Afatinib plus bevacizumab combination after osimertinib resistance in advanced EGFR-mutant non-small cell lung cancer: Phase II ABCD-study.

INTRODUCTION: Many clinical studies showed a synergy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor inhibitors. We hypothesized afatinib plus bevacizumab exerts clinical potency after developing various osimertinib resistant mechanisms. METHODS: EGFR-mutant non-small cell lung cancer patients were enrolled after osimertinib resistance. Afatinib at 30-40 mg/day and bevacizumab at 15 mg/kg tri-weekly were administered until progression. Plasma/histologic rebiopsied samples after osimertinib failure were analyzed to examine resistant mechanisms: gene alterations/copy-number gain using cancer personalized profiling by deep sequencing. RESULTS: Between January 2018 and October 2020, 28 patients were enrolled. Response and disease control rates were 17.9 % and 78.6 %, respectively. Median duration of response was 9.0 (range, 4.2-22.3) months. Median progression-free and overall survivals were 2.7 and 9.3 months, respectively. Twenty-eight (100 %) plasma and/or 21 (75 %) histologic rebiopsies identified: 17 (61 %) TP53; 15 (54 %) T790M; 9 (32 %) uncommon EGFR; 9 (32 %) MET; 6 (21 %) C797S; 3 (11 %) BRAF; 2 (7 %) HER2; 2 (7 %) KRAS; and 2 (7 %) PI3K mutations. One (17 %) of 6 C797S patients showed complete response. Three (33 %) of 9 uncommon EGFR-mutated patients achieved radiographic response. Neither 15 T790M-positive nor 6 EGFR downstream signaling mutations: BRAF; KRAS; or PI3K-positive patients responded, but 5 (38 %) of 13 T790M-negative patients responded. Adverse events ≥ grade 3 and incidence ≥ 5 % were: hypertension (29 %); proteinuria (7 %); and diarrhea (7 %). There were neither treatment-related death nor interstitial lung disease. CONCLUSIONS: Selected population could obtain clinical benefit from afatinib plus bevacizumab, based on rebiopsy results after osimertinib resistance.

Feasibility Study of Nivolumab in Combination with Carboplatin Plus Paclitaxel and Concurrent Thoracic Radiation in Patients with Untreated Unresectable Locally Advanced Non-Small Cell Lung Cancer.

Despite advancements in diagnosing and treating non-small cell lung cancer (NSCLC), the prognosis remains poor. Immune checkpoint inhibitors have shown promise in enhancing survival rates. Therefore, this study aimed to investigate the safety of nivolumab administration with concurrent chemoradiation therapy (CCRT) in patients with unresectable locally advanced NSCLC. Twelve patients with unresectable locally advanced NSCLC at Kansai Medical University Hospital and Izumi City General Medical Center were enrolled from May 2018 to September 2020. They received nivolumab (360 mg) tri-weekly twice, weekly carboplatin (AUC 2 min × mg/mL) and paclitaxel (40 mg/m2) for 6 weeks, and thoracic radiotherapy (60 Gy/30 fractions), followed by maintenance nivolumab therapy (360 mg, tri-weekly) for 6 months. The primary endpoint was incidence of dose-limiting toxicities (DLTs), and the secondary endpoints included safety, response rate, progression-free survival (PFS), overall survival (OS), 2-year survival rate, and treatment completion rate. Three patients completed the protocol. Nine discontinued due directly to interstitial pneumonia (three) and pneumonia (one). Ten patients (83.3%) experienced a grade 3 or higher event, of which three (25%) experienced a grade 4 or higher event, and of these, one (8.3%) experienced a grade 5 event. Three patients experienced DLTs. Concurrent nivolumab with CCRT was tolerated in unresectable locally advanced NSCLC, which offers potential treatment benefits.

Multicenter Pharmacokinetic and Pharmacodynamic Study of Pembrolizumab for Non-small-Cell Lung Cancer in Patients Aged 75 Years and Older.

Pembrolizumab is a major treatment for recurrent or advanced non-small-cell lung cancer (NSCLC). However, data on its use and pharmacokinetics (PK) in older patients are limited. This open-label, multicenter, observational study evaluated real-world data on the safety, efficacy, and PK of pembrolizumab in older patients with NSCLC. In 99 patients aged ≥75 years, PK was determined by liquid chromatography-mass spectrometry on pretreatment samples. Performance status (PS), geriatric assessment (GA), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. The median age was 78 (75-87) years. PS was 2-3 in 14 patients. The median ORR, PFS, and OS were 47.5%, 8.0, and 20.5 months, respectively. Although PK and ORR were not significantly associated, patients with the lowest Cycle 1-trough quartile (Q1) experienced poorer PFS (Q1 vs. Q2-4; 3.4 vs. 11.8 months, P = 0.006) and OS (Q1 vs. Q2-4; 9.9 vs. 21.7 months, P = 0.005) than in other quartiles overall, and even in the PD-L1 ≥50% subset (PFS, Q1 vs. Q2-4; 4.1 vs. 14.7 months, P = 0.005; OS, Q1 vs. Q2-4; 9.4 vs. 22.1 months, P = 0.010). The Q1 subgroup was characterized by poor PS and lower albumin, and more frequent "weight loss ≥ 10%" on the GA. Pembrolizumab therapy had similar PK and efficaciousness in older as well as younger patients. In patients with PS ≥2, low albumin, and vulnerable GA, early increases in PK levels are less likely, potentially diminishing efficacy even when PD-L1 ≥50%.

Impact of the response to platinum-based chemotherapy on the second-line immune checkpoint inhibitor monotherapy in non-small cell lung cancer with PD-L1 expression ≤49%: a multicenter retrospective study.

Introduction: The efficacy of second-line immune checkpoint inhibitor (ICI) therapy is limited in non-small cell lung cancer (NSCLC) patients with ≤ 49% PD-L1 expression. Although chemoimmunotherapy is a promising strategy, platinum-based chemotherapy followed by ICI monotherapy is often used to avoid synergistic adverse events. However, predictors of the efficacy of ICI monotherapy after platinum-based chemotherapy in NSCLC with ≤ 49% PD-L1 expression remain scarce. Methods: This multicenter retrospective study evaluated 54 advanced or recurrent NSCLC patients with ≤ 49% PD-L1 expression who were treated with second-line ICI monotherapy following disease progression on first-line platinum-based chemotherapy at nine hospitals in Japan. The impact of response to platinum-based chemotherapy on the efficacy of subsequent ICI monotherapy was investigated. Results: The response to first-line platinum-based chemotherapy was divided into two groups: the non-progressive disease (PD) group, which included patients who did not experience disease progression after four cycles of chemotherapy, and the PD group, which included patients who showed initial PD or could not maintain disease control during the four cycles of chemotherapy and switched to second-line ICI monotherapy. Among the 54 patients, 32 and 22 were classified into the non-PD and PD groups, respectively. The non-PD group showed better response rates (p = 0.038) and longer overall survival (OS) with ICI monotherapy (p = 0.023) than the PD group. Multivariate analysis identified that maintaining a non-PD status after four cycles of chemotherapy was an independent prognostic factor for ICI monotherapy (p = 0.046). Moreover, patients with a modified Glasgow Prognostic Score (mGPS) of 0 showed a tendency for longer OS with ICI monotherapy (p = 0.079), and there was a significant correlation between maintaining non-PD after four cycles of chemotherapy and an mGPS of 0 (p = 0.045). Conclusion: Maintaining a non-PD status after four cycles of platinum-based chemotherapy was a predictor of OS after second-line ICI monotherapy. These findings will help physicians select the most suitable treatment option for NSCLC patients who were treated with platinum-based chemotherapy and switched to second-line treatment. Those who experienced early PD during platinum-based chemotherapy should not be treated with ICI monotherapy in the second-line setting.

Investigation of a practical assessment index to capture the clinical presentation of cachexia in patients with lung cancer.

OBJECTIVE: Cancer cachexia constitutes a poor prognostic factor in patients with lung cancer. However, the factors associated with cancer cachexia remain unclear. This study aimed to identify factors that influence cancer cachexia in patients with lung cancer. METHODS: In this retrospective observational study conducted at the Kansai Medical University, 76 patients with lung cancer were evaluated for physical function, nutritional status (Mini Nutritional Assessment-Short Form) and physical activity (International Physical Activity Questionnaire-Short Form) at the first visit to the rehabilitation outpatient clinic. The patients were divided into cachexia and noncachexia groups. The log-rank tests and Cox proportional hazards model were used to investigate the relationship between cachexia and prognosis. To examine the factors that influence cachexia, multivariate regression analysis with significant (P < 0.05) variables in the univariate logistic regression analysis was performed. Spearman's correlation analysis was performed to investigate the association between International Physical Activity Questionnaire-Short Form and performance status. RESULTS: Overall, 42 patients (55.2%) had cachexia associated with survival time since their first visit to the outpatient rehabilitation clinic, even after confounders adjustment (hazard ratio: 3.24, 95% confidence interval: 1.12-9.45, P = 0.031). In the multivariate analysis, Mini Nutritional Assessment-Short Form (odds ratio: 20.34, 95% confidence interval: 4.18-99.02, P < 0.001) and International Physical Activity Questionnaire-Short Form (odds ratio: 4.63, 95% confidence interval: 1.20-17.89, P = 0.026) were identified as independent factors for cachexia. There was no correlation between International Physical Activity Questionnaire-Short Form and performance status (r = 0.155, P = 0.181). CONCLUSION: Malnutrition and low physical activity were associated with cachexia in patients with lung cancer. The International Physical Activity Questionnaire-Short Form may be a useful indicator of physical activity in cachexia. Regularly assessing these factors and identifying suitable interventions for cachexia remain challenges to be addressed in the future.

Risk and Prognosis of Upper Extremity Deep Vein Thrombosis.

Objectives: We aimed to investigate the clinical features of upper extremity deep vein thrombosis (UEDVT). Methods: We retrospectively reviewed the background, thrombus site, treatment, and outcome of 76 UEDVT patients. Results: Of the 76 UEDVT patients, 44 (57.9%) were men, and 51 (67.1%) were complicated by malignancy, 44 (57.9%) had an indwelling central vein (CV) catheter, 8 (10.5%) had concomitant pulmonary embolization (PE), and 33 (43.3%) were symptomatic. Regarding the thrombus site, the right internal jugular vein was the most common, with 30 cases (35.3%). As regards the treatment method, 53 patients (69.7%) received oral anticoagulants. In 2015, when direct oral anticoagulants (DOACs) was covered by insurance, there were 44 UEDVT cases, of which 34 (77.3%) received DOACs. Outcomes at a mean observation period of 37.5±41.5 months included 40 deaths (52.6%) with a mean survival of 16.3±21.3 months. The most common cause of death was malignancy, with 33 cases (82.5%). Conclusion: In the background of UEDVT, the combination of indwelling CV catheter placement and malignancy was frequently observed. While the risk of recurrence or PE complications is low, the prognosis of UEDVT complicated by malignancy is extremely poor.

First-Line Chemoimmunotherapy versus Sequential Platinum-Based Chemotherapy Followed by Immunotherapy in Patients with Non-Small Cell Lung Cancer with ≤49% Programmed Death-Ligand 1 Expression: A Real-World Multicenter Retrospective Study.

BACKGROUND: The long overall survival (OS) observed among patients with non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression in chemoimmunotherapy (CIT) groups in previous phase III trials suggests the limited efficacy of CIT among the subgroup with ≤49% PD-L1 expression on tumor cells. Hence, sequential treatment with first-line platinum-based chemotherapy followed by second-line immune checkpoint inhibitor treatment (SEQ) is an option. This study examined whether first-line CIT would provide better outcomes than SEQ in patients with advanced NSCLC with ≤49% PD-L1 expression. METHODS: This retrospective study evaluated patients with untreated NSCLC who received first-line CIT or SEQ at nine hospitals in Japan. OS, progression-free survival (PFS), PFS-2 (the time from first-line treatment to progression to second-line treatment or death), and other related outcomes were evaluated between the CIT and SEQ groups. RESULTS: Among the 305 enrolled patients, 234 eligible patients were analyzed: 165 in the CIT group and 69 in the SEQ group. The COX proportional hazards model suggested a significant interaction between PD-L1 expression and OS (p = 0.006). OS in the CIT group was significantly longer than that in the SEQ group in the 1-49% PD-L1 expression subgroup but not in the <1% PD-L1 expression subgroup. Among the subgroup with 1-49% PD-L1 expression, the CIT group exhibited longer median PFS than the SEQ group (CIT: 9.3 months (95% CI: 6.7-14.8) vs. SEQ:5.5 months (95% CI: 4.5-6.1); p < 0.001), while the median PFS in the CIT group was not statistically longer than the median PFS-2 in the SEQ group (p = 0.586). There was no significant difference between the median PFS in the CIT and SEQ groups among the <1% PD-L1 expression subgroup (p = 0.883); the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group (10.5 months (95% CI: 5.9-15.3) vs. 6.4 months (95% CI: 4.9-7.5); p = 0.024). CONCLUSIONS: CIT is recommended for patients with NSCLC with 1-49% PD-L1 expression because it significantly improved OS and PFS compared to SEQ. CIT had limited benefits in patients with <1% PD-L1 expression, and the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group. These findings will help physicians select the most suitable treatment option for patients with NSCLC, considering PD-L1 expressions.

Real-Time Assessment of Tissue Oxygen Saturation Using a Novel Oximeter During Revascularization for Acute Limb Ischemia: A Case Report.

Emergency surgery was performed to treat acute lower limb ischemia caused by heart thromboembolism and concomitant popliteal artery aneurysm. Using a near-infrared spectroscopy oximeter, regional tissue oxygen saturation (rSO2) was monitored to assess the tissue perfusion pre-, intra-, and postoperatively. rSO2 values did not increase sufficiently following thromboembolectomy of the superficial femoral artery, but they dramatically recovered after additional popliteal-anterior tibial bypass surgery. The affected limb was successfully salvaged. rSO2 monitoring was easily measured intraoperatively, which might be beneficial in evaluating tissue perfusion in patients with acute limb ischemia.

Age-Stratified Analysis of First-Line Chemoimmunotherapy for Extensive-Stage Small Cell Lung Cancer: Real-World Evidence from a Multicenter Retrospective Study.

Chemoimmunotherapy improved overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC) in two phase III trials. They set the age-stratified subgroup analyses at 65 years; however, over half of the patients with lung cancer were newly diagnosed at ≥75 years in Japan. Therefore, treatment efficacy and safety in elderly patients ≥ 75 years with ES-SCLC should be evaluated through real-world Japanese evidence. Consecutive Japanese patients with untreated ES-SCLC or limited-stage SCLC unfit for chemoradiotherapy between 5 August 2019 and 28 February 2022 were evaluated. Patients treated with chemoimmunotherapy were divided into the non-elderly (<75 years) and elderly (≥75 years) groups, and efficacy, including PFS, OS, and post-progression survival (PPS) were evaluated. In total, 225 patients were treated with first-line therapy, and 155 received chemoimmunotherapy (98 non-elderly and 57 elderly patients). The median PFS and OS in non-elderly and elderly were 5.1 and 14.1 months and 5.5 and 12.0 months, respectively, without significant differences. Multivariate analyses revealed that age and dose reduction at the initiation of the first chemoimmunotherapy cycle were not correlated with PFS or OS. In addition, patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) = 0 who underwent second-line therapy had significantly longer PPS than those with ECOG-PS = 1 at second-line therapy initiation (p < 0.001). First-line chemoimmunotherapy had similar efficacy in elderly and non-elderly patients. Individual ECOG-PS maintenance during first-line chemoimmunotherapy is crucial for improving the PPS of patients proceeding to second-line therapy.

Pre-Operative Four Dimensional Flow Sensitive Magnetic Resonance Imaging Assessment of Aortic Side Branches as a Method to Predict Risk of Type II Endoleak Resulting in Sac Enlargement After EVAR.

OBJECTIVE: To predict sac enlargement with type II endoleak (ELII) before endovascular aneurysm repair (EVAR) using four dimensional flow sensitive magnetic resonance imaging (4D flow MRI). METHODS: A single centre retrospective analysis of prospectively collected data was conducted. Patients with an abdominal aortic aneurysm (AAA) who underwent EVAR between 2013 and 2019 were included. Aortic branches occluded pre-EVAR, and patients with endoleaks other than ELII were excluded. The aortic branch diameter, peak flow velocity (PFVe), and amplitude of the dynamics of flow volume (AFV) were measured in each aortic branch pre-EVAR. Total flow volume per minute (TFV/min), defined as the sum of AFV/min, was calculated in each case. According to computed tomography findings one year post-EVAR, the aortic branches and patients were divided into patent vessel and occluded vessel groups and sac expanding and non-expanding groups. PFVe, AFV/min, and TFV/min were analysed via receiver operating characteristic curve analysis. RESULTS: The patent aortic branches pre-EVAR (69 inferior mesenteric arteries [IMAs]; 249 lumbar arteries [LAs]) of 100 patients were included. Patent IMAs (n = 14) and occluded IMAs (n = 55), patent LAs (n = 23) and occluded LAs (n = 226), and expanding (n = 9) and non-expanding (n = 91) groups were compared, respectively. No statistically significant difference was observed in branch diameters (IMA; patent, 2.5 ± 0.8 mm, occluded, 2.5 ± 0.8 mm, p < .78 and LA; patent, 1.5 ± 0.3 mm, occluded, 1.5 ± 0.4 mm, p < .35). PFVe (IMA; patent, 262.6 mm2/sec, occluded, 183.4 mm2/sec and LA; patent, 142.6 mm2/sec, occluded, 47.7 mm2/sec) and AFV/min (IMA; patent, 8.4 mL, occluded, 5.2 mL and LA; patent, 4.2 mL, occluded, 1.4 mL) were higher in the patent vessel group (p < .050). TFV/min was statistically significantly higher in the expanding group (24.1 mL/min) than in the non-expanding group (7.0 mL/min) (p < .010). CONCLUSION: Pre-EVAR haemodynamic analyses using 4D flow MRI were useful to detect aortic branches responsible for ELII and to predict AAA cases with sac enlargement. This analysis suggests a new strategy for pre-EVAR aortic branch embolisation.

Characteristics and Prognostic Factors of Venous Thromboembolism in Cancer Patients.

Background: Improving the prognosis of patients with malignant tumors is increasing the number of patients who develop venous thromboembolism. We examined the characteristics and prognostic factors of VTE patients with cancer. Methods: We diagnosed 725 VTE patients from April 2005 to March 2018. There were 322 cancer associated patients (CAT) and 403 non-cancer associated patients (nonCAT). We examined characteristics and prognostic factors of VTE in CAT patients. Results: There were 156 women and 166 men in CAT, and 132 women and 271 men in nonCAT. There was no significant difference in the location of proximal portion of thrombus. When locations were divided into left leg, right leg, and bilateral legs, bilateral cases were more common in CAT group. Comparing the overall survival after VTE diagnosis in the CAT group, the prognosis was poor in patients with high D-dimer level (≧6 µg/mL) along with cancer metastasis and recurrence. Conclusions: Various VTE factors predict prognosis in CAT patients, and CAT is important in the treatment of cancer patients. (This is secondary publication from Jpn J Phlebol 2020; 31(3): 153-159.).

Role of Subcutaneous Adipose Tissues in the Pathophysiology of Secondary Lymphedema.

Background: Secondary lymphedema (LE) occurs due to the disruption of lymphatic circulation. Lymphatic fluid accumulation in subcutaneous tissues induces adipocyte proliferation. Obesity is an important risk factor for the occurrence and deterioration of LE. Although the relationship between LE and subcutaneous adipose tissue increase has been reported clinically, their pathophysiological relationship remains unknown. Thus, we aimed to verify whether subcutaneous adipose tissue increase is involved in the pathophysiology of secondary LE. Methods and Results: The hindlimb model of secondary LE was created using male Sprague-Dawley rats (control and LE groups; n = 5 each). Skin samples were obtained on postoperative day 168. Histological examination and quantitative real-time polymerase chain reaction analysis of inflammatory adipokines, tumor necrosis factor-alpha (Tnf-α), C-C chemokine ligand 2 (Ccl2), and interleukin-6 (Il-6) were performed. Limb volume and subcutaneous adipose tissues significantly increased in the LE group compared with those in the control. Macrophages aggregated in the augmented adipose tissues, around the adipocytes, and formed crown-like structures (CLSs). The number of CLSs significantly increased in the LE group. These macrophages expressed transforming growth factor-beta 1 (TGF-ß1). Inflammatory adipokine secretion was not observed. Although Il-6 expression increased in the LE group, IL-6 was expressed in subcutaneous myofibroblasts but not in subcutaneous adipocytes. Conclusion: As TGF-ß1 derived from subcutaneous myofibroblasts is involved in skin fibrosis during LE, TGF-ß1 derived from adipose tissues may also play a similar role. Drug treatment for subcutaneous adipose tissue reduction may improve the skin condition in secondary LE and may be a new therapeutic strategy.

Differences in Vasa Vasorum Distribution in Human Aortic Aneurysms and Atheromas.

The pathophysiological difference between aortic atheromas and aneurysms is unknown. We focused on the vasa vasorum (VV), which play a critical role in maintaining aortic homeostasis and are also involved in vascular diseases. We investigated the differences in VV between the atheromas and aneurysms. Human abdominal aortic samples were obtained from patients with abdominal aortic aneurysm during surgery or autopsy cases. Autopsy cases were divided into 2 groups according to atheromas. The VV were evaluated using immunohistochemical staining for von Willebrand factor. Intimal VV increased in both the atheroma and aneurysm groups, medial VV increased, and adventitial VV decreased only in the aneurysm group. We also observed that the medial VV were connected to the adventitial VV in the atheroma group and to intimal VV in the aneurysm group. We suggest the outside-in VV or inside-out VV theories. Atheroma induces hypoxia of aortic walls, and angiogenic factors might induce an increase of intimal VV derived from adventitial VV (outside-in VV). However, adventitial VV decrease induces hypoxia of aortic walls, and angiogenic factors might induce an increase of intimal VV derived from aortic lumen (inside-out VV). These differences of VV may contribute in elucidating the pathophysiology of aortic diseases.

Clinical Significance of Factor XIII Activity and Monocyte-Derived Microparticles in Cancer Patients.

BACKGROUND: The aim was to evaluate factor XIII activity (FXIIIa) and monocyte-derived microparticles (MDMPs) in cancer patients. METHODS: In total, 138 cancer patients (31 malignant lymphomas, 39 multiple myelomas, and 68 lung cancers) were analyzed. We measured various biomarkers including FXIIIa and MDMPs. RESULTS: The values of endothelial activation markers, monocyte chemoattractant peptide (MCP)-1, soluble (s)CD14, and MDMPs were higher in cancer patients than in non-cancerous controls. MCP-1, sCD14, and MDMPs were significantly correlated with FXIIIa in multivariate analysis in cancer patients. In addition, MCP-1, sCD14, and MDMP levels were significantly increased in the high FXIIIa group of patients. Finally, the survival rate of the high FXIIIa group was significantly poor in the Kaplan-Meier analysis. CONCLUSION: These results suggest that abnormal levels of FXIIIa and MDMPs may offer promise as poor prognostic factors in cancer patients.

Development of a Noninvasive Skin Evaluation Method for Lower Limb Lymphedema.

Background: The skin's condition is altered in lymphedema patients, and evaluating this change is important. Some noninvasive methods for evaluating skin condition have been reported, especially in upper limb lymphedema. However, evaluating the skin in lower limb lymphedema remains challenging and is often limited to palpation. We aimed to develop a noninvasive skin evaluation method for lower limb lymphedema patients. Methods and Results: Twenty-five lower limb lymphedema patients were included. Skin induration and elasticity were measured using Indentometer® IDM 400 and Cutometer® MPA580. The relationship between the properties of skin from the healthy forearm and thigh, those of the affected thigh, and age was analyzed. Predicted skin induration age (IA) and elasticity age (EA) were calculated from the forearm, whereas actual values were calculated from the thigh, and the differences (ΔIA and ΔEA) were assessed. Patients were classified according to the International Society of Lymphology clinical staging system, and the differences in ΔIA and ΔEA were analyzed among the three groups (healthy, stage I/IIa, and stage IIb/III). Skin biopsy was performed in five unilateral lower limb lymphedema patients, and the dermal elastic fiber area was determined using microscopy with Elastica van Gieson staining. ΔEA significantly increased with disease progression, but ΔIA did not change significantly. Microscopy revealed elastic fiber filamentous changes, with decreased elastic fiber areas in lymphedema-affected skin. Conclusion: To our knowledge, this is the first report to evaluate lower limb skin elasticity in lymphedema quantitatively and noninvasively. ΔEA is useful for evaluating skin condition progression in lymphedema patients.

Platelet-Derived Microparticles are an Important Biomarker in Patients with Cancer-Associated Thrombosis.

BACKGROUND: Platelet-derived microparticles (PDMPs) that ultimately cause vascular complications might be used as a tool to assess thrombotic areas. We identified PDMPs, high-mobility group box-1 (HMGB1) and soluble endothelial protein C receptor (sEPCR) as useful prognosis indicators for cancer-related thrombosis (CAT) to evaluate the utility of PDMPs in cancer patients. METHODS: We investigated 232 cancer patients: 24 (10.3%) had thrombotic complications within 6 months after their first examination. Levels of PDMP and biomarkers were measured by enzyme-linked immunosorbent assay. RESULTS: The levels of PDMPs, HMGB1 and sEPCR were higher in cancer patients compared with controls. In particular, these levels were significantly elevated in lung cancer patients compared with controls, and all were higher in CAT-positive patients compared with CAT-negative patients. In particular, PDMP levels in CAT-positive patients were significantly elevated compared with CAT-negative patients. PDMP levels were significantly lower in patients who lived for more than 901 days after their first examination compared with previous data. PDMP levels were positively correlated with HMGB1, and caused the dose-dependent elevation of PDMPs in vitro using platelet-rich plasma from healthy persons. CONCLUSION: The combined increase in PDMP and HMGB1 levels might be related to CAT in cancer patients. Therefore, coagulatory dysfunction may result from increased levels of these biomarkers and contribute to the poor prognosis of cancer patients.

Axillo-Axillary Artery Bypass With Coil Embolization of the Innominate Artery for a Traumatic Innominate Artery Aneurysm: A Case Report.

BACKGROUND: Innominate artery aneurysm (IAA) is a rare cervical artery aneurysm. Although atherosclerosis is its most common cause, IAAs due to cervical injury are often reported. Operative indications for IAAs include rupture or symptomatic aneurysm, saccular aneurysm, aneurysm with a diameter of 3 cm or greater, and aneurysmal change of the origin of the innominate artery. Although the ligature of the innominate artery or open surgical repair is well described, the usefulness of endovascular repair has also recently been reported. Herein, we report a case of traumatic IAA with infection in the cervical region after tracheostomy. CASE PRESENTATION: A 40-year-old man with cholecystolithiasis planned to undergo laparoscopic cholecystectomy at another hospital. Urgent tracheostomy was performed because of laryngeal edema at the induction of general anesthesia. Enhanced computed tomography angiography 1 week after the tracheostomy revealed a saccular IAA. The patient was deemed to be at high risk for aneurysm rupture and was referred to our hospital. Preoperative Matas test, Allcock test, and innominate arterial stump pressure measurement were performed to assess the cerebral blood flow and ischemic tolerance of the brain. These examinations showed the patency of the circle of Willis. An axillo-axillary artery bypass with coil embolization of the innominate artery was performed to avoid postoperative vascular graft infection. No postoperative complications such as infection or cerebral infarction occurred. Magnetic resonance imaging angiography performed 6 months after surgical treatment showed that the aneurysm had disappeared, and patency of the bypass graft was present. There were no postoperative complications, such as neurological deficits or graft infection, at more than 5 years after surgery. CONCLUSIONS: We report a successfully treated case of IAA after tracheostomy. Axillo-axillary artery bypass with coil embolization of the innominate artery is an effective treatment of IAA with cervical infection.

Benign metastasizing leiomyoma and 18-FDG-PET/CT: A case report and literature review.

Pulmonary benign metastasizing leiomyoma (PBML) is a rare disease entity that usually occurs in females of reproductive age with a previous history of uterine myoma. It is typically characterized by multiple pulmonary tumors consisting of benign leiomyoma cells. In the present study, two cases of PBML are discussed. The patient in each case underwent 2-deoxy-2-(fluorine-18)-fluoro-D-glucose positron emission tomography/computed tomography (18-FDG-PET/CT) scans. One patient demonstrated a lack of 18-FDG uptake and a quiescent clinical course. However, the second patient exhibited a markedly high uptake of 18-FDG and aggressive cell proliferation. The two tumors revealed significant differences in metabolic behavior and in clinical course; however, they were similar with regard to cellular appearance. A review of previous studies concerning the findings of 18-FDG-PET/CT in published cases of PBML was also conducted and is presented here.

The Metabolic Fate of ortho-Quinones Derived from Catecholamine Metabolites.

ortho-Quinones are produced in vivo through the oxidation of catecholic substrates by enzymes such as tyrosinase or by transition metal ions. Neuromelanin, a dark pigment present in the substantia nigra and locus coeruleus of the brain, is produced from dopamine (DA) and norepinephrine (NE) via an interaction with cysteine, but it also incorporates their alcoholic and acidic metabolites. In this study we examined the metabolic fate of ortho-quinones derived from the catecholamine metabolites, 3,4-dihydroxyphenylethanol (DOPE), 3,4-dihydroxyphenylethylene glycol (DOPEG), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylmandelic acid (DOMA). The oxidation of catecholic substrates by mushroom tyrosinase was followed by UV-visible spectrophotometry. HPLC analysis after reduction with NaBH4 or ascorbic acid enabled measurement of the half-lives of ortho-quinones and the identification of their reaction products. Spectrophotometric examination showed that the ortho-quinones initially formed underwent extensive degradation at pH 6.8. HPLC analysis showed that DOPE-quinone and DOPEG-quinone degraded with half-lives of 15 and 30 min at pH 6.8, respectively, and >100 min at pH 5.3. The major product from DOPE-quinone was DOPEG which was produced through the addition of a water molecule to the quinone methide intermediate. DOPEG-quinone yielded a ketone, 2-oxo-DOPE, through the quinone methide intermediate. DOPAC-quinone and DOMA-quinone degraded immediately with decarboxylation of the ortho-quinone intermediates to form 3,4-dihydroxybenzylalcohol (DHBAlc) and 3,4-dihydroxybenzaldehyde (DHBAld), respectively. DHBAlc-quinone was converted to DHBAld with a half-life of 9 min, while DHBAld-quinone degraded rapidly with a half-life of 3 min. This study confirmed the fact that ortho-quinones from DOPE, DOPEG, DOPAC and DOMA are converted to quinone methide tautomers as common intermediates, through proton rearrangement or decarboxylation. The unstable quinone methides afford stable alcoholic or carbonyl products.