The volume-outcome relationship in free-flap reconstruction: A nationwide study based on the Clinical Database.

BACKGROUND: The association between successful reconstructive surgery with a free flap and hospital volume has not been well established. This study was designed to retrospectively analyze the outcome of free-flap surgery registered in a nationwide surgical registration system in Japan to clarify the relationship between free-flap survival and facilities' average annual number of free-flap surgeries. METHODS: We analyzed data from 19,482 free flaps performed during 2017-2020 at 407 facilities throughout Japan. After adjusting for sex, age, and disease classification that differ between the groups, we examined the differences in the flap survival rates among the different facilities in terms of the average number of free-flap surgeries performed annually. RESULTS: The total overall necrosis rate was 2.8%. Of all procedures, 14.9%, 12.9%, 33.4%, and 38.8% were performed at facilities with an average number of free-flap procedures <10, 10-19, 20-49, and ≥ 50 per year, respectively, and the respective rates of total necrosis were 6.0%, 3.8%, 2.1%, and 1.7%, respectively. The odds ratios and 95% confidence intervals of flap necrosis for facilities with ≥ 50 cases per year relative to those <10 were 2.70 (1.98-3.68) for nonbreast reconstruction cases and 5.72 (2.77-11.8) for breast reconstruction cases. CONCLUSION: This analysis of a nationwide plastic surgery database showed that free-flap surgeries in institutions with a low average annual number of free-flap surgeries had a higher risk of total necrosis. Measures should be taken to either aggregate cases into high-volume centers or improve management at low-volume centers.

Pancreaticoduodenectomy with celiac artery resection (PD-CAR) for unresctable locally advanced pancreatic ductal adenocarcinoma.

PURPOSE: Locally advanced pancreatic ductal adenocarcinoma (LA-PDAC) involving the celiac artery (CeA), the common hepatic artery and the gastroduodenal artery (GDA) is considered unresectable. We developed the novel procedure of pancreaticoduodenectomy with celiac artery resection (PD-CAR) for such LA-PDACs. METHODS: From 2015 to 2018, we performed curative pancreatectomy with major arterial resection for 13 LA-PDACs as a clinical study (UMIN000029501). Of those, four patients with pancreatic neck cancer involving the CeA and GDA were candidates for PD-CAR. Prior to surgery, blood flow alterations were performed to unify the blood flow to the liver, stomach, and pancreas, resulting in feeding from the cancer-free artery. During PD-CAR, arterial reconstruction of the unified artery was performed as needed. Based on the records of PD-CAR cases, we retrospectively analyzed the validity of the operation. RESULTS: R0 resection was achieved in all patients. Arterial reconstruction was performed in three patients. In another patient, the hepatic arterial flow was maintained by preserving of the left gastric artery. The mean operative time was 669 min, and the mean blood loss was 1003 ml. Although Clavien-Dindo classification III-IV postoperative morbidities occurred in three patients, no reoperations nor mortalities occurred. Although two patients died of cancer recurrence, one patient survived for 26 months without recurrence (died of cerebral infarction), and another is alive at 76 months without recurrence. CONCLUSION: PD-CAR, which enabled R0 resection and preservation of the residual stomach, pancreas, and spleen, provided acceptable postoperative outcomes.

CD9-positive Exosomes Derived from Cancer-associated Fibroblasts Might Inhibit the Proliferation of Malignant Melanoma Cells.

BACKGROUND/AIM: Exosomes secreted by various cells in the tumour microenvironment have been reported to be mediators of intercellular communication that play an important role in cancer progression. In this study, we aimed to investigate the effects of exosomes derived from cancer-associated fibroblasts (CAFs) on the proliferation of malignant melanoma (MM) cells and evaluated their clinicopathological significance. MATERIALS AND METHODS: Three malignant melanoma cell lines, A375, MMAc, and COLO679, and three CAFs established from malignant melanomas at stages 1a, 2b, and 3b, were used. The expression of CD9, CD63, and CD81 in CAF-derived exosomes was examined using western blotting. The effect of exosomes on the proliferative potential of cancer cells was analysed using cell counting and MTT assays. The expression of CD9, CD63, and CD81 was also immunohistochemically analysed in 90 malignant melanoma specimens. RESULTS: CAF-derived exosomes were positive for CD9 and CD63 and remarkably inhibited the proliferative capacity of A375 and MMAc cells. The five-year disease-free survival was significantly better in patients with CAF-derived CD9-positive exosomes than in CD9-negative patients. CONCLUSION: CAF-derived exosomes, especially CD9-positive exosomes, have an inhibitory effect on the proliferation of malignant melanoma cells. These findings suggest that CD9 expression in CAFs is a promising prognostic marker for patients with malignant melanoma.

Characteristics, Antithrombotic Patterns, and Prognostic Outcomes in Claudication and Critical Limb-Threatening Ischemia Undergoing Endovascular Therapy.

PURPOSE: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study aimed to clarify differences in clinical features and prognostic outcomes between IC and CLTI, and prognostic factors in patients undergoing endovascular therapy (EVT). MATERIALS AND METHODS: A total of 692 patients with 808 limbs were enrolled from 20 institutions in Japan. The primary measurements were the 3-year rates of major adverse cardiovascular event (MACE) and reintervention. RESULTS: Among patients, 79.0% had IC and 21.0% had CLTI. Patients with CLTI were more frequently women and more likely to have impaired functional status, undernutrition, comorbidities, hypercoagulation, hyperinflammation, distal artery disease, short single antiplatelet and long anticoagulation therapies, and late cilostazol than patients with IC. Aortoiliac and femoropopliteal diseases were dominant in patients with IC and infrapopliteal disease was dominant in patients with CLTI. Patients with CLTI underwent less frequently aortoiliac intervention and more frequently infrapopliteal intervention than patients with IC. Longitudinal change of ankle-brachial index (ABI) exhibited different patterns between IC and CLTI (pinteraction=0.002), but ABI improved after EVT both in IC and in CLTI (p<0.001), which was sustained over time. Dorsal and plantar skin perfusion pressure in CLTI showed a similar improvement pattern (pinteraction=0.181). Distribution of Rutherford category improved both in IC and in CLTI (each p<0.001). Three-year MACE rates were 20.4% and 42.3% and 3-year reintervention rates were 22.1% and 46.8% for patients with IC and CLTI, respectively (log-rank p<0.001). Elevated D-dimer (p=0.001), age (p=0.043), impaired functional status (p=0.018), and end-stage renal disease (p=0.019) were independently associated with MACE. After considering competing risks of death and major amputation for reintervention, elevated erythrocyte sedimentation rate (p=0.003) and infrainguinal intervention (p=0.002) were independently associated with reintervention. Patients with CLTI merely showed borderline significance for MACE (adjusted hazard ratio 1.700, 95% confidence interval 0.950-3.042, p=0.074) and reintervention (adjusted hazard ratio 1.976, 95% confidence interval 0.999-3.909, p=0.05). CONCLUSIONS: The CLTI is characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared with IC. Also, CLTI has approximately twice MACE and reintervention rates than IC, and the underlying inflammatory coagulation disorder per se is associated with these outcomes. CLINICAL IMPACT: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study, JPASSION study found that CLTI was characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared to IC. Also, CLTI had approximately twice major adverse cardiovascular event (MACE) and reintervention rates than IC. Intriguingly, the underlying inflammatory coagulation disorder per se was independently associated with MACE and reintervention. Further studies to clarify the role of anticoagulation and anti-inflammatory therapies will contribute to the development of post-interventional therapeutics in the context of peripheral artery disease.

Venous Flap Reconstruction following Wide Local Excision for Primary Cutaneous Malignancies in Extremities.

Cutaneous malignancies in the extremities are relatively common, and radical treatment such as ray amputation was performed for certain advanced skin cancer cases in the past. The concept of surgical treatment of primary cutaneous malignant tumor has gradually changed, and preservation of the extremity by performing the appropriate excision and reconstruction became possible. Various reconstructive methods after the resection of malignant tumors such as skin grafts, local flaps, and free flaps, including perforator flaps have been noted. Due to limitations and some disadvantages of these reconstructive materials for extremities, the arterialized venous flap arose as an alternative method. The arterialized venous flap, which has arterial inflow through an afferent vein perfusing the flap and venous outflow through the efferent veins, is considered to function as a great reconstructive material for distal extremities. Although efficacy of this flap has been noted in the past, usage of the flap considering the oncological aspects and application of the flap to the toes and feet have never been reported. Methods: Thirteen reconstructive cases from October 2005 to October 2016 using venous flaps after excision of primary cutaneous malignancy in the distal extremities were performed in our institution. Results: For all cases, satisfactory functional and cosmetic outcomes were observed. Conclusions: Reconstruction using the arterialized venous flap is considered a reliable and versatile method. Careful application of this flap satisfies functional, cosmetic, and oncological aspects of all distal extremities with cutaneous malignancy.

Long-term follow up in two cases of pelvic reconstruction using a combined VRAM flap-sacrocolpopexy for severe perineal hernia after abdominoperineal resection.

Perineal hernia is an infrequent complication of abdominoperineal resection (APR) and, currently, there is no consensus as to the optimal operative technique. Surgical repair can be achieved by either cerclage or the use of mesh or autologous tissue, and it has been reported that the recurrence rate after repair using autologous tissue is 33%. We present two post-APR cases of severe perineal hernia with pelvic organ prolapse (POP) which did not improve after repair using mesh. We regenerated the pelvic floor using a vertical rectus abdominis myocutaneous (VRAM) flap and performed a concomitant sacrocolpopexy to fix the POP. Drooping of the perineum and pelvic floor was greatly improved, and the patients have not experienced any recurrence for 6 years. This dual procedure has not been previously mentioned in the literature, and we consider this the first report of its kind.

A Dynamic Costal Cartilage Platform Promotes Ocular Prosthetic Excursion: Preliminary Report.

The quality of life of the face involves mainly its configuration, and it plays an important functional role in communication skills. Thus, having artificial eyes is extremely essential in maintaining the quality of life of patients who have lost their eyeballs. We will present the details of the technique, including tips and innovations for eye socket reconstruction using spherical costal cartilage implant, which leads to dynamic and aesthetic results. METHODS: There were 19 cases of eye socket reconstruction using costal cartilages from 2008 to 2020. The patient age range was 18-77 years old. There were 10 cases of anophthalmia and 9 cases of ocular phthisis. In our operative method, we created the costal cartilage implant by harvesting the sixth costal cartilage of the affected side. If extraocular muscle remained, we sutured each muscle to the cartilage. RESULTS: Our method made application of thin artificial eyes possible in all cases. Regarding postoperative complications, there were 1 case of postoperative infection and 1 case of vascular failure of temporoparietal fascial flap. Seventeen cases were wet socket, and 2 cases were dry socket. We had attained movement of the artificial eye in 15 cases. CONCLUSIONS: Eye socket reconstruction is considered one of the most challenging operations, and various postoperative complications appear in the long term. Costal cartilages are considered as the most suitable materials to create the base of artificial eyes.

Combined Method with Free Omentum Flap and Split-thickness Skin Flap for Hand Reconstruction Following Radical Excision of an Arteriovenous Malformation.

The treatment for arterial venous malformation (AVM) of functionally and aesthetically important parts such as the hand is considered to be challenging. AVM existed in the right forearm and the thenar region of 55-year-old man. Combined method with free omentum flap and split-thickness skin flap was performed for hand reconstruction after radical excision of an AVM. The postoperative course was good. Seven years have passed postoperatively, and functional but aesthetical results are satisfying with no recurrence. Our operative procedure with complete resection of AVM with placement of the free omental flap to the resected area and placing back the original skin as a skin graft is considered to be an ideal curative surgical treatment of the AVM.

The Simultaneous Application of OASIS and Skin Grafting in the Treatment of Tendon-exposed Wound.

In the present case, we successfully applied the OASIS extracellular matrix to a tendon-exposed wound and simultaneously performed skin grafting. In the future, this approach can be used to further reduce a patient's burden, as it is more effective than PAT transplantation for wounds with exposed tendons.

Predictive value of lymphocyte-to-monocyte ratio in the preoperative setting for progression of patients with breast cancer.

BACKGROUND: The lymphocyte-to-monocyte ratio (LMR) has been used as a parameter reflecting systemic inflammation in several tumors, and is reportedly associated with prognosis in cancer patients. In this study, we evaluated the predictive value of LMR for progression and chemosensitivity in breast cancer patients treated with preoperative chemotherapy. METHODS: LMR was evaluated in 239 patients with breast cancer treated with neoadjuvant chemotherapy (NAC) with 5-fluorouracil, epirubicin, and cyclophosphamide, followed by weekly paclitaxel with or without trastuzumab, and subsequent curative surgery. The correlations between LMR and clinicopathological features, prognosis, and pathological complete response (pCR) rate of NAC were evaluated retrospectively. We also evaluated the predictive value of neutrophil-to-lymphocyte ratio (NLR), and compared the predictive values of LMR and NLR. RESULTS: We set 6.00 as the cut-off level for LMR based on the receiver operating characteristic (ROC) curve. A total of 119 patients (49.8%) were classified in the high-LMR group and 120 (50.2%) were classified in the low-LMR group. The low-LMR group had significantly worse disease-free survival rate (DFS) in all patients (p = 0.005) and in triple-negative breast cancer patients (p = 0.006). However, there was no significant correlation between LMR and pCR. Multivariate analysis showed that low LMR was an independent risk factor for DFS (p = 0.008, hazard ratio = 2.245). However, there was no significant difference in DFS (p = 0.143, log-rank) between patients in the low- and high-NLR groups. CONCLUSIONS: LMR may be a useful prognostic marker in patients with breast cancer.

Reconstruction of the Lacrimal Excretory System in the Medial Canthal Region.

The resection of malignant tumors in medial canthal region may lead to full-thickness defects including medial canthal ligament and lacrimal duct. There had been reports on various reconstructive methods, but none of those methods succeeded in lacrimal reconstruction with functional lacrimal excretory system. We experienced a case of conjunctival malignant melanoma at the lacrimal caruncle and performed new method of the reconstruction for full-thickness defects of the medial canthal region with the maintenance of the lacrimal drainage function.

Predictive value of improvement in the immune tumour microenvironment in patients with breast cancer treated with neoadjuvant chemotherapy.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) can be used to monitor the immune tumour microenvironment (iTME) and predict treatment response and outcome in breast cancer. We evaluated the prognostic significance of the levels of CD8+ TILs and forkhead box protein (FOXP3)-positive TILs before and after neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: We examined 136 patients with breast cancer treated with NAC. The number of CD8+ TILs and FOXP3+ TILs in biopsy specimens and residual tumours was evaluated by immunohistochemistry. RESULTS: Patients with a high rate of change in the CD8/FOXP3 ratio (CFR) had significantly better recurrence-free survival (RFS) (p<0.001, log-rank). In multivariate analysis, the rates of change in the CD8+ TIL levels and the CFR were independent predictors for RFS (HR=2.304, p=0.036 and HR=4.663, p<0.001). In patients with triple-negative and hormone receptor-positive breast cancer, the rate of change in the CFR was an independent predictor for RFS (HR=13.021, p=0.002 and HR=4.377, p=0.003). CONCLUSION: Improvement in the iTME following NAC is correlated with good outcome. The rate of change in the CFR may be a useful biomarker to predict prognosis of patients treated with NAC.

C-X-C Motif Ligand 1 (CXCL1) from melanoma cells down-regulates the invasion of their metastatic melanoma cells.

The surgical resection of a primary melanoma is sometimes followed by the immediate development of distant metastases, suggesting that the primary melanoma might control the metastatic process. We hypothesized that a paracrine factor(s) from primary melanoma cells might regulate the progression of metastasizing melanoma cells. Here we attempted to identify the factor(s) from primary melanoma cells that regulate the invasion ability of metastatic melanoma cells. We used two mouse melanoma cell lines, B16 and B16/BL6, that latter of which is a subline of B16 melanoma and shows high metastatic potential to lung. We investigated the interaction between the parent B16 cells and daughter B16/BL6 cells by invasion assay, cell morphology, cytokine array, RT-PCR, and gelatin-zymography. The conditioned medium (CM) from B16 significantly (p=0.02) inhibited the invasion ability of B16/BL6 cells. The morphology of the B16/BL6 cells was changed from bipolar shape to a multipolar shape following the addition of the CM from B16. The B16 cells produced high levels of C-X-C motif ligand 1 (CXCL1), CXCL10, and M-CSF compared to the B16/BL6 cells. CXCL1 significantly (p=0.01) decreased the invasion ability of B16/BL6 cells, but CXCL10 and M-CSF did not. The invasion-inhibitory activity of the CM from B16 was significantly (p=0.046) suppressed following the addition of a neutralizing anti-CXCL1 antibody. The CM of B16 and CXCL1 increased the E-cadherin mRNA level and decreased MMP2 activity of B16/BL6 cells. These findings suggested that primary melanoma cells might down-regulate the invasion activity of metastatic melanoma cells through CXCL1 signaling.

Significance of re-biopsy for recurrent breast cancer in the immune tumour microenvironment.

BACKGROUND: Immune responses in a tumour microenvironment can be evaluated by analysing tumour-infiltrating lymphocyte (TIL) density; this has been verified in the clinical setting. Although there are many reports on TIL density in primary tumours, little is known about its density in recurrent tumours. METHODS: Of 300 patients treated with neoadjuvant chemotherapy during the study period, 29 were considered for evaluation of TIL density in primary and recurrent tumours. We performed a retrospective analysis of the association between TIL density and prognosis. RESULTS: TIL density was significantly lower in recurrent tumours than in primary tumours (P = 0.007). There was no correlation between post-recurrence survival and TIL density in core-needle biopsy specimens obtained from primary tumours (P = 0.837). However, patients with high TIL density in recurrent tumours had significantly better post-recurrence survival than did the corresponding group with low TIL density (P = 0.041). Multivariate analysis revealed that high TIL density contributed significantly towards improving post-recurrence survival in all patients (P = 0.035; hazard ratio, 0.167). CONCLUSIONS: In recurrent breast cancer, a decrease in TILs density was observed as compared to the primary tumour, and this affects the poor prognosis after relapse.

Contemporary critical limb ischemia: Asian multidisciplinary consensus statement on the collaboration between endovascular therapy and wound care.

The burden of peripheral artery disease (PAD) and diabetes in Asia is projected to increase. Asia also has the highest incidence and prevalence of end-stage renal disease (ESRD) in the world. Therefore, most Asian patients with PAD might have diabetic PAD or ESRD-related PAD. Given these pandemic conditions, critical limb ischemia (CLI) with diabetes or ESRD, the most advanced and challenging subset of PAD, is an emerging public health issue in Asian countries. Given that diabetic and ESRD-related CLI have complex pathophysiology that involve arterial insufficiency, bacterial infection, neuropathy, and foot deformity, a coordinated approach that involves endovascular therapy and wound care is vital. Recently, there is increasing interaction among cardiologists, vascular surgeons, radiologists, orthopedic surgeons, and plastic surgeons beyond specialty and country boundaries in Asia. This article is intended to share practical Asian multidisciplinary consensus statement on the collaboration between endovascular therapy and wound care for CLI.

Clinical Significance of the Neutrophil-to-Lymphocyte Ratio in Endocrine Therapy for Stage IV Breast Cancer.

BACKGROUND: Studies have found that patients with cancer exhibit abnormal leukocyte fractions, such as elevated neutrophil count and diminished lymphocyte count, and that the neutrophil-to-lymphocyte ratio (NLR) provides a surrogate marker for prognosis and response to treatment of patients after radical surgery for several different types of cancer. However, few reports have addressed the association between the NLR and response to endocrine therapy. In this study, we carried out a clinical investigation to confirm whether or not the NLR predicted the response to endocrine therapy of stage IV breast cancer. PATIENTS AND METHODS: The study subjects were 34 patients who underwent endocrine therapy as initial drug therapy for stage IV breast cancer. The correlation between NLR and prognosis, including the efficacy of endocrine therapy, was evaluated retrospectively. RESULTS: Among the 34 patients, the NLR was high in 10 (29.4%) and low in 24 (70.6%). In analysis of outcomes, the group with low NLR had a significant prolongation of progression-free survival (p=0.003), time to treatment failure (p=0.031), and overall survival (p=0.013) compared to the group with high NLR. Univariate analysis of progression-free survival found that responding to treatment [hazard ratio (HR)=4.310, p=0.004] and low NLR (HR=3.940, p=0.016) were factors associated with a favorable prognosis. Multivariate analysis also showed that responding to treatment (HR=4.329, p=0.006) and low NLR (HR=3.930, p=0.008) were independent factors associated with a favorable prognosis. CONCLUSION: Our results suggested that the NLR may represent a predictive marker for response to endocrine therapy in stage IV breast cancer.

Prediction of Treatment Response to Neoadjuvant Chemotherapy in Breast Cancer by Subtype Using Tumor-infiltrating Lymphocytes.

BACKGROUND/AIM: Recent interest has focused on the significance of tumor-infiltrating lymphocytes (TILs) on the efficacies and outcomes of the treatment in breast cancer (BC). Based on the recent international recommendation to standardize the evaluation method, the clinical validity and utility of TILs in patients who underwent neoadjuvant chemotherapy (NAC) were investigated in the present study. PATIENTS AND METHODS: TILs were evaluated in 177 patients with BC treated with NAC and subsequent curative surgery. The correlation between TILs evaluated according to the standard method and prognosis, including the efficacy of NAC, was investigated retrospectively. RESULTS: In the high-TIL group (n=96) compared to the low-TIL group (n=81), triple-negative breast cancer (TNBC) (p<0.001) and human epidermal growth factor receptor 2-enriched breast cancer (HER2BC) (p=0.040) were significantly more frequent, and the pathological complete response (pCR) rate was significantly higher (p=0.003). Among patients with TNBC and those with HER2BC, the pCR rate was significantly higher in the high-TIL group than in the low-TIL group (p=0.013 and p=0.014, respectively). Multivariable analysis also showed that high-TIL status was an independent factor predicting favorable prognosis (hazard ratio(HR)=0.24, p=0.023 and HR=0.13, p=0.036). Biopsy specimens from local recurrence after successful NAC frequently showed TILs decreased. CONCLUSION: TILs may be a biomarker for predicting treatment response to NAC in patients with TNBC and HER2BC. A decrease in TILs may also be associated with tumor recurrence.

Mesenchymal-epithelial Transition and Tumor Vascular Remodeling in Eribulin Chemotherapy for Breast Cancer.

BACKGROUND/AIM: Eribulin mesylate (eribulin) is currently used for the treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress the epithelial-mesenchymal transition (EMT) of cancer cells and promote tumor vascular remodeling. In this study, we investigated the expression of markers for EMT and hypoxia in sets of clinical specimens collected before and after eribulin treatment to verify its unique mechanisms. PATIENTS AND METHODS: The expression of markers for EMT and cellular hypoxia [E-cadherin, N-cadherin, vimentin, and carbonic anhydrase 9 (CA9)] was examined immunohistochemically in MBC tissues collected from 20 patients before and after chemotherapy with either eribulin (n=10) or paclitaxel (n=10). RESULTS: An increase of E-cadherin and decrease of CA9 expression were observed in MBC tissues from patients with objective clinical responses to eribulin treatment. Patients with E-cadherin-positive conversion and CA9-negative conversion had significantly higher response rates (p=0.004 and p=0.024, respectively) and prolonged time to treatment failure (p=0.018 and p=0.038, respectively) than patients without changes in marker expression. CONCLUSION: Expression of EMT and hypoxia markers in clinical samples from patients with MBC was suppressed by eribulin treatment. The results provide additional clinical data on improved survival of patients treated with eribulin and the mechanism of response.