Stratification of Stage II Colon Cancer Using Recurrence Prediction Value: A Multi-institutional International Retrospective Study.

OBJECTIVE: To create a recurrence prediction value (RPV) of high-risk factor and identify the patients with high risk of cancer recurrence. SUMMARY BACKGROUND DATA: There are several high-risk factors known to lead to poor outcomes. Weighting each high-risk factor based on their association with increased risk of cancer recurrence can provide a more precise understanding of risk of recurrence. METHODS: We performed a multi-institutional international retrospective analysis of patients with Stage II colon cancer patients who underwent surgery from 2010 to 2020. Patient data from a multi-institutional database were used as the Training data, and data from a completely separate international database from two countries were used as the Validation data. The primary endpoint was recurrence-free survival (RFS). RESULTS: A total of 739 patients were included from Training data. To validate the feasibility of RPV, 467 patients were included from Validation data. Training data patients were divided into RPV low (n = 564) and RPV high (n = 175). Multivariate analysis revealed that risk of recurrence was significantly higher in the RPV high than the RPV low (Hazard ratio (HR) 2.628; 95% confidence interval (CI) 1.887-3.660; P < 0.001). Validation data patients were divided into two groups (RPV low, n = 420) and RPV high (n = 47). Multivariate analysis revealed that risk of recurrence was significantly higher in the RPV high than the RPV low (HR 3.053; 95% CI 1.962-4.750; P < 0.001). CONCLUSIONS: RPV can identify Stage II colon cancer patients with high risk of cancer recurrence world-wide.

Pelvic inlet shape measured by three-dimensional pelvimetry is a predictor of the operative time in the anterior resection of rectal cancer.

PURPOSE: We evaluated pelvic shape as a predictor of the surgical outcome of anterior resection in patients with rectal cancer. METHODS: In total, 228 patients who had undergone anterior resection (R0 resection and double-stapling anastomosis) for rectal cancer from 2005 to 2014 were included in this study. The anteroposterior (AP) and transverse (T) diameters of the pelvic inlet and outlet and pelvic depth were analyzed on three-dimensional volume-rendered images, and the AP/T ratio was calculated. Univariate and multivariate analyses were performed to determine the predictive significance of the operative time and intraoperative blood loss as surgical outcomes. RESULTS: No difference was observed between the inlet AP/T and patient sex ratios, but the other pelvic dimensions were significantly shorter in males than in females. The univariate analysis revealed that the operative time was significantly correlated with the inlet T diameter and that it tended to be correlated with the outlet T diameter and the inlet AP/T ratio. A multivariate analysis adjusted for operation-related factors revealed that the inlet AP/T ratio was the only independent risk factor for an extended operative time (p = 0.036). None of the pelvic dimensions were independent risk factors for increased blood loss. CONCLUSION: The shape of the pelvic inlet may be useful for predicting the operative time.

Optimization method of MRI scan parameters of a double inversion recovery sequence using a T1 map and a developed analysis algorithm.

BACKGROUND: Optimizing scan parameters for double inversion recovery (DIR) sequences remains difficult. OBJECTIVE: To evaluate a new method for optimizing DIR sequence scan parameters using T1 mapping and a newly developed analysis algorithm. METHODS: Twelve healthy volunteers underwent T1 mapping and DIR magnetic resonance imaging. The following steps were used for image optimization including: 1) measurement of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) T1 values to create a T1 map; 2) calculation of optimized scan parameters by using a developed analysis algorithm; 3) performance assessment of DIR magnetic resonance imaging by using the calculated optimized imaging parameters. Additionally, we used scan parameters from previous studies to obtain DIR images in order to evaluate our new method. The contrast between GM and suppressed tissues was compared between these images and those obtained using the optimized parameters. RESULTS: Using our optimization method, WM and CSF regions were suppressed uniformly for all scan conditions. The contrast was significantly higher in images obtained using this optimization method compared to those obtained using previously published parameters (p < 0.01). CONCLUSIONS: It is possible to obtain superior DIR images by using an optimization method that involves T1 mapping and a newly developed analysis algorithm.

Relationship between Blurring and Refocus Flip Angle in 3D-double Inversion Recovery MRI.

It is important to optimize imaging parameters in 3D-double inversion recovery (DIR) magnetic resonance imaging (MRI) for detecting cortical micro lesions. However, inadequate parameters markedly raise blurring in 3DDIR MRI. The purpose of this study was to evaluate the relationship between the blurring and refocus flip angle (RFA) in 3D-DIR MRI. White matter attenuated inversion recovery (WAIR) images as a test sample were obtained by 1.5T MRI with various RFA settings (30°, 40°, 60°, 100°, 140°, 180°, and variable refocus flip angle (VRFA)). Optimal RFA was evaluated using Scheffé's method (Nakaya changing method) by five observers. The results of average preferences indicated that RFA settings of under the 60° of RFA or VRFA suppressed the blurring in 3DDIR MRI. The yard sticks of RFAs of 30° and 40° were significantly higher than the yard sticks of other RFAs (p<0.01). For detecting cortical microlesions, it is very important to obtain WAIR images with no blurring. Using low RFA or VRFA didn't cause significant differences of signal intensity between high-frequency region and low-frequency region in k-space of 3D-DIR MRI. Therefore, it is recommended to set lower RFA (under 60° or VRFA) for suppressing blur in 3D-DIR MRI.

Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma.

The anti-programmed cell death-1 monoclonal antibody (mab), nivolumab has recently been approved for the treatment of unresectable or metastatic malignant melanoma and non-small-cell lung cancers in Japan. Ipilimumab, an anti-cytotoxic T lymphocyte antigen-4 mab for malignant melanoma that was approved earlier than nivolumab in Western countries, is known to frequently cause endocrine immune-related adverse events such as hypophysitis and thyroid dysfunction. We herein report a patient with advanced melanoma who appeared to develop hypophysitis as a consequence of the inhibition of PD-1 by nivolumab. One week after the 6th administration of nivolumab, the patient developed progressive fatigue and appetite loss. Laboratory data on admission for the 7th administration of nivolumab showed eosinophilia and hyponatremia. Since ACTH and cortisol levels were low, nivolumab was discontinued and a large dose of hydrocortisone (100 mg/d) was promptly administered intravenously. A magnetic resonance imaging scan revealed the mild enlargement of the anterior pituitary gland and thickening of the stalk with homogenous contrast. A detailed assessment of anterior pituitary functions with hypothalamic hormone challenges showed that hormonal secretions other than ACTH and TSH were normal. With a replacement dose of hydrocortisone (20 mg/d), the 7th administration of nivolumab was completed without exacerbating the patient's general condition. The present report provides the first detailed endocrinological presentation of nivolumab-induced hypophysitis showing the enlargement of the pituitary gland and stalk in a malignant melanoma patient in Japan. Oncologists and endocrinologists need to be familiar with potentially life-threatening hypophysitis induced by immune-checkpoint inhibitors.

Transanal drainage tube placement to prevent anastomotic leakage following colorectal cancer surgery with double stapling reconstruction.

PURPOSE: Anastomotic leakage (AL) is a critical complication of colorectal cancer surgery. The transanal drainage tube (TDT) is designed to prevent AL caused by decompression and stasis at the anastomosis. We conducted this study to investigate the feasibility of using the TDT to prevent AL following double-stapling technique reconstruction (DST). METHODS: The subjects of this study were 179 patients who underwent curative resection and DST reconstruction for sigmoid colon and rectal cancer in our institution between 2008 and 2013. We analyzed the effectiveness of the TDT for preventing AL. RESULTS: A TDT was placed in 78 patients (43.6 %, TDT group) and not placed in the remaining 101 patients (56.4 %, NTDT group). AL developed in 2 (2.6 %) patients from the TDT group and in 14 (13.9 %) patients from the NTDT group (p = 0.009). Univariate analysis revealed that AL was significantly correlated with tumor distance from the anal verge (AV), the number of staples, and TDT placement. Multivariate analysis revealed a significantly positive correlation between AL and AV [OR 0.877 (0.783-0.982) p = 0.023] and a significantly negative correlation between AL and TDT placement [OR 0.07 (0.013-0.374) p = 0.002]. CONCLUSIONS: Anastomotic decompression with TDT placement may prevent AL after colorectal cancer surgery with DST reconstruction.

Intestinal obstruction in a mentally retarded patient due to pica.

A 40-year-old mentally retarded Japanese man was admitted at rehabilitation facility for handicapped persons and found dead in his bed. His neonatal period was complicated by seizures, and he had a medical history of schizophrenia. A postmortem computed tomography scan suggested an intestinal obstruction, but the cause was unknown. To clarify the cause of death, a medicolegal autopsy was carried out. The gastrointestinal tract was found to contain copious amounts of cloth pieces. A diagnosis of intestinal obstruction secondary to pica of clothes was made. Despite still being an essentially neglect condition; mental retardation is cause to significant burden to the patient, his relatives and caregivers and the whole society. Moreover, people with mental retardation may be at increased risk for potentially self-injury due to ingestion of non-eating substance or incongruent intake of eating substances, which may on turn lead to severe or even life-threatening medical and surgical complications as herein reported. Specific attention also to pica in mentally-retarded patients with sudden, severe, gastrointestinal events, should therefore be placed in order to prevent potential death or otherwise severe chronic consequences, ideally aiming at enhancing the early recognition and multi-disciplinary management of those psychological stressors or triggers potentially responsible for pica too.

[Development of an Optimizing Program of Scanning Parameters for Double Inversion Recovery MRI].

The purpose of this study was to develop an optimizing program of scanning parameters for double inversion recovery (DIR) MRI. The optimization algorithm consists of the following steps: (1) obtaining the initial parameters (TR, TE, and T1 values of the two attenuated tissues); (2) iterative calculation for minimization of errors; and (3) determination of the optimized TI(1st) and TI(2nd). To evaluate the developed algorithm, we performed the phantom and simulation studies using the phantoms which were imitated T1 values of white and gray matters and cerebrospinal fluid. In addition, white matter attenuated inversion recovery (WAIR) and gray matter attenuated inversion recovery (GAIR) images were obtained by optimized scan parameters in one volunteer. The developed algorithm could calculate the optimized TI(1st) and TI(2nd) values at once. Results of summation of signal intensity (SI) of two attenuated tissues shows that the SI of the two tissues were well-attenuated using the theoretical values which were calculated using the developed algorithm. The correlation coefficient of the SI of the phantom of the gray matter between actual and simulation measurements was r=0.997. The SI obtained by actual measurements well correlated with the SI obtained by the simulation measurements. The WAIR and GAIR images in the volunteer were well enhanced gray or white matters. We thus conclude that it is possible to calculate the optimized parameters for the DIR-MRI using the developed algorithm.

Comorbid rectus abdominis diastasis is a risk factor for recurrence of umbilical hernia in Japanese patients.

INTRODUCTION: Rectus abdominis diastasis (RAD) is characterized by thinning and widening of the linea alba and laxity of the ventral abdominal muscle. RAD, when coexistent with umbilical hernia, is considered a risk factor for hernia recurrence. We investigated the impact of comorbid RAD in patients with umbilical hernia who had undergone hernia repair. METHODS: We enrolled 30 patients who had undergone umbilical hernia repair using either a laparoscopic or anterior approach between April 2006 and May 2018. We diagnosed RAD according to preoperative CT. The outcomes of patients with umbilical hernia, the RAD group, and the non-RAD group were compared, especially in terms of recurrence. RESULTS: Twenty-five patients (83%) presented with RAD, including three patients (12%) with postoperative recurrence who were allocated to the RAD group. The median BMI in the RAD group was 27.2 kg/m2 . In the RAD group, a prosthesis mesh was used in 12 patients (48%), and nonabsorbable suture material was used in four patients (16%). There was no statistically significant difference between the two groups in terms of age, hernial orifice diameter, surgical technique, or operative time. CONCLUSION: The rate of comorbid umbilical hernia in Japanese patients with RAD was high, as was the recurrence rate of umbilical hernia. We strongly recommend preoperative detection of RAD. We also recommend mesh-based repair of the midline and nonabsorbable suture material to decrease the recurrence rate, irrespective of hernia size.

Inhibition of Heat-shock Protein 27 Reduces 5-Fluorouracil-acquired Resistance in Human Colon Cancer Cells.

BACKGROUND/AIM: In previous work we showed that expression of heat-shock protein 27 (HSP27; encoded by HSPB1) was associated with inherent resistance to 5-fluorouracil (5-FU). However, the relationship between HSP27 and acquired resistance remains unknown. MATERIALS AND METHODS: We generated an acquired resistance model (WiDr-R) of a colon cancer cell line by exposing WiDr cells to 5-FU. Cell viability assays under treatment with 5-FU, as well as down-regulation of HSP27 using small interfering HSP27 RNA, were performed. HSP27 mRNA and protein expression was analyzed using real-time polymerase chain reaction and western blotting. RESULTS: 5-FU-acquired resistance induced overexpression of HSP27 mRNA and protein levels in WiDr-R cells. Furthermore, siRNA knockdown of HSP27 in WiDr-R cells reduced 5-FU-acquired resistance. CONCLUSION: These findings demonstrate that HSP27 is associated with 5-FU resistance in human colon cancer cell cells and suggest that HSP27 regulation represents a novel approach to overcoming chemoresistance in colorectal cancer.

BAF57 Is a Potential Determinant of Colorectal Cancer Malignancy.

BACKGROUND/AIM: The role of brahma-related gene 1 (BRG1)-associated factor 57 (BAF57), a transcription factor, has been determined in prostate, breast, and ovarian cancer. However, the relationship between BAF57 and colorectal cancer (CRC) is obscure. Thus, we examined the functional correlation between BAF57 expression and oncological malignancy in CRC in vitro. MATERIALS AND METHODS: BAF57 expression in WiDr and HT29 CRC cell lines and clinical specimens from CRC patients was analysed by western blotting and/or RT-PCR. BAF57 expression was down-regulated in WiDr cells through siRNA transfection. An invasion assay was also performed to assess malignancy. RESULTS: BAF57 was expressed in both human CRC cell lines. Overall survival and recurrence-free survival rates were significantly reduced in high BAF57-expressing specimens. BAF57 expression was an independent predictive factor for long-term survival. CONCLUSION: BAF57 correlates with oncological malignancy and may be a novel therapeutic target in CRC.

Thermographic assessment of heat-induced cellular damage during orthopedic surgery.

The heat generated during orthopedic surgery can cause thermal damage to bone cells, leading to cell necrosis, death, and bone resorption. In this study, the drill-exit surface in cortical bone drilling was firstly investigated by infrared thermography to understand the thermal characteristics of bone cutting. In order to mimic the short-term thermal condition of high temperature during surgical cutting, the osteoblasts were exposed to heat shock for short periods of time to investigate the effect of cutting heat on the bone. Necrosis and apoptosis were investigated immediately after heat shock for 2 s, 5 s, and 15 s at 50 °C, 60 °C, 70 °C, and 80 °C, respectively. The cells were then incubated for 4 days at 37 °C and analyzed by fluorescein annexin V-FITC/PI double staining. The temperature and heat-duration were precisely controlled by a novel heating approach. In comparison to the control group (37 °C), immediate necrotic and apoptotic response to heat shock was found in cells exposed to 50 °C for 5 s (11.8%, p<0.05); however, the response was negligible in cells exposed to 50 °C for 2 s. In addition, recovery was found in the group exposed to 50 °C and 60 °C for 2 s (p ≤ 0.05) after incubation for 4 days. Cell damage depends on the magnitude and duration of heat exposure. These findings provide fundamental knowledge for future developments of surgical tool design and cutting methods.

Tattoo image composed of radiopaque deposits demonstrated by postmortem computed tomography.

Postmortem computed tomography (PMCT) is becoming used more commonly in routine forensic investigation. CT is sensitive for detection of metal foreign bodies. Here we report a case of suicide due to self-ignition of kerosene that the victim had poured over herself. Prior to autopsy, PMCT detected tiny radiopaque particles arranged in a row in the surface of the back and either thigh, together with a series of similar particles under the skin lateral to the breasts or the bilateral inguinal region. At autopsy, external examination revealed third-degree burns involving charred tissues all over the body except for the head. Tattoos were visible on the back and on either thigh. The tattoos had colored designs, and the red portions corresponded to the radiopaque particles in the surface of the body. Internal examination demonstrated swelling of the axillary and inguinal lymph nodes, which corresponded to the radiopaque particles. A wave length-dispersive X-ray spectroscopy revealed deposition of mercury and titanium in the inguinal lymph nodes. Thus, it was plausible that the ink could have contributed to the radiopaque particles found by PMCT in the surface of the back and thighs, as well in the lymph nodes. The present case was able to provide clues for interpretation of radiopaque particles revealed by PMCT in the surface of the body.

Heat shock protein 27 knockdown using nucleotide­based therapies enhances sensitivity to 5-FU chemotherapy in SW480 human colon cancer cells.

Heat shock protein 27 (Hsp27) is a chaperone protein of low molecular weight that is produced in response to various stresses and has a cytoprotective function. In the present study we found that there is a strong correlation between sensitivity to 5-fluorouracil (5-FU) and the expression of Hsp27 in colorectal cancer. Apatorsen is an antisense oligonucleotide that targets Hsp27 and has various antitumor effects in some types of cancer, such as bladder and prostate. Although several clinical studies are currently studying apatorsen in many malignancies, to date no promising results have been reported for colorectal cancer. In the present study, we examined the impact of Hsp27 downregulation (via apatorsen) on 5-FU sensitivity in colon cancer both in vitro and in vivo. In vitro, apatorsen significantly decreased the levels of Hsp27 in a dose-dependent manner in human colon cancer SW480 cells. A cell proliferation assay revealed that although apatorsen did not inhibit tumor growth, it resulted in greater 5-FU sensitivity in comparison with treatment with OGX-411 (control). In vivo, intraperitoneal injection of apatorsen decreased the levels of Hsp27 in subcutaneous tumors in a xenograft mouse model using SW480 cells and enhanced 5-FU sensitivity, compared to controls. Although further research is warranted, the present study confirmed that concurrent treatment with Hsp27 knockdown using apatorsen and 5-FU could be a promising therapy for colon cancer.

Usefulness of coronary postmortem computed tomography angiography to detect lesions in the coronary artery and myocardium in cases of sudden death.

Coronary postmortem computed tomography angiography (coronary PMCTA) has been introduced as a routine examination procedure for autopsy at our department. Here, we reviewed eight autopsy cases in which apparent histopathological changes including acute myocardial infarction (AMI), anomalous aortic origin of a coronary artery (AAOCA), hypertrophic obstructive cardiomyopathy (HOCM) and acute myocarditis were involved in the cause of death. For investigation of the coronary artery and shape of the heart, coronary PMCTA was valuable in detecting narrowing or obstruction of coronary artery in AMI, indicating an anomalous aortic origin of the left coronary artery in AAOCA, and demonstrating septal hypertrophy and intracavitary obstruction in HOCM. However, it was debatable whether the hypervascularity demonstrated by coronary PMCTA in the case of acute myocarditis was more prominent than the vascular images obtained in other cases without inflammation. Thus, coronary PMCTA appeared to be useful not only for detection of coronary artery stenosis, but also for indicating other distinctive changes involved in AAOCA and HOCM.

Use of postmortem computed tomography to retrieve small metal fragments derived from a weapon in the bodies of victims in two homicide cases.

Postmortem computed tomography (PMCT) is becoming a commonly used modality in routine forensic investigation. Mechanical injuries including lacerations, incisions, stab wounds and gunshot wounds frequently contain foreign bodies that may have significant value as clues in criminal investigations. CT is a sensitive modality for detection of metal foreign bodies that may be associated with injuries to the victim in cases of homicide or traffic accidents. Here we report two cases in which PMCT was able to act as a guide to forensic pathologists for retrieval of metal fragments in the corpses of the victims, the retrieved fragments then being used to validate the confessions of the assailants through comparison with the knife and the crowbar, respectively, that had been used in the crimes. In these cases, the small metal fragments retrieved from the corpses of the victims with the aid of PMCT were decisive pieces of evidence confirming the circumstances of the crimes. These cases illustrate how PMCT can be used to complement the findings of classical autopsy for integrative investigation of corpses with injury.

Double inversion recovery imaging of the brain: deriving the most relevant sequence through real images.

We propose a practical method for setting the optimal inversion times (TI) for double inversion recovery (DIR) sequences. Our method used the measurement of signal intensity (SI) from real images to set the optimal TI for white-matter (WM) and gray-matter (GM)-attenuated inversion recovery (WAIR and GAIR, respectively) images. 3D-DIR images of healthy volunteers were obtained on 1.5- and 3.0-T magnetic resonance (MR) scanners and the SIs of GM, WM, and cerebrospinal fluid (CSF) were evaluated on real images. We found TI2s at which the SI of WM or GM was null. Then, we found TI1+2 (=TI1 + TI2) at which the SI of CSF was null. We defined the two TIs as optimal TIs. We assessed the utility of these TIs with additional volunteers and patients, and similar images were obtained with the determined TIs. Optimal TIs for DIR images could be efficiently determined using this method.

Postmortem computed tomography evaluation of fatal gas embolism due to connection of an intravenous cannula to an oxygen supply.

An 84-year-old man who had suffered from chronic obstructive pulmonary disease accompanied by moderate pneumonia as well as gastric cancer with liver metastasis was found dead by a nurse, who noticed that the patient's intravenous catheter in the left forearm had been erroneously connected to an oxygen supply in his hospital room, leading to infusion of oxygen into a vein. Postmortem CT scanning demonstrated multiple accumulations of gas in the pulmonary artery, the right atrium and ventricle, as well as the left subclavian and brachiocephalic veins, corresponding to the route that the infused gas would have taken to the heart and pulmonary artery. Conventional autopsy revealed the presence of gas in the right ventricle. These findings suggested that the immediate cause of death was a gas embolus due to oxygen that had entered the cardiopulmonary circulation via the intravenous catheter. This case highlights the usefulness of postmortem imaging as an aid to conventional autopsy for demonstrating gas embolism.

Use of postmortem coronary computed tomography angiography with water-insoluble contrast medium to detect stenosis of the left anterior descending artery in a case of sudden death.

A 40-year-old man was found dead on a sidewalk in an expressway parking area one hour after he had entered the area on a motorcycle. A medicolegal autopsy was performed to reveal the cause of this sudden and unexpected death. Postmortem coronary CT angiography after introduction of 5% gelatin-barium emulsion as a radiopaque contrast medium into the heart demonstrated a significant arterial luminal filling defect in the left anterior descending (LAD) coronary artery. Macroscopic and microscopic examinations revealed that a thrombus had become deposited on ruptured plaque within the LAD artery, and that a small amount of the contrast medium was present between the thrombus and the vessel endothelium. These histological findings were consistent with incomplete occlusion of the LAD artery in the 3D reconstructed image. The cause of death in this case was definitively determined to be ischemic heart disease. Postmortem angiography played a role in screening of a vascular lesion that was subsequently verified by histology to have been responsible for sudden and unexpected death.

Use of postmortem computed tomography angiography to detect vascular injuries accompanying skull base fracture.

A 58-year-old woman who had presented for upper gastrointestinal barium examination accidently slipped from the movable bed, and her head became compressed between the end of the bed and the side wall. She suffered massive bleeding from her nose and ear followed by cardiac arrest, and subsequent attempts at cardiopulmonary resuscitation failed. A medicolegal autopsy was performed to reveal the cause of death, as part of the investigation of the accident. During the autopsy, postmortem cerebral CT angiography was carried out by injection of 5% gelatin-barium emulsion as a radiopaque contrast medium into the bilateral common carotid arteries, demonstrating transudation of the contrast medium into the right acoustic meatus and the sphenoidal sinus cavity. Considering that the body appeared anemic and that PMCTA suggested vascular injuries, the cause of death was definitively determined to be hemorrhagic shock due to injuries to the right internal carotid artery, accompanied by skull base fracture. Postmortem CT angiography played an important role in confirming that the vascular injuries had been responsible for the bleeding, as the lesions could not be fully confirmed by native CT or macroscopic examination.