Validity of the diagnostic criteria from the Asian Working Group for Cachexia in advanced cancer.

BACKGROUND: Recently, the Asian Working Group for Cachexia (AWGC) published a consensus statement on diagnostic criteria for cachexia in Asians. We aimed to validate the criteria in adult patients in Japan with advanced cancer. METHODS: We conducted a single-institution retrospective cohort study between April 2021 and October 2022. The AWGC criteria include chronic comorbidities and either a weight loss of >2% over 3-6 months or a body mass index (BMI) of <21 kg/m2 . In addition, any of the following items were required: anorexia as a subjective symptom, decreased grip strength as an objective measurement and an elevated C-reactive protein (CRP) level as a biomarker. We used the cut-off value of grip strength of 28/18 kg for male/female individuals and CRP level of 5 mg/L. RESULTS: Of the 449 consecutive patients, 85 of those who could not be evaluated because of end-of-life or refractory symptoms (n = 41) or missing data (n = 44) were excluded from the primary analysis. The prevalence of the AWGC-defined cachexia was 76% (n = 277), and the median survival time (MST) for all patients was 215 (95% confidence interval [CI] 145-270) days. The prevalence of the following criteria was significantly higher in patients with cachexia than in those without cachexia: a BMI of <21 kg/m2 (65% vs. 15%, P < 0.001), a weight loss of >2% in 6 months (87% vs. 14%, P < 0.001), anorexia (75% vs. 47%, P < 0.001), a grip strength of <28 kg in male individuals (63% vs. 28%, P < 0.001) and CRP level of >5 mg/L (85% vs. 56%, P < 0.001). Overall survival was significantly shorter in patients with cachexia than in those without cachexia (MST 157 days, 95% CI 108-226 days vs. MST 423 days, 95% CI 245 days to not available, P = 0.0023). The Cox proportional hazards analysis showed that best supportive care (hazard ratio [HR] 2.91, P ≤ 0.001), lung cancer (HR 1.67, P = 0.0046), an Eastern Cooperative Oncology Group Performance Status score of ≥3 (HR 1.58, P = 0.016), AWGC-defined cachexia (HR 1.56, P = 0.015), an age of ≥70 years (HR 1.53, P = 0.0070), oedema (HR 1.31, P = 0.022) and head/neck cancer (HR 0.44, P = 0.023) were found to be the significant predictors for mortality. CONCLUSIONS: We demonstrated that AWGC-defined cachexia has a significant prognostic value in advanced cancer.

Factors associated with early discontinuation of anamorelin in patients with cancer-associated cachexia.

PURPOSE: Cancer-associated cachexia, a multifactorial syndrome involving loss of muscle mass and anorexia, is an unremitting problem for cancer patients. Anamorelin has become available for cancer-associated cachexia, but early discontinuation is common in clinical practice. This study aimed to explore factors related to the early discontinuation of anamorelin and its relationship to survival. PATIENTS AND METHODS: This prospective, observational study of multimodal clinical practice involved patients who took anamorelin (100 mg) for cancer-associated cachexia at Aichi Medical University Hospital between 14 May 2021 and 31 March 2022. In July 2022, clinical data were extracted from electronic clinical records. Patients who discontinued anamorelin less than 4 weeks after initiation were defined as the early discontinuation group, and their clinical data and survival time were compared with those of the continuation group. This study was approved by the Ethics Committee of the university (approval no. 2021-124). RESULTS: Of the 42 patients treated with anamorelin, 40 (median age 72.5 years, median BMI 18.7 kg/m2) were analyzed, including 13 with non-small cell lung cancer, and 12 with pancreatic, 8 with colorectal, and 7 with gastric cancers. On univariate analysis, the early discontinuation group included more patients with worse performance status (PS) (p=0.028), low prognostic nutritional index (PNI) (p=0.001), and no concomitant anticancer drugs (p=0.003). On multivariate analysis, PS and PNI were related to anamorelin continuation. Survival time was significantly shorter in the early discontinuation group (p=0.039). CONCLUSION: Worse PS and low PNI were associated with early discontinuation of anamorelin. Longer survival time was observed in the continuation group.

Nutrition provided during the final weeks to patients with non-gastrointestinal solid malignancies.

BACKGROUND & AIMS: Data regarding the delivery of nutrition and nutritional infusions to patients with terminal cancer remain limited; therefore, this real-world analysis investigated differences in nutrition delivery and infusion statuses for patients with terminal-stage cancers. METHODS: Patients who had died following hospitalization for more than seven days due to neoplasms between April 2014 and December 2018 were identified using the medical claims database of Japan. Data regarding oral diets, enteral feeding, infusion volumes, and infusion energies were extracted. The maximum observation period was 28 days prior to patient death. RESULTS: A total of 12,908 patients were included in our analysis. The proportion of patients without dietary or enteral nutrition increased closer to their dates of death. Observations were recorded at 28 (18.9%), 21 (20.9%), 14 (24.6%), 7 (33.0%), and 0 (80.2%) days prior to death. The infusion volumes given to the patients, as well as their energy contents, decreased near death (P-value for the trend <0.001). CONCLUSIONS: Our study revealed the current status of nutritional therapy for patients with terminal cancer in Japan. The number of patients receiving only parenteral nutrition increased near death, while the amount of nutritional intake was low.

Regulation of 4-HNE via SMARCA4 Is Associated with Worse Clinical Outcomes in Hepatocellular Carcinoma.

Accumulation of 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation, has various favorable and unfavorable effects on cancer cells; however, the clinicopathological significance of its accumulation in hepatocellular carcinoma (HCC) and its metabolic pathway remain unknown. This study analyzed 4-HNE accumulation and its clinicopathological significance in HCC. Of the 221 cases, 160 showed relatively low accumulation of 4-HNE in HCC tissues, which was an independent prognostic predictor. No correlation was found between 4-HNE accumulation and the expression of the antioxidant enzymes glutathione peroxidase 4, ferroptosis suppressor protein 1, and guanosine triphosphate cyclohydrolase 1. Therefore, we hypothesized that 4-HNE metabolism is up-regulated in HCC. A database search was focused on the transcriptional regulation of aldo-keto reductases, alcohol dehydrogenases, and glutathione-S-transferases, which are the metabolic enzymes of 4-HNE, and seven candidate transcription factor genes were selected. Among the candidate genes, the knockdown of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) increased 4-HNE accumulation. Immunohistochemical analysis revealed an inverse correlation between 4-HNE accumulation and SMARCA4 expression. These results suggest that SMARCA4 regulates 4-HNE metabolism in HCC. Therefore, targeting SMARCA4 provides a basis for a new therapeutic strategy for HCC via 4-HNE accumulation and increased cytotoxicity.

Successful in Vitro Fertilization Pregnancy and Delivery by an Infertile Woman with Ovotesticular Disorder of Sex Development: A Case Report.

On the basis of postoperative histopathological findings, a 29-year-old nulliparous woman was diagnosed as having ovotesticular disorder of sex development (DSD). She had undergone unilateral gonadectomy at age 6 years and vulvoplasty and vaginoplasty at age 8 years. Her karyotype was 46, XX. She had dyspareunia because of a narrow vagina, but her uterus and left gonad were normal. Spontaneous ovulation was confirmed, but sexual intercourse was impossible because of dyspareunia, despite vaginal self-dilatation with a vaginal dilator. Artificial insemination was initiated; however, five cycles failed to yield a viable pregnancy. We decided to perform in vitro fertilization (IVF), which resulted in conception. During IVF we administered intravenous anesthesia before oocyte collection to reduce her distress due to insufficient lumen expansion after vaginoplasty. The patient delivered a healthy male infant weighing 2,558 g at 37 weeks of gestation via cesarean section, which was performed because of gestational hypertension. This is the eighth report of a viable neonate born from a patient with ovotesticular DSD after gonadectomy and the first such pregnancy achieved by IVF. Therefore, IVF may be an effective option for infertile patients with ovotesticular DSD. Additionally, to prevent dyspareunia, self-management of the plastic vagina is important during the peri- and postoperative periods of early vaginoplasty.

High SARC-F score predicts poor survival of patients with cancer receiving palliative care.

PURPOSE: A high score determined by SARC-F, a simple screening questionnaire for sarcopenia, has been reportedly associated with worse medical outcomes. However, information regarding whether high SARC-F scores are associated with a poor prognosis in patients with advanced cancer remains limited. We clarified whether a SARC-F score ≥ 4 predicts poor prognosis in patients with cancer receiving palliative care. METHODS: We conducted a retrospective cohort study of patients with cancer who received palliative care at a university hospital between May 2019 and April 2020. Patient characteristics including age, sex, height, weight, cancer type, serum albumin level, C-reactive protein level, presence of edema, Eastern Cooperative Oncology Group-Performance Status (ECOG-PS), SARC-F score, history of anticancer therapy, and clinical outcomes were collected from electronic medical records. RESULTS: Of 304 patients, 188 had a SARC-F score < 4, and 116 patients had a SARC-F score ≥ 4. The overall survival of patients with a SARC-F score ≥ 4 was 40 days (95% CI 29-47), which was significantly worse than 121 days (95% CI 95-156) for patients with a SARC-F score < 4 (p < 0.001). SARC-F score ≥ 4 (hazard ratio: HR 1.56), edema (HR 1.94), head and neck cancer (HR 0.51), C-reactive protein (HR 1.05), ECOG-PS ≥ 3 (HR 1.47), and radiotherapy (HR 0.52) were associated with overall survival. The ability to climb stairs was a SARC-F sub-item significantly associated with mortality (HR 1.59). CONCLUSION: The SARC-F questionnaire is a useful predictor of prognosis for patients with cancer receiving palliative care because a SARC-F ≥ 4 score predicts worse overall survival.

Evaluation of skeletal muscle mass using prediction formulas at the level of the 12th thoracic vertebra.

OBJECTIVES: People with cancer have a high risk of cachexia and sarcopenia, which are associated with worse clinical outcomes. We evaluated the prediction accuracy of the Matsuyama et al. and Ishida et al. formulas using computed tomography (CT) slices from the twelfth thoracic vertebra (Th12) level in people with cancer. METHODS: This retrospective study included patients with advanced cancer who underwent thoracic and abdominal CT scans (n = 173). The cross-sectional area (CSA) on CT images was measured at the levels of Th12 and the third lumbar vertebra (L3). The Matsuyama et al. formula used the Th12 CSA, whereas the Ishida et al. formula used only the Th12 CSA of the spinal erectors; thus, the measurements were performed separately. The correlation between predicted and actual L3 CSA was assessed using r and the intraclass correlation coefficient. A prediction-accuracy analysis of the predicted values was also performed. RESULTS: The mean participant age was 66.2 ± 12.8 y; 50.3% of participants were women and 49.7% were men. Strong correlations were observed between the predicted and measured L3 values calculated from the two prediction formulas. The prediction-accuracy analysis using previously reported cutoff values showed that the Ishida et al. method had high sensitivity and the Matsuyama et al. method had high specificity for low skeletal muscle index determined by the predicted and measured L3 skeletal muscle index. CONCLUSIONS: Both the Matsuyama et al. and Ishida et al. formulas had good reliability on CT slices at the Th12 level in people with advanced cancer, indicating that these formulas can be applied in clinical practice.

Addendum: Ishida et al. Formula for the Cross-Sectional Area of the Muscles of the Third Lumbar Vertebra Level from the Twelfth Thoracic Vertebra Level Slice on Computed Tomography. Geriatrics 2020, 5, 47.

The authors would like to make an addendum to their published paper [...].

Assessing skeletal muscle mass based on the cross-sectional area of muscles at the 12th thoracic vertebra level on computed tomography in patients with oral squamous cell carcinoma.

OBJECTIVES: This study aimed to create a formula to estimate the third lumbar vertebra (L3)1 level skeletal muscle cross-sectional area (CSA), known as a standard value to evaluate skeletal muscle mass on computed tomography (CT), using the twelfth thoracic vertebra (Th12) level skeletal muscle CSA on chest CT. MATERIALS AND METHODS: This retrospective observational study included patients aged 40 + years with a diagnosis of oral squamous cell carcinoma (n = 164). Skeletal muscle CSA on CT images was measured using the Th12 and the L3 levels of pretreatment CT scans. The predictive formula was created based on the five-fold cross-validation method with a linear regression model. Correlations between the predicted L3-level CSA and the actual L3-level CSA were evaluated using r and Intraclass Correlation Coefficients (ICC). RESULTS: The predictive formula for L3-level CSA from Th12-level CSA was: CSA at L3 (cm2) = 14.143 + 0.779 * CSA at Th12 (cm2) - 0.212 * Age (y) + 0.502 * Weight (kg) + 13.763 * Sex. Correlations between the predicted and measured L3-level CSA were r = 0.915 [0.886-0.937] and ICC = 0.911 [0.881-0.934]. CONCLUSION: We developed a formula for predicting skeletal muscle mass from the Th12-level CT slice. The predicted L3-level CSA correlated with the measured L3-level CSA.

Determining the optimal value of the Geriatric Nutritional Risk Index to screen older patients with malnutrition risk: A study at a university hospital in Japan.

AIM: The Geriatric Nutritional Risk Index (GNRI) can predict nutritional risk. However, just a few studies have validated the optimal cut-off value of GNRI for nutrition screening in older patients. Hence, this study aimed to determine the optimal value of GNRI to screen the risk of malnutrition among older patients. METHODS: This retrospective cross-sectional study was carried out with 5867 consecutive older adult patients who were admitted to an academic hospital in Japan. Receiver operating characteristic curve analyses were carried out to obtain the optimal cut-off value of GNRI, and the results were compared against the Mini Nutritional Assessment - Short Form and Malnutrition Universal Screening Tool. The validation of the obtained cut-off value was examined on the concordance rate of malnutrition diagnosis based on the European Society of Clinical Nutrition and Metabolism criteria. RESULTS: The mean age of the patients was 76.0 ± 7.0 years. The optimal cut-off value of GNRI for Mini Nutritional Assessment - Short Form ≤11 points was 95.92 (area under the curve 0.827 [0.817-0.838], P < 0.001), and that for Malnutrition Universal Screening Tool ≥1 point was 95.95 (area under the curve 0.788 [0.776-0.799], P < 0.001). By adapting GNRI <96 points as an initial screening cut-off in the European Society of Clinical Nutrition and Metabolism-defined malnutrition process, the concordance rates of comparisons were 98.5% and 98.5% for Mini Nutritional Assessment - Short Form-based and MUST-based diagnosis, respectively. CONCLUSIONS: The study showed GNRI <96 points as the optimal cut-off value for nutritional screening. GNRI might be one of the easy-to-use tools for nutritional screening and for diagnosing malnutrition in older adults. Geriatr Gerontol Int 2020; 20: 811-816.

Formula for the Cross-Sectional Area of the Muscles of the Third Lumbar Vertebra Level from the Twelfth Thoracic Vertebra Level Slice on Computed Tomography.

The purpose of this study was to investigate a means by which to reflect muscle mass using chest computed tomography (CT). A cross-sectional study was conducted with patients aged ≥ 65 years having abdominal and chest CT scans. The formula to predict third lumbar vertebra (L3) cross-sectional area (CSA) of the muscles from the erector muscles of the spine at the twelfth thoracic vertebra (Th12) level slice on CT was created using the five-fold cross-validation method. Correlation between predicted L3 CSA and measured L3 CSA of the muscles was assessed by intraclass correlation coefficients (ICC) and correlation coefficients (r) in the data of the development, and predictability was examined with accuracy and F-values in the validation study. The development study included 161 patients. The developed formula was as follows: -1006.38 + 16.29 × age + 1161.80 × sex (if female, 0; if male, 1) + 55.91 × body weight + 2.22 × CSA of the erector muscles at Th12. The formula demonstrated strong concordance and correlation (ICC = 0.849 [0.800-0.887] and r = 0.858 [0.811-0.894]). The validation study included 34 patients. The accuracy and F-value between predicted CSA and measured CSA were high (accuracy = 0.889-0.944, F-value = 0.931-0.968). We developed a formula predicting CSA at L3 using Th12 CT slice. This formula could be used to assess decreased muscle mass even with chest CT alone.

Distinguishing coagulase-negative Staphylococcus bacteremia from contamination using blood-culture positive bottle detection pattern and time to positivity.

AIM: Detection of coagulase-negative Staphylococcus in blood culture may be a result of either bacteremia or contamination. This often leads to diagnostic uncertainly. Our objective was to develop a method for differentiating whether a coagulase-negative Staphylococcus sp. positive blood culture represents bacteremia or contamination based on positive bottle detection pattern and time to positivity (TTP). METHODS: This study included 155 and 51 adults with positive blood cultures for Staphylococcus epidermidis and Staphylococcus hominis, respectively, over a three-year period from 2016 to 2018. Positive blood culture cases were categorized as either bacteremia or contamination based on the clinically available information, and the detection pattern and TTP in each category were investigated. RESULTS: A total of 57, 92, and 6 S. epidermidis positive blood cultures were categorized as bacteremia, contamination, and undetermined, respectively, whereas 15 and 36 S. hominis positive blood cultures were categorized as bacteremia and contamination, respectively. For positive blood cultures categorized as bacteremia, all four bottles in two sets of blood cultures were positive in 47/47 S. epidermidis and 14/14 S. hominis, respectively, whereas either one bottle in each of two sets or three bottles in two sets were positive in 10/19 S. epidermidis and 1/4 S. hominis, respectively; most of those TTPs were <48 h. Among them, the TTP in catheter-related blood stream infection was <24 h. CONCLUSION: Although clinical assessment is crucial to differentiate between bacteremia and contamination, a combination of positive bottle detection pattern and TTP is a valuable diagnostic auxiliary tool.

Malnutrition at Admission Predicts In-Hospital Falls in Hospitalized Older Adults.

Malnutrition leads to poor prognoses, including a predisposition to falls. Few studies have investigated the relationship between malnutrition and falls during hospitalization. This study aimed to determine malnutrition's association with falls during hospitalization. A retrospective observational study was conducted. Patients aged ≥65 years that were admitted to and discharged from a university hospital between April 2018 and March 2019 were examined. Patients with independent basic activities of daily living were included. Diagnosis of malnutrition was based on the European Society for Clinical Nutrition and Metabolism (ESPEN) criteria at admission. Disease information such as the Charlson Comorbidity Index (CCI) and reasons for hospitalization were reviewed. Kaplan-Meier curve and multivariate Cox regression analyses were performed. Data from 6081 patients (mean age: 74.4 ± 6.1 years; males: 58.1%) were analyzed. The mean CCI was 2.3 ± 2.8 points. Malnutrition was detected in 668 (11.0%) and falls occurred in 55 (0.9%) patients. Malnourished patients experienced a higher fall rate than those without malnutrition (2.4% vs. 0.7%, log-rank test p < 0.001). In multivariate analysis, malnutrition had the highest hazard ratio for falls among covariates (hazard ratio 2.78, 95% confidence interval 1.51-5.00, p = 0.001). In conclusion, malnutrition at the time of admission to hospital predicts in-hospital falls.

Impact of edema on length of calf circumference in older adults.

AIM: Calf circumference, which is a known simple indicator of muscle mass, increases during edema. However, the extent to which edema increases calf circumference in older adults is unclear. METHODS: This retrospective cross-sectional study included patients aged ≥65 years whose nutritional status was assessed by nutrition support teams. Two different types of matching models in each sex were created according to the presence of edema on the right lower limb. All models were adjusted by age, body height, handgrip strength and performance status. Sarcopenia was diagnosed based on both reduced calf circumference and decline of handgrip strength. The prevalence of sarcopenia was estimated before and after adjustment for increment of calf circumference. RESULTS: In total, 2101 patients were included. Multifactor matching models showed that the mean difference in calf circumference between pairs was 1.6 cm (95% confidence interval [CI] 1.1-2.1, P < 0.001) for women and 2.1 cm (95% CI 1.6-2.7, P < 0.001) for men. The propensity score matching model similarly showed a mean difference of 1.6 cm (95% CI 1.1-2.1, P < 0.001) for women and 2.0 cm (95% CI 1.5-2.6, P < 0.001) for men. The prevalence of sarcopenia before and after adjusting for an edema-related increase in calf circumference was 42.6%/48.6% for women and 35.3%/38.5%-38.7% for men. CONCLUSIONS: Edema in the lower limb increased the calf circumference by approximately 2 cm. When using calf circumference to assess muscle mass in patients with edema, the increase in circumference should be subtracted from the baseline circumference for an accurate assessment. Geriatr Gerontol Int 2019; 19: 993-998.

Development and Predictors of Sarcopenic Dysphagia during Hospitalization of Older Adults.

The study aimed to investigate the impact of sarcopenia and sarcopenia-related conditions on the development of swallowing disorders during hospitalization. Older adult inpatients (n = 8768) without swallowing disorders in the premorbid period were studied. Sarcopenia-related conditions were evaluated in terms of nutritional status, physical status, and ambulatory conditions as well as hand-grip strength and muscle mass assessed by calf circumference. Development of swallowing disorders was defined based on food texture at discharge from the hospital. The patients' mean age was 76.1 ± 6.9 years. A total of 374 (4.3%) patients developed swallowing disorders during hospitalization. They were older, with poorer nutritional status, and had more decline of physical performance than those without swallowing disorders. Performance Status score (odds ratio (OR) = 1.28 (1.12-1.46) p < 0.001), ambulatory dependency (OR = 1.72 (1.09-2.71), p = 0.020), malnutrition score (OR = 0.92 (0.87-0.97), p = 0.002), insufficient nutritional intake (OR = 2.33 (1.60-3.40), p < 0.001), and length of stay (OR = 1.01 (1.00-1.01), p = 0.001) were independent contributing factors for swallowing disorder development in the multivariate analysis. The presence of possible sarcopenia was also a contributor to swallowing disorder development. In conclusion, swallowing disorders could develop in patients with possible sarcopenia and sarcopenia-related conditions during hospitalization. Clinicians should be aware of this risk and provide appropriate interventions to prevent sarcopenic dysphagia.

Plantar injection of formalin in rats reduces the expression of a potassium chroride cotransporter KCC2 in the spinal cord and a kinase inhibitor suppresses this reduction.

Brain-derived neurotrophic factor (BDNF) is released from activated microglia during neuropathic pain and is hypothesized to downregulate the expression of the potassium chloride cotransporter 2 (KCC2) via the TrkB receptor. Previous studies reported that KCC2 is downregulated 5 min after the plantar injection of formalin in rats; however, the mechanism behind this decrease in KCC2 expression during acute inflammatory pain remains unknown. In this study, we determined whether the TrkB receptor contributes to the expression of KCC2 during the acute pain. Five minutes after the plantar injection of formalin in rats, the ratio of KCC2-immunoreactive area in layer II of the spinal cord significantly decreased on the stimulated side compared to the unaffected side. On the other hand, this response was inhibited by the injection of a kinase inhibitor, K252a, in the subarachnoid space 15 min before the formalin injection. These findings suggest that in acute pain, the TrkB receptor may contribute to the decrease in the expression of KCC2.

Dexmedetomidine suppresses long-term potentiation in the hippocampal CA1 field of anesthetized rats.

PURPOSE: The aim of this study was to evaluate the effect of dexmedetomidine (DEX) on hippocampal synaptic activity in vivo. METHODS: The adult rats used for this study received a intraperitoneal bolus injection of 3, 10, 30, or 100 µg/kg of DEX or an equivalent volume of saline. Electrophysiological recording of the hippocampal CA1 region was initiated 20 min after drug administration. The results are expressed as the percentages of the population spike amplitude measured just before high-frequency stimulation (HFS). The electrophysiological data were analyzed with an area under the curve (AUC) of 10-60 min after HFS. Moreover, to investigate the sedative dose of DEX in rats, we recorded the duration of loss of spontaneous movement after the administration of each dose of DEX. RESULTS: Intraperitoneal administration of DEX at doses of 30 and 100 µg/kg induced a range of sedative effects. The AUC measurements were significantly lower in the 30 and 100 µg/kg groups than in those injected with vehicle (vehicle: 8.81 ± 0.49, n = 7; DEX 30 µg/kg: 6.02 ± 0.99, n = 6; DEX 100 µg/kg: 5.10 ± 0.43, n = 5; P < 0.05). CONCLUSION: The results of our in vivo study reveal that sedative doses of DEX impaired the induction of hippocampal long-term potentiation (LTP). These findings may signify a causal link between DEX-induced sedative action and hippocampal LTP suppression, providing a better understanding of the mechanisms underlying the DEX-induced sedative and/or amnestic effect.

Novel inhibitor of bacterial sphingomyelinase, SMY-540, developed based on three-dimensional structure analysis.

CONTEXT: Bacterial sphingomyelinase (SMase) is thought to play a crucial role in bacterial evasion of the immune response during the early stages of infections. OBJECTIVE: The objective of this study was to predict the chemical structure required for competitive SMase inhibition, then synthesize and test the effect of potential inhibitors on the hydrolysis of sphingomyelin (SM) and protection against infection by Bacillus cereus. MATERIALS AND METHODS: We synthesized 10 potential SMase inhibitors, derivatives of RY221B-a analogues, based on predictions from three-dimensional structural analysis. We then tested the effect of these compounds on the inhibition of SM hydrolysis and protection of mice inoculated with B. cereus. RESULTS: One compound, SMY-540, displayed a strong inhibitory effect (IC50 = 0.8 µM) upon SMase and prevented mortality in mice. CONCLUSION: SMY-540 is an effective inhibitor of Bc-SMase and has potential for use in the development of drugs to treat infectious diseases caused by bacteria that produce SMase.