Senescent tumor cells in colorectal cancer are characterized by elevated enzymatic activity of complexes 1 and 2 in oxidative phosphorylation

Background@#Cellular senescence is defined as an irreversible cell cycle arrest caused by various internal and external insults. While the metabolic dysfunction of senescent cells in normal tissue is relatively well-established, there is a lack of information regarding the metabolic features of senescent tumor cells. @*Methods@#Publicly available single-cell RNA-sequencing data from the GSE166555 and GSE178341 datasets were utilized to investigate the metabolic features of senescent tumor cells. To validate the single-cell RNA-sequencing data, we performed senescence-associated β-galactosidase (SA-β-Gal) staining to identify senescent tumor cells in fresh frozen colorectal cancer tissue. We also evaluated nicotinamide adenine dinucleotide dehydrogenase–tetrazolium reductase (NADH-TR) and succinate dehydrogenase (SDH) activity using enzyme histochemical methods and compared the staining with SA-β-Gal staining. MTT assay was performed to reveal the complex 1 activity of the respiratory chain in in-vitro senescence model. @*Results@#Single-cell RNA-sequencing data revealed an upregulation in the activity of complexes 1 and 2 in oxidative phosphorylation, despite overall mitochondrial dysfunction in senescent tumor cells. Both SA-β-Gal and enzyme histochemical staining using fresh frozen colorectal cancer tissues indicated a high correlation between SA-β-Gal positivity and NADH-TR/SDH staining positivity. MTT assay showed that senescent colorectal cancer cells exhibit higher absorbance in 600 nm wavelength. @*Conclusions@#Senescent tumor cells exhibit distinct metabolic features, characterized by upregulation of complexes 1 and 2 in the oxidative phosphorylation pathway. NADH-TR and SDH staining represent efficient methods for detecting senescent tumor cells in colorectal cancer.

A Deep Learning Model with High Standalone Performance for Diagnosis of Unruptured Intracranial Aneurysm

Purpose@#This study aimed to investigate whether a deep learning model for automated detection of unruptured intracranial aneurysms on time-of-flight (TOF) magnetic resonance angiography (MRA) can achieve a target diagnostic performance comparable to that of human radiologists for approval from the Korean Ministry of Food and Drug Safety as an artificial intelligence-applied software. @*Materials and Methods@#In this single-center, retrospective, confirmatory clinical trial, the diagnostic performance of the model was evaluated in a predetermined test set. After sample size estimation, the test set consisted of 135 aneurysm-containing examinations with 168 intracranial aneurysms and 197 aneurysm-free examinations. The target sensitivity and specificity were set as 87% and 92%, respectively. The patient-wise sensitivity and specificity of the model were analyzed. Moreover, the lesion-wise sensitivity and false-positive detection rate per case were also investigated. @*Results@#The sensitivity and specificity of the model were 91.11% [95% confidence interval (CI): 84.99, 95.32] and 93.91% (95% CI:89.60, 96.81), respectively, which met the target performance values. The lesion-wise sensitivity was 92.26%. The overall falsepositive detection rate per case was 0.123. Of the 168 aneurysms, 13 aneurysms from 12 examinations were missed by the model. @*Conclusion@#The present deep learning model for automated detection of unruptured intracranial aneurysms on TOF MRA achieved the target diagnostic performance comparable to that of human radiologists. With high standalone performance, this model may be useful for accurate and efficient diagnosis of intracranial aneurysm.

A Deep Learning Model with High Standalone Performance for Diagnosis of Unruptured Intracranial Aneurysm

Purpose@#This study aimed to investigate whether a deep learning model for automated detection of unruptured intracranial aneurysms on time-of-flight (TOF) magnetic resonance angiography (MRA) can achieve a target diagnostic performance comparable to that of human radiologists for approval from the Korean Ministry of Food and Drug Safety as an artificial intelligence-applied software. @*Materials and Methods@#In this single-center, retrospective, confirmatory clinical trial, the diagnostic performance of the model was evaluated in a predetermined test set. After sample size estimation, the test set consisted of 135 aneurysm-containing examinations with 168 intracranial aneurysms and 197 aneurysm-free examinations. The target sensitivity and specificity were set as 87% and 92%, respectively. The patient-wise sensitivity and specificity of the model were analyzed. Moreover, the lesion-wise sensitivity and false-positive detection rate per case were also investigated. @*Results@#The sensitivity and specificity of the model were 91.11% [95% confidence interval (CI): 84.99, 95.32] and 93.91% (95% CI:89.60, 96.81), respectively, which met the target performance values. The lesion-wise sensitivity was 92.26%. The overall falsepositive detection rate per case was 0.123. Of the 168 aneurysms, 13 aneurysms from 12 examinations were missed by the model. @*Conclusion@#The present deep learning model for automated detection of unruptured intracranial aneurysms on TOF MRA achieved the target diagnostic performance comparable to that of human radiologists. With high standalone performance, this model may be useful for accurate and efficient diagnosis of intracranial aneurysm.

Lactoferrin Induces Tolerogenic Bone Marrow-Derived Dendritic Cells

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that initiate both T-cell responses and tolerance. Tolerogenic DCs (tDCs) are regulatory DCs that suppress immune responses through the induction of T-cell anergy and Tregs. Because lactoferrin (LF) was demonstrated to induce functional Tregs and has a protective effect against inflammatory bowel disease, we explored the tolerogenic effects of LF on mouse bone marrow-derived DCs (BMDCs). The expression of CD80/86 and MHC class II was diminished in LF-treated BMDCs (LF-BMDCs). LF facilitated BMDCs to suppress proliferation and elevate Foxp3 +induced Treg (iTreg) differentiation in ovalbumin-specific CD4 + T-cell culture. Foxp3 expression was further increased by blockade of the B7 molecule using CTLA4-Ig but was diminished by additional CD28 stimulation using anti-CD28 Ab. On the other hand, the levels of arginase-1 and indoleamine 2,3-dioxygenase-1 (known as key T-cell suppressive molecules) were increased in LF-BMDCs. Consistently, the suppressive activity of LF-BMDCs was partially restored by inhibitors of these molecules. Collectively, these results suggest that LF effectively causes DCs to be tolerogenic by both the suppression of T-cell proliferation and enhancement of iTreg differentiation. This tolerogenic effect of LF is due to the reduction of costimulatory molecules and enhancement of suppressive molecules.

Lactoferrin Induces Tolerogenic Bone Marrow-Derived Dendritic Cells

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that initiate both T-cell responses and tolerance. Tolerogenic DCs (tDCs) are regulatory DCs that suppress immune responses through the induction of T-cell anergy and Tregs. Because lactoferrin (LF) was demonstrated to induce functional Tregs and has a protective effect against inflammatory bowel disease, we explored the tolerogenic effects of LF on mouse bone marrow-derived DCs (BMDCs). The expression of CD80/86 and MHC class II was diminished in LF-treated BMDCs (LF-BMDCs). LF facilitated BMDCs to suppress proliferation and elevate Foxp3 +induced Treg (iTreg) differentiation in ovalbumin-specific CD4 + T-cell culture. Foxp3 expression was further increased by blockade of the B7 molecule using CTLA4-Ig but was diminished by additional CD28 stimulation using anti-CD28 Ab. On the other hand, the levels of arginase-1 and indoleamine 2,3-dioxygenase-1 (known as key T-cell suppressive molecules) were increased in LF-BMDCs. Consistently, the suppressive activity of LF-BMDCs was partially restored by inhibitors of these molecules. Collectively, these results suggest that LF effectively causes DCs to be tolerogenic by both the suppression of T-cell proliferation and enhancement of iTreg differentiation. This tolerogenic effect of LF is due to the reduction of costimulatory molecules and enhancement of suppressive molecules.

Feasibility of Selective Neck Irradiation with Lower Elective Radiation Dose in Treating Nasopharynx Cancer Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study aimed to report the clinical outcomes following selective neck irradiation (SNI) with lower elective radiation therapy (RT) dose in treating nasopharyngeal cancer (NPC) patients. MATERIALS AND METHODS: A total of 347 NPC patients received definitive RT according to our SNI policy and were retrospectively analyzed. The clinical target volumes (CTVs) were subdivided into CTV at high risk (CTV-HR) and CTV at low risk (CTV-LR). The typical doses to gross tumor volume (GTV), CTV-HR, and CTV-LR were 68.4-70.0 Gy, 54.0-60.0 Gy, and 36.0 Gy. RESULTS: With the median follow-up of 68.1 months (range, 2.3 to 197.1 months), the 5-year rates of loco-regional control and progression-free survival in all the patients were 85.0% and 70.8%, respectively. Thirty patients developed regional failure and the regional control rates at 3 and 5 years were 92.6% and 91.4%, respectively. The sites of regional failure in relation to the target volume were exclusively inside GTV/CTV-HR in 20, inside and outside GTV/CTVHR in three, and exclusively outside GTV/CTV-HR in seven, which were 5.7%, 0.9%, and 2.0% of total patients, respectively. CONCLUSION: The clinical outcomes by the current SNI policy were feasible and comparable to those following classic elective nodal irradiation policy.

Salvage Concurrent Chemo-radiation Therapy for Loco-regional Recurrence Following Curative Surgery of Non-small Cell Lung Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study is to report clinical outcomes of salvage concurrent chemo-radiation therapy (CCRT) in treating patients with loco-regional recurrence (LRR) following initial complete resection of non-small cell lung cancer. MATERIALS AND METHODS: Between February 2004 and December 2016, 127 patients underwent salvage CCRT for LRR. The median radiation therapy (RT) dose was 66 Gy and clinical target volume was to cover recurrent lesion with margin without elective inclusion of regional lymphatics. Majority of patients (94.5%) received weekly platinum-based doublet chemotherapy during RT course. RESULTS: The median follow-up time from the start of CCRT was 25 months. The median survival duration was 49 months, and overall survival (OS) rates at 2 and 5 years were 72.9% and 43.9%. The 2- and 5-year rates of in-field failure-free survival, distant metastasis free survival, and progression free survival were 82.4% and 73.8%, 50.4% and 39.9%, and 34.6% and 22.3%, respectively. Grade ≥ 3 radiation-related esophagitis and pneumonitis occurred in 14 (11.0%) and six patients (4.7%), respectively. On both univariate and multivariate analysis, higher biologically equivalent dose (BED₁₀) (≥ 79.2 Gy₁₀ vs. 80 cm³; HR, 0.403), and longer disease-free interval (> 1 year vs. ≤ 1 year; HR, 0.489) were significantly favorable factors for OS. CONCLUSION: The current study has demonstrated that high dose salvage CCRT focused to the involved lesion only was highly effective and safe. In particular, higher BED₁₀, smaller CTV, and longer disease-free interval were favorable factors for improved survival.

Demographic and Socioeconomic Factors for Renouncing Further Active Therapy for Patients with Brain Metastasis of Non-Small Cell Lung Cancer

BACKGROUND: As patients with brain metastasis (BM) of non-small cell lung cancer (NSCLC) have dismal prognosis, some of them decide to discontinue further treatment for BM. The objective of this study was to determine factors for renouncing further active therapy in patients with BM of NSCLC, focusing on their demographic and socioeconomic status. METHODS: Medical records of 105 patients with radiological diagnosis of BM of NSCLC for the recent 11 years at authors' institution were retrospectively reviewed. Clinical features as well as demographic and socioeconomic characteristics such as marriage status, cohabiting family members, religious affiliations, educational background, and economic responsibility were reviewed. RESULTS: Median overall survival (OS) was 13.84 (95% CI: 10.26–17.42) years in 67 patients (group A) who underwent active treatment (radiotherapy and/or chemotherapy) and 4.76 (95% CI: 3.12–6.41) years in 38 patients (group B) who renounced active treatment. Less patients were unmarried (p=0.046), more cohabitating family members (p=0.008), and economically independent (p=0.014) in group A than those in group B. Similarly, the unmarried, and none cohabitating family members had short OS (5.17 and 7.38 years, respectively). In multivariate analysis for predisposing factors of OS in these patients, the following demographic and socioeconomic factors had independent significance: marriage status and cohabitating family members. CONCLUSION: This study suggests that demographic and socioeconomic status as well as clinical factors could influence the decision of further active treatment and prognosis of patients with BM of NSCLC.

Extraskeletal Ewing's Sarcoma of the Thoracic Nerve Root: A Case Report

Extraskeletal Ewing's sarcoma (EES) is a rare malignant soft tissue tumor which is morphologically indistinguishable from skeletal ES. EES usually occurs in young adults and children and there has been only one case reported in a patient aged over 70 years old. We report a case of an EES arising from the first thoracic spinal nerve root in a 73-year-old female, which was misdiagnosed as benign nerve sheath tumor in preoperative imaging evaluation.

Extranasopharyngeal Angiofibroma of the Nasal Septum: A Case Report

Angiofibroma is benign hypervascular tumor that usually occurs in the nasopharynx of adolescent male patient and rarely originates from outside of the nasopharynx, called extranasopharyngeal angiofibroma. The clinical and radiologic findings of extranasopharyngeal angiofibroma are similar to other hypervascular tumors, which may delay diagnosis and treatment. We present a case of extranasopharyngeal angiofibroma arising from nasal septum of a 43-year-old male who complained of right nasal obstruction. Contrast enhancement CT revealed a hypervascular tumor of the nasal septum and the tumor was removed by endoscopic resection. Histopathologic examination confirmed the diagnosis of angiofibroma.

Mixed Adenoneuroendocrine Carcinoma of the Small Bowel in a Patient with Crohn's Disease: A Case Report

Mixed adenoneuroendocrine carcinoma (MANEC) is a rare tumor of the gastrointestinal tract that has both exocrine and neuroendocrine components. There are only 5 case reports about this combined tumor in the small bowel, arose in a background of long-standing Crohn's disease. Here, we report a case of small bowel MANEC in a 54-year-old male with Crohn's disease, who presented a heterogeneous enhancing, asymmetric small bowel wall thickening with small bowel obstruction and had a difficulty in differential diagnosis before surgery.

A Case of Granular Cell Tumor of the Breast in a Male Patient

A 52-year-old male complained of a painless, firm, and slow-growing mass in his right breast outer portion. The chest CT revealed a 3.3 cm-sized oval shaped, microlobulated, mild enhancing mass. Ultrasound showed a microlobulated marginated heterogeneous hypoechoic mass with internal vascularity and calcifications in the mass. On the ultrasound-guided core needle biopsy, the mass was confirmed as a benign granular cell tumor (GCT). The patient transferred to another hospital and underwent surgical removal of the lesion. GCT of the breast is uncommon and mostly benign neoplasm to originate from Schwann cell. Clinical and radiologic features of GCTs, including CT and ultrasound images, mimic malignancy and make diagnosis of GCT more difficult. The CT images of GCTs are much rarely reported. Physicians and radiologists must be aware of radiologic characteristics of this rare benign tumor for male breast, to avoid misdiagnosis this tumor for breast malignancy and overtreat.

Retroperitoneal Extraskeletal Osteosarcoma without Calcification Mimicking Pancreas Tumor: CT Imaging of a Case Report

Retroperitoneal extraskeletal osteosarcoma is a rare tumor. Typical imaging findings include a soft tissue mass accompanied with internal calcifications. The authors encountered a case involving a 44-year-old woman with a large retroperitoneal extraskeletal osteosarcoma, without calcification, that mimicked a pancreatic tumor. The present report highlights computed tomography features of retroperitoneal extraskeletal osteosarcoma, followed by a brief literature review. It is challenging for radiologists to diagnose retroperitoneal masses. However, in patients who present with large retroperitoneal masses, combined with clinical information including the elevation of serum alkaline phosphatase levels, retroperitoneal extraskeletal osteosarcoma should be considered in the differential diagnosis, even if the mass does not exhibit a gross calcification on the imaging.

Breast Cavernous Hemangioma with Increased Size on Ultrasonography: A Case Report

Cavernous hemangioma of the breast is a rare benign vascular tumor. It is usually diagnosed as non-palpable mass during imaging examination, incidentally. Common sonographic finding of the breast hemangioma is a superficially located, oval shape, circumscribed margin mass. But the appearance of breast hemangioma is variable and it can be difficult to diagnose in preoperatively. Here, we report a 68-year-old female case with palpable breast mass and increased size on follow up ultrasonography.

Isolated Myxoma in the External Auditory Canal: A Case Report

Myxoma is a benign mesenchymal neoplasm found in the heart, bone, and other soft tissues. However, myxoma of the external auditory canal is extremely rare. Since myxoma of the external auditory canal can be manifested as a part of the Carney complex, an autosomal dominant multiple familial neoplastic disorder, correct diagnosis and thorough investigation is important. We report a case of a 59-year-old man who presented to hospital with a complaint of growing mass within the right external auditory canal during one month. The surgical excision was done, and the histopathological examination revealed myxoma. In this article, we report the magnetic resonance imaging and computed tomography findings of the myxoma of the external auditory canal and correlate with the histopathological finding.

Patterns of initial failure after resection for gallbladder cancer: implications for adjuvant radiotherapy

PURPOSE: This study sought to identify potential candidates for adjuvant radiotherapy and patterns of regional failure in patients who underwent curative-intent surgery for gallbladder cancer. MATERIALS AND METHODS: Records for 70 patients with gallbladder cancer who underwent curative resection at a single institution between 2000 and 2016 were analysed retrospectively. No patients received adjuvant radiotherapy. Initial patterns of failure were evaluated. Regional recurrence was categorized according to the definitions of lymph node stations suggested by the Japanese Society of Hepato-Biliary-Pancreatic Surgery. RESULTS: Median follow-up was 23 months. Locoregional recurrence as any component of first failure occurred in 29 patients (41.4%), with isolated locoregional recurrence in 13 (18.6%). Regional recurrence occurred in 23 patients, and 77 regional recurrences were identified. Commonly involved regional stations were #13, #12a2, #12p2, #12b2, #16a2, #16b1, #9, and #8. Independent prognostic factors for locoregional recurrence were ≥pT2 disease (hazard ratio [HR], 5.510; 95% confidence interval [CI], 1.260–24.094; p = 0.023) and R1 resection (HR, 6.981; 95% CI, 2.378–20.491; p < 0.001). CONCLUSION: Patients with pT2 disease or R1 resection after curative surgery for gallbladder cancer may benefit from adjuvant radiotherapy. Our findings on regional recurrence may help physicians construct a target volume for adjuvant radiotherapy.

Effect of leukocyte alteration on treatment outcomes following preoperative chemoradiotherapy in patients with rectal cancer

PURPOSE: Hematotoxicity following anti-cancer treatment is known to be related to treatment efficacy in several malignancies. The purpose of this study was to examine the hematologic parameters related to the tumor response and survival in patients treated with curative surgery following preoperative chemoradiotherapy (CRT) for rectal cancer. MATERIALS AND METHODS: Four hundred eighteen patients with rectal cancer who underwent preoperative CRT and curative surgery were analyzed, retrospectively. The main clinical factors and blood cell counts before and after CRT were investigated with respect to their relationships with tumor downstaging and patient survival. RESULTS: The post-CRT leukocyte count was significantly different between the tumor downstaging group and the nondownstaging group (median, 4740/uL vs. 5130/uL; p = 0.013). Multivariate analysis showed that histological grade, circumferential extent, and post-CRT leukocyte count were related to tumor downstaging. In addition, histological grade, post-CRT leukocyte count, and tumor downstaging were related to disease-free survival. The 5-year disease-free survival and overall survival in patients with post-CRT leukocyte count ≤3730/uL, which is the cut-off value derived from the receiver operation characteristic (ROC) curve analysis, were significantly higher than those with higher counts (88.0% vs. 71.6%, p = 0.001; 94.4% vs. 84.1%, p = 0.024). CONCLUSION: Post-CRT leukocyte count of ≤3730/uL could be regarded as a good prognostic factor for tumor response and survival in rectal cancer patients treated with preoperative CRT.

Effect of leukocyte alteration on treatment outcomes following preoperative chemoradiotherapy in patients with rectal cancer

PURPOSE: Hematotoxicity following anti-cancer treatment is known to be related to treatment efficacy in several malignancies. The purpose of this study was to examine the hematologic parameters related to the tumor response and survival in patients treated with curative surgery following preoperative chemoradiotherapy (CRT) for rectal cancer. MATERIALS AND METHODS: Four hundred eighteen patients with rectal cancer who underwent preoperative CRT and curative surgery were analyzed, retrospectively. The main clinical factors and blood cell counts before and after CRT were investigated with respect to their relationships with tumor downstaging and patient survival. RESULTS: The post-CRT leukocyte count was significantly different between the tumor downstaging group and the nondownstaging group (median, 4740/uL vs. 5130/uL; p = 0.013). Multivariate analysis showed that histological grade, circumferential extent, and post-CRT leukocyte count were related to tumor downstaging. In addition, histological grade, post-CRT leukocyte count, and tumor downstaging were related to disease-free survival. The 5-year disease-free survival and overall survival in patients with post-CRT leukocyte count ≤3730/uL, which is the cut-off value derived from the receiver operation characteristic (ROC) curve analysis, were significantly higher than those with higher counts (88.0% vs. 71.6%, p = 0.001; 94.4% vs. 84.1%, p = 0.024). CONCLUSION: Post-CRT leukocyte count of ≤3730/uL could be regarded as a good prognostic factor for tumor response and survival in rectal cancer patients treated with preoperative CRT.

Femoro-Supragenicular Popliteal Bypass with a Bridging Stent Graft in a Diffusely Diseased Distal Target Popliteal Artery: Alternative to Below-Knee Popliteal Polytetrafluoroethylene Bypass

BACKGROUND: Lesions in distal target arteries hinder surgical bypass procedures in patients with peripheral arterial occlusive disease. METHODS: Between April 2012 and October 2015, 16 patients (18 limbs) with lifestyle-limiting claudication (n=12) or chronic critical limb ischemia (n=6) underwent femoral–above-knee (AK) polytetrafluoroethylene (PTFE) bypass grafts with a bridging stent graft placement between the distal target popliteal artery and the PTFE graft. Ring-supported PTFE grafts were used in all patients with no available vein for graft material. Follow-up evaluations assessed clinical symptoms, the ankle-brachial index, ultrasonographic imaging and/or computed tomography angiography, the primary patency rate, and complications. RESULTS: All procedures were successful. The mean follow-up was 12.6 months (range, 11 to 14 months), and there were no major complications. The median baseline ankle-brachial index of 0.4 (range, 0.2 to 0.55) significantly increased to 0.8 (range, 0.5 to 1.0) at 12 months (p<0.01). The primary patency rate at 12 months was 83.3%. The presenting symptoms resolved within 2 weeks. CONCLUSION: In AK bypasses with a diffusely diseased distal target popliteal artery or when below-knee (BK) bypass surgery is impossible, this procedure could be clinically effective and safe when used as an alternative to femoral-BK bypass surgery.

Femoro-Supragenicular Popliteal Bypass with a Bridging Stent Graft in a Diffusely Diseased Distal Target Popliteal Artery: Alternative to Below-Knee Popliteal Polytetrafluoroethylene Bypass

BACKGROUND: Lesions in distal target arteries hinder surgical bypass procedures in patients with peripheral arterial occlusive disease. METHODS: Between April 2012 and October 2015, 16 patients (18 limbs) with lifestyle-limiting claudication (n=12) or chronic critical limb ischemia (n=6) underwent femoral–above-knee (AK) polytetrafluoroethylene (PTFE) bypass grafts with a bridging stent graft placement between the distal target popliteal artery and the PTFE graft. Ring-supported PTFE grafts were used in all patients with no available vein for graft material. Follow-up evaluations assessed clinical symptoms, the ankle-brachial index, ultrasonographic imaging and/or computed tomography angiography, the primary patency rate, and complications. RESULTS: All procedures were successful. The mean follow-up was 12.6 months (range, 11 to 14 months), and there were no major complications. The median baseline ankle-brachial index of 0.4 (range, 0.2 to 0.55) significantly increased to 0.8 (range, 0.5 to 1.0) at 12 months (p<0.01). The primary patency rate at 12 months was 83.3%. The presenting symptoms resolved within 2 weeks. CONCLUSION: In AK bypasses with a diffusely diseased distal target popliteal artery or when below-knee (BK) bypass surgery is impossible, this procedure could be clinically effective and safe when used as an alternative to femoral-BK bypass surgery.