Multiple Lymphaticovenular Anastomoses for Chyluria in Klippel-Trenaunay Syndrome.

ABSTRACT: Klippel-Trenaunay syndrome (KTS) is characterized by port-wine stains, mixed vascular malformations, and soft tissue and bone hypertrophy. Klippel-Trenaunay syndrome is occasionally complicated by chyluria, for which there is no effective treatment currently. We report a case of KTS complicated by intractable chyluria and hematuria due to a lymphatic-ureteral fistula. The patient was successfully treated with multiple lymphaticovenular anastomoses (LVAs).A 66-year-old woman with an enlarged left lower extremity since childhood was diagnosed with KTS. At 60 years of age, she developed chyluria (urine albumin, 2224 µg/mL) and hematuria. Lymphoscintigraphy showed a lymphatic-ureteral fistula near the ureterovesical junction. Conservative treatment was ineffective. She also developed left lower extremity lymphedema, which gradually worsened. Leg cellulitis and purulent pericarditis developed because of hypoalbuminemia (minimum serum albumin level, 1.3 g/dL).We performed 14 LVAs in 2 surgeries to reduce lymphatic fluid flow through the lymphatic-ureteral fistula. The chyluria and hematuria resolved soon after the second operation, and the urine albumin level decreased (3 µg/mL). After 28 months, she had no chyluria or hematuria recurrence and her serum albumin level improved (3.9 g/dL). Multiple LVAs can definitively treat chyluria caused by a lymphatic-ureteral fistula in patients with KTS.

Identification of circular dorsal ruffles as signal platforms for the AKT pathway in glomerular podocytes.

Circular dorsal ruffles (CDRs) are rounded membrane ruffles induced by growth factors to function as precursors of the large-scale endocytosis called macropinocytosis. In addition to their role in cellular uptake, recent research using cell line systems has shown that CDRs/macropinocytosis regulate the canonical AKT-mTORC1 growth factor signaling pathway. However, as CDRs have not been observed in tissues, their physiological relevance has remained unclear. Here, utilizing ultrahigh-resolution scanning electron microscopy, we first report that CDRs are expressed in glomerular podocytes ex vivo and in vivo, and we visually captured the transformation process to macropinocytosis. Moreover, through biochemical and imaging analyses, we show that AKT phosphorylation localized to CDRs upstream of mTORC1 activation in podocyte cell lines and isolated glomeruli. These results demonstrate the physiological role of CDRs as signal platforms for the AKT-mTORC1 pathway in glomerular podocytes at the tissue level. As mTORC1 plays critical roles in podocyte metabolism, and aberrant activation of mTORC1 triggers podocytopathies, our results strongly suggest that targeting CDR formation could represent a potential therapeutic approach for these diseases.

Circular dorsal ruffles disturb the growth factor-induced PI3K-AKT pathway in hepatocellular carcinoma Hep3B cells.

BACKGROUND: Circular dorsal ruffles (CDRs) are rounded membrane ruffles induced on the dorsal surfaces of cells stimulated by growth factors (GF). They can serve as signal platforms to activate AKT protein kinase. After GF stimulation, phosphatidylinositol 3-kinase (PI3K) generates phosphatidylinositol (3,4,5)-triphosphate (PIP3) in the plasma membrane. PIP3 accumulates inside CDRs, recruits AKT into the structures, and phosphorylates them (pAKT). Given the importance of the PI3K-AKT pathway in GF signaling, CDRs are likely involved in cell growth. Interestingly, some cancer cell lines express CDRs. We hypothesized that CDRs contribute to carcinogenesis by modulating the AKT pathway. In the present study, we identified CDR-expressing cancer cell lines and investigated their cellular functions. METHODS: CDR formation was examined in six cancer cell lines in response to epidermal growth factor (EGF) and insulin. The morphology of the CDRs was characterized, and the related signaling molecules were observed using confocal and scanning electron microscopy. The role of CDRs in the AKT pathway was studied using biochemical analysis. The actin inhibitor cytochalasin D (Cyto D) and the PI3K inhibitor TGX221 were used to block CDRs. RESULTS: GF treatment induced CDRs in the hepatocellular carcinoma (HCC) Hep3B cell line, but not in others, including HCC cell lines HepG2 and Huh7, and the LO2 hepatocyte cell line. Confocal microscopy and western blot analysis showed that the PI3K-PIP3-AKT pathway was activated at the CDRs and that receptor proteins were recruited to the structures. Cyto D and TGX221 completely blocked CDRs and partially attenuated GF-induced pAKT. These results indicate that CDRs regulate the receptor-mediated PI3K-AKT pathway in Hep3B cells and the existence of CDR-independent pAKT mechanisms. CONCLUSIONS: Our results showed that CDRs modulate the AKT pathway in Hep3B cells. Since CDRs were not observed in other HCC and hepatocyte cell lines, we propose that CDRs in Hep3B would determine the carcinoma characteristic of the cell by aberrantly triggering the AKT pathway. Signaling molecules involved in CDR formation are promising therapeutic targets for some types of HCC. Video abstract.

Lymphaticovenular anastomosis for lymph vessel injury in the pelvis and groin.

BACKGROUND: Lymphatic diseases due to lymph vessel injuries in the pelvis and groin require immediate clinical attention when conventional treatments fail. We aimed to clarify the effectiveness of and indications for lymphaticovenular anastomosis (LVA) to treat these lymphatic diseases. METHODS: We retrospectively evaluated six patients who underwent LVA for lymphatic diseases due to lymph vessel injuries in the pelvis and groin. Specific pathologies included groin lymphorrhea (N = 3), chylous ascites (N = 2), and retroperitoneal lymphocele (N = 1). The maximum lymphatic fluid leakage volume was 150-2600 mL daily. Conventional treatments (compression, drainage, fasting, somatostatin administration, negative pressure wound therapy, or lymph vessel ligation) had failed to control leakage in all cases. We performed lower extremity LVAs after confirming the site of lymph vessel injury using lymphoscintigraphy. We preferentially placed LVAs in thigh sites that showed a linear pattern by indocyanine green lymphography. Postoperative lymphatic fluid leakage volume reduction was evaluated, and leakage cessation was recorded when the drainage volume approached 0 mL. RESULTS: LVA was performed at an average of 4.3 sites (range, 3-6 sites) in the thigh and 2.7 sites (range, 0-6 sites) in the lower leg. Lymphatic fluid leakage ceased in all cases after a mean of 6 days (range, 1-11 days) postoperatively. No recurrence of symptoms was observed during an average follow-up of 2.9 (range, 0.5-5.5) years. CONCLUSIONS: LVA demonstrates excellent and rapid effects. We recommend lower extremity LVA for the treatment of lymphatic diseases due to lymph vessel injuries in the pelvis and groin.

Dorsal ruffles enhance activation of Akt by growth factors.

In fibroblasts, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) stimulate the formation of actin-rich, circular dorsal ruffles (CDRs) and phosphatidylinositol 3-kinase (PI3K)-dependent phosphorylation of Akt. To test the hypothesis that CDRs increase synthesis of phosphorylated Akt1 (pAkt), we analyzed the contributions of CDRs to Akt phosphorylation in response to PDGF and EGF. CDRs appeared within several minutes of growth factor addition, coincident with a peak of pAkt. Microtubule depolymerization with nocodazole blocked CDR formation and inhibited phosphorylation of Akt in response to EGF but not PDGF. Quantitative immunofluorescence showed increased concentrations of Akt, pAkt and phosphatidylinositol (3,4,5)-trisphosphate (PIP3), the phosphoinositide product of PI3K that activates Akt, concentrated in CDRs and ruffles. EGF stimulated lower maximal levels of pAkt than did PDGF, which suggests that Akt phosphorylation requires amplification in CDRs only when PI3K activities are low. Accordingly, stimulation with low concentrations of PDGF elicited lower levels of Akt phosphorylation, which, like responses to EGF, were inhibited by nocodazole. These results indicate that when receptor signaling generates low levels of PI3K activity, CDRs facilitate local amplification of PI3K and phosphorylation of Akt.This article has an associated First Person interview with the first author of the paper.

Loss of PTEN promotes formation of signaling-capable clathrin-coated pits.

Defective endocytosis and vesicular trafficking of signaling receptors has recently emerged as a multifaceted hallmark of malignant cells. Clathrin-coated pits (CCPs) display highly heterogeneous dynamics on the plasma membrane where they can take from 20 s to over 1 min to form cytosolic coated vesicles. Despite the large number of cargo molecules that traffic through CCPs, it is not well understood whether signaling receptors activated in cancer, such as epidermal growth factor receptor (EGFR), are regulated through a specific subset of CCPs. The signaling lipid phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3], which is dephosphorylated by phosphatase and tensin homolog (PTEN), is a potent tumorigenic signaling lipid. By using total internal reflection fluorescence microscopy and automated tracking and detection of CCPs, we found that EGF-bound EGFR and PTEN are enriched in a distinct subset of short-lived CCPs that correspond with clathrin-dependent EGF-induced signaling. We demonstrated that PTEN plays a role in the regulation of CCP dynamics. Furthermore, increased PI(3,4,5)P3 resulted in higher proportion of short-lived CCPs, an effect that recapitulates PTEN deletion. Altogether, our findings provide evidence for the existence of short-lived 'signaling-capable' CCPs.

Macropinocytosis, mTORC1 and cellular growth control.

The growth and proliferation of metazoan cells are driven by cellular nutrient status and by extracellular growth factors. Growth factor receptors on cell surfaces initiate biochemical signals that increase anabolic metabolism and macropinocytosis, an actin-dependent endocytic process in which relatively large volumes of extracellular solutes and nutrients are internalized and delivered efficiently into lysosomes. Macropinocytosis is prominent in many kinds of cancer cells, and supports the growth of cells transformed by oncogenic K-Ras. Growth factor receptor signaling and the overall metabolic status of the cell are coordinated in the cytoplasm by the mechanistic target-of-rapamycin complex-1 (mTORC1), which positively regulates protein synthesis and negatively regulates molecular salvage pathways such as autophagy. mTORC1 is activated by two distinct Ras-related small GTPases, Rag and Rheb, which associate with lysosomal membranes inside the cell. Rag recruits mTORC1 to the lysosomal surface where Rheb directly binds to and activates mTORC1. Rag is activated by both lysosomal luminal and cytosolic amino acids; Rheb activation requires phosphoinositide 3-kinase, Akt, and the tuberous sclerosis complex-1/2. Signals for activation of Rag and Rheb converge at the lysosomal membrane, and several lines of evidence support the idea that growth factor-dependent endocytosis facilitates amino acid transfer into the lysosome leading to the activation of Rag. This review summarizes evidence that growth factor-stimulated macropinocytosis is essential for amino acid-dependent activation of mTORC1, and that increased solute accumulation by macropinocytosis in transformed cells supports unchecked cell growth.

Toxic Shock Syndrome Caused by Staphylococcal Infection After Breast Implant Surgery: A Case Report and Literature Review.

Toxic shock syndrome is a rare but life-threatening complication after breast implant surgery. We describe a 77-year-old woman who developed toxic shock syndrome caused by methicillin-resistant Staphylococcus aureus after breast implant reconstruction. Despite a high fever and markedly increased white blood cell count, suggesting severe infection, she initially had no symptoms of local findings, such as wound swelling and redness of the breast. Soon after diagnosis of toxic shock syndrome and removal of her breast implant, she was recovered from the shock state. To date, 16 cases of toxic shock syndrome have been reported, including this case, and they were related to breast implants or tissue expander surgery. The common and noteworthy characteristic of these cases was the lack of local findings, such as swelling or redness, which suggests infection. Therefore, early diagnosis is generally difficult, and the initiation of proper treatment can be delayed without knowledge of this characteristic. Toxic shock syndrome requires early diagnosis and treatment. If the patient has a deteriorated vital sign after breast implant surgery or tissue expander breast reconstruction, toxic shock syndrome should be suspected, even if there are no local signs of infection, and removal of the artifact should be considered as soon as possible.

Simultaneous deep inferior epigastric and bilateral anterolateral thigh perforator flap reconstruction of an extended perineoscrotal defect in Fournier's gangrene: A case report.

Fournier's gangrene is lethal necrotizing fasciitis that involves the perineum and external genitalia. We describe the case of a 52-year-old man with Fournier's gangrene who underwent reconstruction of an extensive perineoscrotal defect using three pedicled perforator flaps. Three debridement procedures resulted in a skin and soft tissue defect of 36 × 18 cm involving the perineum, scrotum, groin, medial thigh, buttocks, and circumferential perianal area and left the perforating arteries originating from these locations unavailable for reconstruction. We repaired the defect using left deep inferior epigastric artery perforator (DIEP) (29 × 8 cm) and bilateral anterolateral thigh perforator (ALT) flaps (35 × 8 cm and 22 × 7 cm). The flaps reached the defect without tension, and the defect was successfully covered without a skin graft. No postoperative complications occurred except for epidermal necrosis involving a tiny part of the DIEP flap tip. Nine months postoperatively, the patient experienced no impairment of bowel function or hip joint movement. There was also no avulsion or ulceration of the reconstructed perineal skin, and the cosmetic appearances of the healed wound and donor site were satisfactory. The combination of these three perforator flaps enabled us to achieve a satisfactory outcome while avoiding skin grafts.

Securing split-thickness skin grafts using negative-pressure wound therapy without suture fixation.

OBJECTIVE: Negative-pressure wound therapy (NPWT) is generally applied as a bolster for split-thickness skin grafts (STSG) after the graft has been secured with sutures or skin staples. In this study, NPWT was applied to secure STSGs without any sutures or staples. Surgical outcomes of using NPWT without sutures was compared with a control group. METHODS: Patients with STSGs were divided into two groups: a 'no suture' group using only NPWT, and a control group using conventional fixings. In the no suture group, the grafts were covered with meshed wound dressing and ointment. The NPWT foam was placed over the STSG and negative pressure applied. In the control group, grafts were fixed in place using tie-over bolster, securing with fibrin glue, or NPWT after sutures. RESULTS: A total of 30 patients with 35 graft sites participated in the study. The mean rate of graft take in the no suture group was 95.1%, compared with 93.3% in the control group, with no significant difference between them. No graft shearing occurred in the no suture group. Although the difference did not reach statistical significance, mean surgical time in the no suture group (31.5 minutes) tended to be shorter than that in the control group (55.7 minutes). CONCLUSION: By eliminating sutures, the operation time tended to be shorter, suturing was avoided and suture removal was not required meaning that patients could avoid the pain associated with this procedure. Furthermore, the potential for staple retention and its associated complications was avoided, making this method potentially beneficial for both medical staff and patients.

2-Aminomethylthieno[3,2-d]pyrimidin-4(3H)-ones bearing 3-methylpyrazole hinge binding moiety: Highly potent, selective, and time-dependent inhibitors of Cdc7 kinase.

In order to increase the success rate for developing new Cdc7 inhibitors for cancer therapy, we explored a new chemotype which can comply with the previously-constructed pharmacophore model. Substitution of a pyridine ring of a serendipitously-identified Cdc7 inhibitor 2b with a 3-methylpyrazole resulted in a 4-fold increase in potency and acceptable kinase selectivity, leading to the identification of thieno[3,2-d]pyrimidin-4(3H)-one as an alternative scaffold. Structure-activity relationship (SAR) study revealed that incorporation of a substituted aminomethyl group into the 2-position improved kinase selectivity. Indeed, a pyrrolidinylmethyl derivative 10c was a potent Cdc7 inhibitor (IC50=0.70nM) with high selectivity (Cdk2/Cdc7≥14,000, ROCK1/Cdc7=200). It should be noted that 10c exhibited significant time-dependent Cdc7 inhibition with slow dissociation kinetics, cellular pharmacodynamic (PD) effects, and COLO205 growth inhibition. Additionally, molecular basis of high kinase selectivity of 10c is discussed by using the protein structures of Cdc7 and Cdk2.

Identification of a new class of potent Cdc7 inhibitors designed by putative pharmacophore model: Synthesis and biological evaluation of 2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-ones.

Cell division cycle 7 (Cdc7) is a serine/threonine kinase that plays important roles in the regulation of DNA replication process. A genetic study indicates that Cdc7 inhibition can induce selective tumor-cell death in a p53-dependent manner, suggesting that Cdc7 is an attractive target for the treatment of cancers. In order to identify a new class of potent Cdc7 inhibitors, we generated a putative pharmacophore model based on in silico docking analysis of a known inhibitor with Cdc7 homology model. The pharmacophore model provided a minimum structural motif of Cdc7 inhibitor, by which preliminary medicinal chemistry efforts identified a dihydrothieno[3,2-d]-pyrimidin-4(1H)-one scaffold having a heteroaromatic hinge-binding moiety. The structure-activity relationship (SAR) studies resulted in the discovery of new, potent, and selective Cdc7 inhibitors 14a, c, e. Furthermore, the high selectivity of 14c, e for Cdc7 over Rho-associated protein kinase 1 (ROCK1) is discussed by utilizing a docking study with Cdc7 and ROCK2 crystal structures.

Role of Ragulator in the Regulation of Mechanistic Target of Rapamycin Signaling in Podocytes and Glomerular Function.

Aberrant activation of mechanistic target of rapamycin complex 1 (mTORC1) in glomerular podocytes leads to glomerular insufficiency and may contribute to the development of glomerular diseases, including diabetic nephropathy. Thus, an approach for preventing mTORC1 activation may allow circumvention of the onset and progression of mTORC1-dependent podocyte injury and glomerular diseases. mTORC1 activation requires inputs from both growth factors and nutrients that inactivate the tuberous sclerosis complex (TSC), a key suppressor of mTORC1, on the lysosome. Previous studies in mice revealed that the growth factor-phosphatidylinositol 3-kinase pathway and mTORC1 are essential for maintaining normal podocyte function, suggesting that direct inhibition of the phosphatidylinositol 3-kinase pathway or mTORC1 may not be an ideal approach to sustaining physiologic podocyte functions under certain disease conditions. Here, we report the role of the Ragulator complex, which recruits mTORC1 to lysosomes in response to nutrient availability in podocytes. Notably, podocytes lacking Ragulator maintain basal mTORC1 activity. Unlike podocyte-specific mTORC1-knockout mice, mice lacking functional Ragulator in podocytes did not show abnormalities in podocyte or glomerular function. However, aberrant mTORC1 activation induced by active Rheb in podocyte-specific TSC1-knockout (podo-TSC1 KO) mice did require Ragulator. Moreover, ablation of Ragulator in the podocytes of podo-TSC1 KO mice or streptozotocin-induced diabetic mice significantly blocked the development of pathologic renal phenotypes. These observations suggest that the blockade of mTORC1 recruitment to lysosomes may be a useful clinical approach to attenuate aberrant mTORC1 activation under certain disease conditions.

T-3256336, a novel and orally available small molecule IAP antagonist, induced tumor cell death via induction of systemic TNF alpha production.

Inhibitors of apoptosis proteins (IAPs) are a family of antiapoptotic regulators that have attracted attention as potential targets for cancer therapeutics. Although recent studies have revealed that small-molecule IAP antagonists induce tumor selective cell death in an autocrine tumor necrosis factor (TNF)α-dependent manner, the single-agent efficacy of IAP antagonists is restricted to a small subset of cancer cells. In this study, we showed that the single-agent activity of T-3256336 was limited to a few cancer cell lines in vitro, and these cell lines were defined by relatively high levels of TNFα mRNA expression. However, some other cancer cells, including PANC-1 cells, become drastically sensitive to T-3256336 when costimulated with exogenous TNFα. In PANC-1 mouse xenograft models, the administration of T-3256336 increased levels of several cytokines including TNFα and lead to tumor regression as a single agent, which was attenuated by the neutralization of circulating mouse TNFα with an antibody. These results suggest dual roles of IAP antagonists, increase systemic cytokines including TNFα, and sensitization of tumors to IAP antagonist-induced death.

An inhibitor of apoptosis protein antagonist T-3256336 potentiates the antitumor efficacy of the Nedd8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924).

Inhibitors of apoptosis proteins (IAPs) are antiapoptotic regulators that block cell death, and are frequently overexpressed in several human cancers, where they facilitate evasion of apoptosis and promote cell survival. IAP antagonists are also known as second mitochondria-derived activator of caspase (SMAC)-mimetics, and have recently been considered as novel therapeutic agents for inducing apoptosis, alone and in combination with other anticancer drugs. In this study, we showed that T-3256336, the orally available IAP antagonist has synergistically enhances the antiproliferative effects of the NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924), and these effects were attenuated by a TNFα-neutralizing antibody. In the present mechanistic analyses, pevonedistat induced TNFα mRNA and triggered IAP antagonist-dependent extrinsic apoptotic cell death in cancer cell lines. Furthermore, synergistic effects of the combination of T-3256336 and pevonedistat were demonstrated in a HL-60 mouse xenograft model. Our findings provide mechanistic evidence of the effects of IAP antagonists in combination with NAE inhibitors, and demonstrate the potential of a new combination therapy for cancer.

Tracheobronchial fistula during the perioperative period of esophagectomy for esophageal cancer.

BACKGROUND: Tracheobronchial (TB) injury and fistula formation during the perioperative period of esophagectomy is a rare but life-threatening complication. METHODS: We examined the development of intraoperative TB injury and postoperative TB fistulas in consecutive 763 patients with esophageal cancer who underwent esophagectomy, including 494 patients who underwent transthoracic subtotal esophagectomy. RESULTS: TB injury and fistulas developed in two (0.4 %) and four patients (0.8 %), respectively, who received transthoracic esophagectomy. TB injury developed during the dissection of a tumor invading a major airway. Direct suturing of the laceration and covering it using a muscle flap was effective for one patient, while additional repair with a major pectoral muscle flap was needed in another patient. Postoperative TB fistulas developed due to peri-tracheal infection in two patients, and conservative treatment with drainage was performed. In another two patients, gastro-tracheal fistulas developed due to mechanical compression of staplers on the gastric tube, which was elevated via the posterior mediastinal route. The direct repair of the gastric tube and covering it with a major pectoral muscle flap resulted in the resolution of these fistulas. CONCLUSION: Careful dissection with direct vision of the esophagus, as well as oversewing of the staplers on the gastric tube, is mandatory for preventing TB injury and fistula formation. Appropriate drainage is effective in cases with peri-tracheal abscesses. If the TB fistula fails to heal within a 4- to 6-week period, conservative management should be abandoned. Direct surgical intervention with coverage by a muscle flap is important for TB fistulas.

Surgical resection of hypopharynx and cervical esophageal cancer with a history of esophagectomy for thoracic esophageal cancer.

BACKGROUND: Cancer of the hypopharynx and cervical esophagus (PhCe cancer) frequently develops synchronously or metachronously with esophageal cancer. The surgical approach is usually difficult, especially in metachronous PhCe cancer after esophagectomy. The purpose of this study was to clarify the treatment outcomes of patients with metachronous PhCe cancer with a history of esophagectomy. METHODS: The subjects evaluated in this study were 14 patients with metachronous PhCe cancer who underwent pharyngo-laryngo-esophagectomy after subtotal esophagectomy and gastric tube pull-up for primary esophageal cancer. RESULTS: Definitive chemoradiotherapy (CRT; radiation dose >50 Gy) was performed for primary laryngeal (n = 1), pharyngeal (n = 2), esophageal (n = 1), and recurrent esophageal cancer (n = 2). For seven patients with metachronous PhCe cancer, induction CRT (radiation dose <40 Gy) was performed. In all 14 patients, pharyngo-laryngo-esophagectomy was followed by free jejunal graft interposition with reconstruction of the jejunal vessels. Although postoperative complications developed in four patients, no perioperative death or necrosis of the reconstructed free jejunum occurred. The 2- and 5-year overall survival rates were 84 and 50 %, respectively. CONCLUSIONS: Pharyngo-laryngo-esophagectomy with free jejunal transfer is considered to be safe for metachronous PhCe cancer, even in patients with a history of CRT and esophagectomy.

Technical improvement of total pharyngo-laryngo-esophagectomy for esophageal cancer and head and neck cancer.

PURPOSE: Total pharyngo-laryngo-esophagectomy (PLE) is highly invasive, and the subsequent reconstruction is difficult. The purpose of this study was to clarify the techniques that can decrease the surgical stress and allow for safe reconstruction after this operation. METHODS: The surgical method and clinical outcomes of total PLE were reviewed in 12 patients with either cervicothoracic esophageal cancer or double cancer of the esophagus and pharynx. Microscopic venous anastomosis was principally performed, and arterial anastomosis was added, if needed. RESULTS: A narrow gastric tube was used in ten patients, including two patients who underwent free jejunal interposition, while the colon was used as the main reconstructed organ in two other patients. Staged operations were performed in three high-risk patients. All six patients treated after 2010 were able to undergo thoracoscopic and/or laparoscopic surgery. No critical postoperative complications developed, although minor anastomotic leakage developed in two patients who were successfully treated conservatively. CONCLUSION: When performing PLE, it is important to decrease the surgical stress and ensure a reliable reconstruction by adopting techniques that are appropriate for each case, such as thoracoscopic and laparoscopic surgery, staged operations, microvascular anastomosis, and muscular flaps.

Surgical strategies for esophageal cancer associated with head and neck cancer.

Esophageal cancer is frequently associated with squamous cell carcinoma in the head and neck. Both cigarette smoking and alcohol consumption are risk factors for multiple cancers of the head and neck, as well as the esophagus. Routine screening and close follow-up for second cancers are important in patients with esophageal cancer or head and neck cancer. For this purpose, endoscopy with Lugol's staining, as well as narrow-band imaging combined with magnifying endoscopy, is a powerful tool for the early detection of esophageal cancer. Multimodal therapy is essential for patients with double cancers. When considering surgical treatment, the curability of both cancers must be carefully evaluated. If both tumors are potentially curable, each lesion should be treated individually. In patients with metachronous double cancers, the prior treatment of the first primary carcinoma often affects the treatment of the second cancer. Close cooperation among medical staff members is essential for complicated surgeries for double cancers. Techniques that are appropriate for each case must be adopted, such as careful dissection, staged operations, muscular flaps and microvascular anastomosis.