d8; group C: 7.5 mg/kg d1, d8). Results: The objective response rate (ORR) of MPE was 50%. The median progression-free survival (PFS) of MPE was 7.0 months (95% CI 4.9-9.2). The ORR and PFS of MPE from group B were better than those of group A and group C. The most common adverse events (AEs) were hypertension (15%) and anemia (15%). Conclusion: Bevacizumab has certain efficacy in non-squamous NSCLC patients with MPE. Clinical Trial Registration: NCT02942043 (ClinicalTrials.gov).

A Novel off-the-Shelf Trastuzumab-Armed NK Cell Therapy (ACE1702) Using Antibody-Cell-Conjugation Technology.

Natural killer (NK) cells harbor efficient cytotoxicity against tumor cells without causing life-threatening cytokine release syndrome (CRS) or graft-versus-host disease (GvHD). When compared to chimeric antigen receptor (CAR) technology, Antibody-Cell Conjugation (ACC) technology has been developed to provide an efficient platform to arm immune cells with cancer-targeting antibodies to recognize and attack cancer cells. Recently, we established an endogenous CD16-expressing oNK cell line (oNK) with a favorable expression pattern of NK activation/inhibitory receptors. In this study, we applied ACC platform to conjugate oNK with trastuzumab and an anti-human epidermal growth factor receptor 2 (HER2) antibody. Trastuzumab-conjugated oNK, ACE-oNK-HER2, executed in vitro and in vivo cytotoxicity against HER2-expressing cancer cells and showed enhanced T cell-recruiting capability and secretion of IFNγ. The irradiated and cryopreserved ACE-oNK-HER2, designated as ACE1702, retained superior HER2-specific in vitro and in vivo potency with no tumorigenic potential. In conclusion, this study provides the evidence to support the potential clinical application of ACE1702 as a novel off-the-shelf NK cell therapy against HER2-expressing solid tumors.

Clinical Application and Challenges of Telomere and Telomerase Research in Lung Cancer / 中国肺癌杂志

Lung cancer is one of the malignant tumors with high incidence rate and high mortality worldwide. Telomere and telomerase are closely related to the occurrence and development of lung cancer. Although telomerase may not be the direct cause of carcinogenesis, it plays a key role in maintaining telomere length and tumor growth. The length of most tumors, including lung cancer, is shortened. The change of telomere length is related to the risk of lung cancer, and may become the therapeutic target and predictive index. Target drugs for telomere and telomerase signaling pathway are constantly being explored, and drugs represented by telomerase inhibitors are expected to be used in clinical treatment of lung cancer in the future. However, the research on telomere and telomerase is far from enough. The bypass mechanism of telomere length maintenance may be the direction of further research.
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Research progress on the mechanism of resistance to MET inhibitors in non-small cell lung cancer and review of MET inhibitor resistance-related strategies / 中国肿瘤临床

The MET gene is an important tumor-driving gene for non-small cell lung cancer (NSCLC). Drugs targeting tumor with MET exon 14 skipping mutations bring new hope for patients. Although MET inhibitors such as tepotinib and savolitinib have shown good antitumor effects, resistance is inevitable. Studies on the hepatocyte growth factor (HGF)/mesenchymal- epithelial transition factor (MET) signaling pathway will not only help explore the mechanism underlying resistance to MET inhibitors, they may aid in the discovery of strategies for inhibiting and reversing drug resistance, thereby expanding the field of novel drug development. Preliminary studies have shown that the combination of HGF/MET inhibitors with other drugs may have great potential for clinical applications. This article reviews the characteristics of MET gene abnormalities, the mechanism of resistance against MET inhibitors, and the strategies for responding to resistance. Finally, the challenges posed by MET inhibitors is discussed and guidance on the direction of future development of MET inhibitors is proposed.

Analysis of the characteristics of second primary malignancy affecting the survival of lymphoma patients / 中华肿瘤杂志

Objective@#To analyze the characteristics of the second primary tumor affecting the survival of patients with lymphoma, and to explore the risk factors of death from the second primary tumor.@*Methods@#The medical records and related death information of 1 173 lymphoma patients who had already died with known causes were collected. The basic causes of death and the characteristics of patients who died of the second primary tumor were analyzed. Cox regression model was used to analyze the risk factors of lymphoma patients who died of the second primary tumor.@*Results@#Among the 1 173 patients who had died, 94 (8.0%) died of the second primary tumor, 935 (79.7%) died of the primary lymphoma and 144 (12.3%) died of other diseases. The second primary tumor accounted for 17.5% (38/217) of all causes of death in patients with the survival period of more than 5 years, and the second primary tumor accounted for 28.3% (17/60) of all causes of death in patients with the survival period of more than 10 years. Among 94 cases who died of second primary tumors, 31 died of lung cancer, 15 died of gastric cancer, 13 died of liver cancer, 9 died of pancreatic cancer, 6 died of colorectal cancer, 6 died of second primary lymphoma and 14 died of other types of tumors. Univariate Cox regression analysis showed that age, first-line treatment effect, and chest or mediastinal radiotherapy were associated with the death from second primary tumors for lymphoma patients (all P<0.05). Multivariate Cox regression analysis showed that the effect of first-line treatment (P=0.030) and the chest or mediastinal radiotherapy (P=0.039) were independent factors for the death of lymphoma patients from the second primary tumor.@*Conclusions@#The second primary tumor is an important factor affecting the survival of lymphoma patients, and the risk of death from second primary tumors increases significantly over time. The effect of first-line treatment and radiotherapy in the chest or mediastinum are independent factors for the death of lymphoma patients from the second primary tumor.

Long non-coding RNAs in liver diseases: Focusing on nonalcoholic fatty liver disease, alcohol-related liver disease, and cholestatic liver disease

Long non-coding RNAs (lncRNAs), a class of transcribed RNA molecules with the lengths exceeding 200 nucleotides, are not translated into protein. They can modulate protein-coding genes by controlling transcriptional and posttranscriptional processes. The dysregulation of lncRNAs has been related to various pathological disorders. In this review, we summarized the current knowledge of lncRNAs and their implications in the pathogenesis of three common liver diseases: nonalcoholic fatty liver disease, alcohol-related liver disease, and cholestatic liver disease. Future studies to further define the role of lncRNAs and their mechanisms in various types of liver diseases should be explored. An improved understanding from these studies will provide us a useful perspective leading to mechanism-based intervention by targeting specific lncRNAs for the treatment of liver diseases.

Progress on Mechanism of MET Gene Mutation and Targeted Drugs in Non-small Cell Lung Cancer / 中国肺癌杂志

Mesenchymal-epithelial transition factor (MET) gene is an important tumor driver gene of non-small cell lung cancer (NSCLC). Drugs targeting MET 14 exon skipping mutation bring new hope to patients. MET inhibitors that are currently on the market or are about to be marketed include: crizotinib, cabozantinib, savolitinib and tepotinib. The objective response rate of MET inhibitors is high, and the safety is good. However, resistance of MET-tyrosine kinase inhibitor (TKI) is inevitable, so it is necessary to pay attention to the study of drug resistance mechanism. In addition, the combined use of hepatocyte growth factor (HGF)/MET inhibitors and other drugs may play an important role in inhibiting and reversing drug resistance.

Corrigendum to: Nicorandil alleviated cardiac hypoxia/reoxygenation-induced cytotoxicity via upregulating ketone body metabolism and ACAT1 activity

The affiliation of the second author, Lei Sen Han, should be corrected.

Causes of death in 1,173 patients with lymphoma / 中国肿瘤临床

Objective: To understand the causes of death and long-term prognosis of lymphoma patients. Methods: Data from 6 200 patients with lymphoma admitted to the Department of Lymphoma, Peking University Cancer Hospital, from January 1995 to Decem-ber 2017, were collected. Those who had died and whose causes of death were known were selected. Clinical records and information on death were collected. Results: A total of 1,173 patients were selected, 742 of whom were male (63.3% ), and 431 were female (36.7%). The median age was 56 (8-92) years. There were 77 cases (6.6%) of Hodgkin's lymphoma, 1,095 cases (93.4%) of non-Hodg-kin's lymphoma, and 1 case of unclear pathological classification. Overall population survival was 0-253 months, with a median surviv-al rate of 20 months. The direct causes of death included lymphoma in 688 (58.7%), various infectious diseases in 119 (10.1%), cardio-vascular diseases in 96 (8.2%), secondary primary tumors in 68 (5.8%), and other diseases in 202 cases (17.2%). The underlying causes of death included lymphoma in 936 (79.8%), secondary primary tumors in 94 (8.0%), cardiovascular diseases in 75 (6.4%), respiratory diseases in 32 (2.7%) and other diseases in 36 cases (3.1%). The underlying causes of death in cases wherein survival time exceeded 5 years included lymphoma in 129 (59.4%), secondary primary tumors in 38 (17.5%), cardiovascular diseases in 35 (16.1%), and other dis-eases in 15 cases (6.9%). The underlying causes of death in cases wherein survival time exceeded 10 years included lymphoma in 28 (46.7%), secondary primary tumors in 17 (28.3%), cardiovascular diseases in 7 (11.7%), and other diseases in 8 cases (13.3%). Conclu-sions: Primary tumors remain the main cause of death in patients with lymphoma. After primary tumors, secondary primary tumors and cardiovascular diseases are the most common causes of death, and with the prolongation of survival, the risk of death caused by these factors increases significantly.

Causes of death in patients with lymphoma during long-term follow-up / 中国肿瘤临床

The prognosis of lymphoma patients is relatively good, and most patients may survive for a long time after standard treatment. Long-term follow-up of lymphoma survivors may reveal some late complications related to the treatment. Analysis of the causes of death is helpful in further improving the prognosis of lymphoma patients. The purpose of this article is to review the causes of death in patients with lymphoma during long-term follow-up to generate new ideas for follow-up and treatment of lymphoma patients.

Nicorandil alleviated cardiac hypoxia/reoxygenation-induced cytotoxicity via upregulating ketone body metabolism and ACAT1 activity

To study the effect of nicorandil pretreatment on ketone body metabolism and Acetyl-CoA acetyltransferase (ACAT1) activity in hypoxia/reoxygenation (H/R)-induced cardiomyocytes. In our study, we applied H9c2 cardiomyocytes cell line to evaluate the cardioprotective effects of nicorandil. We detected mitochondrial viability, cellular apoptosis, reactive oxygen species (ROS) production and calcium overloading in H9c2 cells that exposed to H/R-induced cytotoxicity. Then we evaluated whether nicorandil possibly regulated ketone body, mainly β-hydroxybutyrate (BHB) and acetoacetate (ACAC), metabolism by regulating ACAT1 and Succinyl-CoA:3-keto-acid coenzyme A transferase 1 (OXCT1) protein and gene expressions. Nicorandil protected H9c2 cardiomyocytes against H/R-induced cytotoxicity dose-dependently by mitochondria-mediated anti-apoptosis pathway. Nicorandil significantly decreased cellular apoptotic rate and enhanced the ratio of Bcl-2/Bax expressions. Further, nicorandil decreased the production of ROS and alleviated calcium overloading in H/R-induced H9c2 cells. In crucial, nicorandil upregulated ACAT1 and OXCT1 protein expressions and either of their gene expressions, contributing to increased production of cellular BHB and ACAC. Nicorandil alleviated cardiomyocytes H/R-induced cytotoxicity through upregulating ACAT1/OXCT1 activity and ketone body metabolism, which might be a potential mechanism for emerging study of nicorandil and other K(ATP) channel openers.

Declining free thyroxine levels over time in irradiated childhood brain tumor survivors.

OBJECTIVE: The incidence of cranial radiotherapy (cRT)-induced central hypothyroidism (TSHD) in childhood brain tumor survivors (CBTS) is reported to be low. However, TSHD may be more frequent than currently suspected, as its diagnosis is challenging due to broad reference ranges for free thyroxine (FT4) concentrations. TSHD is more likely to be present when FT4 levels progressively decline over time. Therefore, we determined the incidence and latency time of TSHD and changes of FT4 levels over time in irradiated CBTS. DESIGN: Nationwide, 10-year retrospective study of irradiated CBTS. METHODS: TSHD was defined as 'diagnosed' when FT4 concentrations were below the reference range with low, normal or mildly elevated thyrotropin levels, and as 'presumed' when FT4 declined ≥ 20% within the reference range. Longitudinal FT4 concentrations over time were determined in growth hormone deficient (GHD) CBTS with and without diagnosed TSHD from cRT to last follow-up (paired t-test). RESULTS: Of 207 included CBTS, the 5-year cumulative incidence of diagnosed TSHD was 20.3%, which occurred in 50% (25/50) of CBTS with GHD by 3.4 years (range, 0.9-9.7) after cRT. Presumed TSHD was present in 20 additional CBTS. The median FT4 decline in GH-deficient CBTS was 41.3% (P < 0.01) to diagnosis of TSHD and 12.4% (P = 0.02) in GH-deficient CBTS without diagnosed TSHD. CONCLUSIONS: FT4 concentrations in CBTS significantly decline over time after cRT, also in those not diagnosed with TSHD, suggesting that TSHD occurs more frequently and earlier than currently reported. The clinical relevance of cRT-induced FT4 decline over time should be investigated in future studies.

Analysis of non-tumor diseases affecting the diagnosis and treatment of cancer patients / 中国肿瘤临床

Objective:To investigate the types of non-tumor diseases in patients with cancer, and to explore the effects of those dis-eases on the diagnosis and treatment of cancer patients. Methods:We collected the medical records of cancer patients from January 2013 to December 2017 in Peking University Cancer Hospital, and screened for non-tumor diseases. The clinical records of the patients in this group were analyzed retrospectively, and the effects of those diseases on the diagnosis and treatment of tumors were dis-cussed. Results:Of the 1,323 cases of inter-hospital consultation, 1,153 cases of non-tumor disease (87.2％) were selected. There were 773 men (67.0％) and 380 women (33.0％) included. The median age was 62 (14-90) years. The primary tumor types included lung can-cer, gastric cancer, lymphoma, colorectal cancer, esophageal cancer, breast cancer, malignant melanoma, liver cancer, cholangiocarci-noma/gallbladder cancer, pancreatic cancer, and other tumors. Non-neoplastic diseases included cardiovascular disease in 356 cases (30.9％), respiratory system disease (17.0％) in 196 cases, digestive system disease in 107 cases (9.3％), skin and venereal diseases in 81 cases (7.0％), nervous system lesions (6.4％) in 74 cases, urinary system disease in 72 cases (6.2％), blood disease in 70 cases (6.1％), en-docrine and metabolic diseases in 47 cases (4.1％), autoimmune disease in 23 cases (2.0％), and other diseases (11.0％) in 127 cases. Impact on tumor diagnosis and treatment was as follows:direct, 771 cases (66.9％);no influence, 313 cases (27.1％);and uncertain, 69 cases (6.0％). Conclusions:Cardiovascular disease is a major non-tumor disease associated with cancer. Non-neoplastic diseases are important factors affecting the diagnosis and treatment plans of cancer.

Prevalence and Risk Factors of Early Endocrine Disorders in Childhood Brain Tumor Survivors: A Nationwide, Multicenter Study.

Purpose To evaluate the prevalence of, and risk factors for, early endocrine disorders in childhood brain tumor survivors (CBTS). Patients and Methods This nationwide study cohort consisted of 718 CBTS who were diagnosed between 2002 and 2012, and who survived ≥ 2 years after diagnosis. Patients with craniopharyngeoma or a pituitary gland tumor were excluded. Results of all endocrine investigations, which were performed at diagnosis and during follow-up, were collected from patient charts. Multivariable logistic regression was used to study associations between demographic and tumor- and treatment-related variables and the prevalence of early endocrine disorders. Results After a median follow-up of 6.6 years, 178 CBTS (24.8%) were diagnosed with an endocrine disorder. A total of 159 CBTS (22.1%) presented with at least one endocrine disorder within the first 5 years after diagnosis. The most common endocrine disorders were growth hormone deficiency (12.5%), precocious puberty (12.2%), thyroid-stimulating hormone deficiency (9.2%), and thyroidal hypothyroidism (5.8%). The risk of hypothalamic-pituitary dysfunction (n = 138) was associated with radiotherapy (odds ratio [OR], 15.74; 95% CI, 8.72 to 28.42), younger age at diagnosis (OR, 1.09; 95% CI, 1.04 to 1.14), advanced follow-up time (OR, 1.10; 95% CI, 1.02 to 1.18), hydrocephalus at diagnosis (OR, 1.77; 95% CI, 1.09 to 2.88), and suprasellar (OR, 34.18; 95% CI, 14.74 to 79.29) and infratentorial (OR, 2.65; 95% CI, 1.48 to 4.74) tumor site. Conclusion The prevalence of early endocrine disorders among CBTS is high. The observation that 22.1% of CBTS developed at least one endocrine disorder within the first 5 years after diagnosis stresses the importance of early and regular assessment of endocrine function in CBTS who are at risk for endocrine damage.

Internal Medicine residents use heuristics to estimate disease probability.

BACKGROUND: Training in Bayesian reasoning may have limited impact on accuracy of probability estimates. In this study, our goal was to explore whether residents previously exposed to Bayesian reasoning use heuristics rather than Bayesian reasoning to estimate disease probabilities. We predicted that if residents use heuristics then post-test probability estimates would be increased by non-discriminating clinical features or a high anchor for a target condition. METHOD: We randomized 55 Internal Medicine residents to different versions of four clinical vignettes and asked them to estimate probabilities of target conditions. We manipulated the clinical data for each vignette to be consistent with either 1) using a representative heuristic, by adding non-discriminating prototypical clinical features of the target condition, or 2) using anchoring with adjustment heuristic, by providing a high or low anchor for the target condition. RESULTS: When presented with additional non-discriminating data the odds of diagnosing the target condition were increased (odds ratio (OR) 2.83, 95% confidence interval [1.30, 6.15], p = 0.009). Similarly, the odds of diagnosing the target condition were increased when a high anchor preceded the vignette (OR 2.04, [1.09, 3.81], p = 0.025). CONCLUSIONS: Our findings suggest that despite previous exposure to the use of Bayesian reasoning, residents use heuristics, such as the representative heuristic and anchoring with adjustment, to estimate probabilities. Potential reasons for attribute substitution include the relative cognitive ease of heuristics vs. Bayesian reasoning or perhaps residents in their clinical practice use gist traces rather than precise probability estimates when diagnosing.

Right hemicolectomy and multivisceral resection of right colon cancer: A report of 21 cases / 华中科技大学学报（医学）（英德文版）

The long- and short-term outcomes in 21 patients with right colon cancer after right hemicolectomy and multivisceral resection surgery were investigated. Short-term therapeutic effects and long-term survival rate were retrospectively analyzed in patients with right colon cancer. These individuals underwent right hemicolectomy in combination with multivisceral resections including pancreatic head, duodenum, kidney, liver, gallbladder, and abdominal wall at the Department of General Surgery in the Henan Tumor Hospital between January 2003 and August 2014. The patients had an average age of 58.9 years (range: 39-78). Three patients had metastatic invasion only to the duodenum; meanwhile 18 patients had invasion to the duodenum and other adjacent organs. The median survival time was 41 months (95% CI: 6.972-75.028) with one death in the perioperative period. No patients lost follow-up. One-, 3-, and 5-year survival rate was 75%, 56%, and 43%, respectively. It was concluded that indications for surgery should be tightly controlled. Favorable clinical outcomes of right hemicolectomy and multivisceral resection surgery were demonstrated for patients with right colon cancer at the T4 stage.

Right hemicolectomy and multivisceral resection of right colon cancer: A report of 21 cases / 华中科技大学学报（医学）（英德文版）

The long- and short-term outcomes in 21 patients with right colon cancer after right hemicolectomy and multivisceral resection surgery were investigated. Short-term therapeutic effects and long-term survival rate were retrospectively analyzed in patients with right colon cancer. These individuals underwent right hemicolectomy in combination with multivisceral resections including pancreatic head, duodenum, kidney, liver, gallbladder, and abdominal wall at the Department of General Surgery in the Henan Tumor Hospital between January 2003 and August 2014. The patients had an average age of 58.9 years (range: 39-78). Three patients had metastatic invasion only to the duodenum; meanwhile 18 patients had invasion to the duodenum and other adjacent organs. The median survival time was 41 months (95% CI: 6.972-75.028) with one death in the perioperative period. No patients lost follow-up. One-, 3-, and 5-year survival rate was 75%, 56%, and 43%, respectively. It was concluded that indications for surgery should be tightly controlled. Favorable clinical outcomes of right hemicolectomy and multivisceral resection surgery were demonstrated for patients with right colon cancer at the T4 stage.

Estimation of post-test probabilities by residents: Bayesian reasoning versus heuristics?

Although the process of diagnosing invariably begins with a heuristic, we encourage our learners to support their diagnoses by analytical cognitive processes, such as Bayesian reasoning, in an attempt to mitigate the effects of heuristics on diagnosing. There are, however, limited data on the use ± impact of Bayesian reasoning on the accuracy of disease probability estimates. In this study our objective was to explore whether Internal Medicine residents use a Bayesian process to estimate disease probabilities by comparing their disease probability estimates to literature-derived Bayesian post-test probabilities. We gave 35 Internal Medicine residents four clinical vignettes in the form of a referral letter and asked them to estimate the post-test probability of the target condition in each case. We then compared these to literature-derived probabilities. For each vignette the estimated probability was significantly different from the literature-derived probability. For the two cases with low literature-derived probability our participants significantly overestimated the probability of these target conditions being the correct diagnosis, whereas for the two cases with high literature-derived probability the estimated probability was significantly lower than the calculated value. Our results suggest that residents generate inaccurate post-test probability estimates. Possible explanations for this include ineffective application of Bayesian reasoning, attribute substitution whereby a complex cognitive task is replaced by an easier one (e.g., a heuristic), or systematic rater bias, such as central tendency bias. Further studies are needed to identify the reasons for inaccuracy of disease probability estimates and to explore ways of improving accuracy.