Clinical significance of postoperative subcutaneous emphysema after video-assisted thoracoscopic surgery for esophageal cancer.

BACKGROUND: Postoperative subcutaneous emphysema (SE) is a possible complication of thoracoscopic or laparoscopic surgery. This study investigated the risk factors and clinical significance of SE after video-assisted thoracoscopic surgery for esophageal cancer (VATS-e). METHODS: This study included 135 patients who underwent VATS-e with artificial CO2 pneumothorax. Based on the X-ray images on the first postoperative day, patients were divided into two groups: N/L group (no SE or SE localized at the thoracic area, n = 65) and SE group (SE extended to the cervical area, n = 70). We compared clinicopathological features, surgical findings, and short-term outcomes between the two groups. RESULTS: In SE group, there were more patients who received neoadjuvant chemotherapy compared to N/L group. SE group had significantly lower preoperative body mass index. SE group had more frequently two-lung ventilation than N/L group. Multivariate analysis demonstrated that low BMI, NAC, and two-lung ventilation were independent risk factors for SE extended to the cervical area. Although pulmonary complication was relatively frequent in SE group, there were no significant differences in surgical outcomes between two groups, and all patients had SE disappeared within 21 days without serious complications. CONCLUSIONS: Despite extension to the cervical area, SE had a modest impact on the short-term result of VATS-e with artificial CO2 pneumothorax.

The potential of a polyglycolic acid sheet for preventing intrathoracic sleeve migration.

INTRODUCTION: Postoperative gastroesophageal reflux disease (GERD) can be a consequence of laparoscopic sleeve gastrectomy (LSG). Intrathoracic sleeve migration (ITSM) is a factor contributing to its development. This study aimed to investigate whether the occurrence of ITSM can be prevented by applying a polyglycolic acid (PGA) sheet around the His angle. MATERIAL AND METHODS: In this retrospective analysis, 46 consecutive patients who underwent LSG were divided into two groups: Group A - our standard LSG in the first half (n = 23) and Group B - our standard LSG with PGA sheet covering the angle of His in the second half (n = 23). We compared the two groups for one-year postoperative GERD and the incidence of ITSM. RESULTS: No significant differences were found between the two groups in terms of patient background, operation time, and one-year postoperative total body weight loss, and no adverse effects related to the PGA sheet were observed. Group B had a significantly lower incidence of ITSM than Group A, and the rate of acid-reducing medicine usage was less pronounced in Group B during follow-up (p < .05). CONCLUSION: This study suggests that applying a PGA sheet can be safe and effective in reducing postoperative ITSM and preventing exacerbations of postoperative GERD.

Trunk fat volume can be a predictor of postoperative complications after gastrectomy: a retrospective cohort study.

BACKGROUND: Obesity can affect postoperative outcomes of gastrectomy. Visceral fat area is superior to body mass index in predicting postoperative complications. However, visceral fat area measurement is time-consuming and is not optimum for clinical use. Meanwhile, trunk fat volume (TFV) can be easily measured via bioelectrical impedance analysis. Hence, the current study aimed to determine the ability of TFV to predict the occurrence of complications after gastrectomy. METHODS: We retrospectively reviewed patients who underwent curative gastrectomy for gastric cancer between November 2016 and November 2019. The trunk fat volume-to-the ideal amount (%TFV) ratio was obtained using InBody 770 before surgery. The patients were classified into the obese and nonobese groups according to %TFV (TFV-H group, ≥ 150%; TFV-L group, < 150%) and body mass index (BMI-H group, ≥ 25 kg/m2; BMI-L group, < 25 kg/m2). We compared the short-term postoperative outcomes (e.g., operative time, blood loss volume, number of resected lymph nodes, and duration of hospital stay) between the obese and nonobese patients. Risk factors for complications were assessed using logistic regression analysis. RESULTS: In total, 232 patients were included in this study. The TFV-H and BMI-H groups had a significantly longer operative time than the TFV-L (p = 0.022) and BMI-L groups (p = 0.006). Moreover, the TFV-H group had a significantly higher complication rate (p = 0.004) and a lower number of resected lymph nodes (p < 0.001) than the TFV-L group. In the univariate analysis, %TFV ≥ 150, total or proximal gastrectomy, and open gastrectomy were found to be potentially associated with higher complication rates (p < 0.1 for all). Moreover, the multivariate analysis revealed that %TFV ≥ 150 (OR: 2.73; 95% CI: 1.37-5.46; p = 0.005) and total or proximal gastrectomy (OR: 3.57; 95% CI: 1.79-7.12; p < 0.001) were independently correlated with postoperative morbidity. CONCLUSIONS: %TFV independently affected postoperative complications. Hence, it may be a useful parameter for the evaluation of obesity and a predictor of complications after gastrectomy.

Preoperative Exercise Habits are Associated with Post-gastrectomy Complications.

BACKGROUND: Sarcopenia is reportedly associated with postoperative complications of gastrectomy, which would presumably be affected by exercise habits aimed at maintaining muscle quantity and quality. However, the potential benefits of exercise habits have yet to be clarified. METHODS: We included 178 patients undergoing gastrectomy in this study. Postoperative complications above grade 2 according to the Clavien-Dindo classification were regarded as clinically significant. Patients were classified according to exercise quantity employing the International Physical Activity Questionnaire Short Form and relationships between exercise habits and complications were investigated. RESULTS: On univariate analysis, low exercise habits (p = 0.008) and total gastrectomy (p = 0.004) were significantly associated with morbidity after gastrectomy. Although severe comorbidity (p = 0.095) and combined resection (p = 0.064) tended to be associated with complications, multivariate analysis demonstrated only low levels of exercise (Odds ratio = 2.42, p = 0.014) and total gastrectomy (Odds ratio = 3.67, p = 0.028) to be independently associated with postoperative complications. Anastomotic leakage (p = 0.028) and systemic complications (p = 0.006), especially pneumonia, were significantly more frequent in the low exercise group. CONCLUSIONS: Preoperative exercise habits independently affected short-term postoperative outcomes. Our results raise the possibility that exercise intervention would reduce the morbidity experienced by gastrectomy patients.

The postoperative patient-reported quality of recovery in colorectal cancer patients under enhanced recovery after surgery using QoR-40.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols may reduce postoperative complications and the length of hospital stay. Studies of the effectiveness of ERAS should include not only doctor-reported outcomes, but also patient-reported outcomes, in order to better estimate their impact on recovery. However, patient-reported outcomes are not commonly reported. Thus, it needs to be assessed whether early discharge from the hospital is compatible with a better outcome from the viewpoint of the patients themselves. METHODS: The 40-item quality of recovery score (QoR-40) is a recovery-specific, and patient-rated questionnaire, which provides a good measurement of early postoperative recovery. Ninety-four colorectal cancer patients undergoing surgery under ERAS protocol management were asked to answer QoR-40 questionnaires preoperatively and on post-operative day (POD) 1, 3, 6 and one month after surgery. RESULTS: The median (25th, 75th percentiles) preoperative global QoR-40 scores as an indicator of the baseline health status, was 189 (176.75, 197). On POD1 and POD3, the scores had decreased significantly to 154 (132.5, 164.25) and 177 (161.75, 190), respectively. On POD 6, the score dramatically recovered up to 183.5 (167.9, 191), which was not significantly different from the baseline level (p = 0.06). The scores at 1 month after surgery were 190 (176, 197). Younger patients, compared to older patients, and rectal cancer patients, compared to colon cancer patients, had significantly lower scores on POD1. CONCLUSION: This study clearly demonstrated that the quality of recovery based on patient-reported outcomes is in agreement with discharge around POD6 for colorectal cancer patients under ERAS.

Piriform Fossa Injury during Calibration Tube Insertion in Laparoscopic Sleeve Gastrectomy.

Piriform fossa and/or esophageal injuries caused by calibration tubes are relatively rare and remain unelucidated. Herein, we report the case of a 36-year-old woman with morbid obesity, sleep apnea, and menstrual abnormalities who was scheduled to undergo laparoscopic sleeve gastrectomy (LSG). We inserted a 36-Fr Nelaton catheter made of natural rubber as a calibration tube during the surgery. However, excessive resistance was observed. We confirmed a submucosal layer detachment approximately 5 cm from the left piriform fossa to the esophagus using intraoperative endoscopy. Additionally, LSG was performed using an endoscope as the guiding calibration tube. We inserted a nasogastric tube under endoscopy with a guidewire before completing the surgery, hoping for a guiding effect on the saliva flow. After 17 months, the patient had successfully lost weight postoperatively without complaints of neck pain or discomfort during swallowing. Therefore, in cases where the damage is limited to the submucosal layer, as in this case, conservative therapy should be considered; this is similar to the concept of endoscopic submucosal dissection not requiring suture closure. This case highlights the risk of iatrogenic injuries to the piriform fossa and/or esophagus during LSG and the importance of careful calibration tube insertion to prevent them.

Feasibility of Laparoscopic Sleeve Gastrectomy for Patients with Obesity and Disorders of Intellectual Development: a Single Institutional Experience.

BACKGROUND: Owing to their difficulty following clinical advice for procedural safety and ideal surgical outcomes, bariatric and metabolic surgery (BMS) for patients with disorders of intellectual development (DID) is concerning. Studies reporting the feasibility of BMS for this population remain scarce. This study aims to clarify the feasibility of laparoscopic sleeve gastrectomy (LSG) for patients with clinically severe obesity and DID. METHODS: A retrospective analysis of a single institutional prospective database collected from 2010 to 2022 was performed. The Wechsler Adult Intelligence Scale (WAIS) was used to measure intellectual ability before LSG. A multidisciplinary team approach was implemented to give special support and care to patients with DID. Patients were categorized into groups according to their WAIS scores. LSG outcomes were statistically compared between the DID and average intellectual ability groups. RESULTS: Using the WAIS to measure intellectual ability among patients who underwent LSG, we identified 14 patients with DID (IQ score: < 69, mean IQ: 63.4) and 71 with average intellectual ability (IQ score: 90-109, mean IQ: 98.9). Operative outcomes were comparable between the groups as follows: operation time (DID: 163 ± 41 min, average intelligence: 162 ± 30 min), hospital stay (DID: 4 [4-5] days, average intelligence: 5 [4-6] days), and total comorbidities (DID: 7.1%, average intelligence: 8.4%). No reoperations were performed, and no mortalities were observed. CONCLUSIONS: With medical and social support and care, performing LSG on patients with clinically severe obesity and DID is safe, with good short-term results.

Treatments for Staple Line Leakage after Laparoscopic Sleeve Gastrectomy.

The number of laparoscopic sleeve gastrectomies (LSGs) performed in patients with obesity who are eligible for bariatric and metabolic surgery is currently much lower in Japan than in other countries. Considering the large number of potential patients with obesity and type 2 diabetes and the unique Japanese national health insurance system that guarantees fair healthcare delivery, there is room to increase the number of LSGs in Japan in the near future. However, strict health insurance regulations may limit access to mandatory devices needed to treat postoperative complications, such as staple line leakage, which can cause severe morbidity and even mortality. Therefore, understanding the pathogenesis and treatment options for this complication is crucial. This article examined the current situation in Japan and its impact on staple line leakage management, including the role of endoscopic treatment in reducing reoperation. The authors suggest increasing education and collaboration between healthcare professionals to optimize management and improve patient outcomes.

Tolerability of neoadjuvant chemotherapy for esophageal cancer in elderly patients over 76 years of age.

Although the Japan Clinical Oncology Group trial demonstrated that neoadjuvant chemotherapy (NAC) with 5-fluorouracil plus cis-diamminedichloroplatinum had significant survival benefits, it excluded elderly patients aged ≥ 76 years. Therefore, our study aimed to evaluate the tolerability of NAC in elderly patients with esophageal cancer. Classified 174 patients with clinical stage II/III esophageal cancer who underwent esophagectomy from 2010 to 2020 into the E (aged ≥ 76 years; 55 patients) and Y (aged < 76; 119 patients) groups, and retrospectively investigated for clinicopathological findings, tolerability of NAC, relative dose intensity (RDI) and short- and long-term result. Patients who received NAC were fewer in the E group than in the Y group (51% vs 77%, p = 0.001). The E group had relatively lower completion rate of NAC (71% vs 85%, p = 0.116) and significantly lower mean RDI of 5-fluorouracil and cis-diamminedichloroplatinum than the Y group (73% vs 89%, p < 0.001). However, histological and radiological were comparable between both groups. Severe adverse events (grade ≥ 3) were relatively frequent (E, 42.9%; Y, 27.5%, p = 0.091), especially, neutropenia was significantly more frequent in the E group (25.0% vs 7.7%, p = 0.022). There were no differences in the incidence of postoperative complications between with and without NAC in both E and Y groups. Elderly patients with esophageal cancer might be more susceptible to toxicity of NAC. Hence, adequate case selection and careful of dose reduction are needed for elderly with esophageal cancer.

Long-term survival achieved by repeated administration of ramucirumab after drug holidays due to proteinuria in recurrent gastric cancer.

BACKGROUND: The prognosis of recurrent and unresectable gastric cancer remains poor despite the development of multidisciplinary treatments. Ramucirumab (RAM) has been proven effective against unresectable or recurrent gastric cancer. However, its administration is often discontinued because of adverse events, including hypertension and proteinuria. We report a patient with recurrent gastric cancer involving the paraaortic lymph node (PALN), who achieved long-term survival after repeated RAM administration following long-term drug holidays due to proteinuria. CASE PRESENTATION: A 79-year-old woman was diagnosed with advanced gastric cancer (cT4aN2) with PALN metastasis. Seven courses of S-1 plus cisplatin (SP) achieved downstaging. A distal gastrectomy with D2 lymphadenectomy was performed as a conversion surgery. The pathological diagnosis was ypT3N2M0. The dissected PALN did not contain viable cancer cells. CT and positron emission tomography/CT scans revealed PALN recurrence 1 year after the surgery. S-1 plus oxaliplatin (SOX) therapy was initiated. The recurrent PALN enlarged after seven courses of SOX therapy. Paclitaxel (PTX) plus ramucirumab (RAM) therapy was initiated as second-line chemotherapy. After three courses of PTX plus RAM therapy, a partial response was observed. PTX was discontinued because of a hematological adverse event 3.5 months after PALN recurrence. Disease progression was not observed after six courses of RAM monotherapy. However, RAM caused proteinuria and was withdrawn for 7 weeks. The recurrent PALN was enlarged on CT, and RAM monotherapy was resumed at a reduced dose of 6 mg/kg. The lesion subsequently shrank, but 4 + proteinuria occurred after three courses of RAM monotherapy. Thus, RAM was discontinued. The patient had chemotherapy-free days for 14 months until the PALN was re-enlarged to 13 mm in size. The three administrations of RAM successfully controlled PALN metastasis and proteinuria for 3 years. CONCLUSION: In conclusion, even if RAM withdrawal led to disease progression, re-administration of RAM monotherapy while considering its side effects reduced the tumor size and provided long-term survival benefits.

Correction to: A Comparison of the Bariatric Procedures that Are Performed in the Treatment of Super Morbid Obesity.

On page 2539, in the section "The Perioperative Outcome (Table 3)" in line 8 "LRYGB, 165 ± 42.6" should be corrected to "LRYGB, 160 ± 42.6".

Laparoscopic treatment of gastroparesis: a single center experience.

BACKGROUND: Gastroparesis (GP) is a chronic disorder of gastric motility with delayed gastric emptying. Gastric electrical stimulator (GES) implantation and Roux-en-Y gastric bypass (RYGB) are surgical options for medically refractory GP. OBJECTIVE: Evaluate operational outcomes and symptom improvement of patients with diabetic (DM) and idiopathic (IP) GP. SETTING: University Hospital, United States. METHODS: A retrospective chart review was performed of all patients who underwent surgical treatment of GP from February 2003 to December 2014. Subgroup analysis was performed based on etiology of GP (DM versus IP) and procedure received (GES versus RYGB). Postoperative outcomes and postoperative symptom improvements were compared between groups. RESULTS: Of 93 patients, 47 (50.5%) had IP and 46 (49.5%) had DM. The majority underwent GES implantation (83.8%, n = 78), and 15 patients (16%) underwent RYGB. There were significant differences in hospital stay (2 versus 3 days) and reoperation rate (30% versus 7%) between IP and DM. Operation time, complication rate, and 30-day readmission rate were similar in both groups. DM patients significantly improved GP-related complaints compared with preoperatively. IP patients also improved nausea and vomiting and had no change in abdominal pain between pre- and postoperative period. GES showed significant improvement of nausea, vomiting, and abdominal pain. RYGB showed improvement of nausea, but not vomiting or abdominal pain. CONCLUSIONS: Surgery is a feasible intervention for GP for both DM and IP patients; however, based on the data presented in this manuscript and the current literature, the use of gastric bypass as an effective treatment modality for patients with intractable GP remains highly controversial. Care must be taken for IP patients in the postoperative period due to high incidence of reoperation. Although both procedures offer some degree of symptomatic improvement, GES seems to provide improvement of more GP symptoms. However, there is no significant difference in the need for postoperative medications regardless of the procedure used.

Mid-term results of bariatric surgery in morbidly obese Japanese patients with slow progressive autoimmune diabetes.

INTRODUCTION: Bariatric surgery is recognized as an effective treatment for type 2 diabetes mellitus, but data on its efficacy for type 1 diabetes mellitus, especially slowly progressive insulin-dependent diabetes mellitus, are limited. METHODS: We investigated five Japanese patients with slowly progressive insulin-dependent diabetes mellitus who underwent bariatric surgery at our center. RESULTS: Five morbidly obese glutamic acid decarboxylase antibody-positive diabetic patients underwent two different types of bariatric surgery. The mean titer of anti-glutamic acid decarboxylase antibody was 4.6 U/mL, and the mean preoperative bodyweight and BMI were 113 kg and 39.6 kg/m2 , respectively. The mean hemoglobin A1c was 8.4%. The mean fasting serum C-peptide was 5.0 ng/mL. Laparoscopic sleeve gastrectomy was performed in two patients, while laparoscopic sleeve gastrectomy with duodenojejunal bypass was performed in three patients. At one year after surgery, the mean bodyweight and BMI significantly dropped, and the mean percentage of excess weight loss was 96.4%. The mean hemoglobin A1c was 5.7%. This favorable trend was maintained at mid-term. CONCLUSION: Bariatric surgery for morbidly obese patients with anti-glutamic acid decarboxylase antibody-positive type 1 diabetes mellitus, especially slow progressive autoimmune diabetes, seemed effective in achieving mid-term glycemic control. Longer follow-up with a larger number of patients, as well as validation with more advanced patients with slowly progressive insulin-dependent diabetes mellitus, will be needed.

Prevalence of Chronic Kidney Disease in Morbidly Obese Japanese and the Impact of Bariatric Surgery on Disease Progression.

BACKGROUND: The prevalence of chronic kidney disease (CKD) among Japanese morbidly obese patients undergoing bariatric surgery and the impact of bariatric surgery on their renal function has not previously been investigated. OBJECTIVES: The aims were to assess the prevalence of CKD patients who underwent bariatric surgery in our institution and to elucidate the impact of bariatric surgery on their kidney function as measured by the estimated glomerular filtration rate by Cystatin-C (eGFRcys). SETTING: The setting of the study was in a single private hospital. METHODS: Two hundred fifty-four consecutive Japanese patients who underwent bariatric surgery were retrospectively analyzed to elucidate the prevalence of CKD. The eGFRcys was calculated to assess the change in the kidney function for 1 year after surgery. RESULTS: The preoperative prevalence of CKD was as follows: G1, 45.3%; G2, 47.2%; G3, 6.5%; and G4, 0.9%. The eGFRcys values before and after surgery were compared; the G1 and G2 patients showed significantly improved eGFRcys values after surgery (G1 101 [94-108] vs 114 [103-127]; G2 79 [74-84] vs 97 [87-104] ml/min/1.73 m2; p < 0.01) with significant weight loss (G1 38.1 ± 6.2 vs 26.5 ± 3.4; G2 38.5 ± 6.9 vs 26.7 ± 3.6 kg/m2; p < 0.01). Although the renal function of G3 patients was not improved after surgery (44 [42-47] vs 45 [43-63] ml/min/1.73 m2; p = 0.08), successful weight loss was achieved (36.1 ± 6.3 vs 26.6 ± 3.6 kg/m2; p < 0.01). In multivariate analysis, postoperative eGFRcys correlated negatively with proteinuria (p < 0.01), age (p < 0.01), and body mass index (p < 0.01) and positively with persistence of antihypertensive drugs. CONCLUSION: Bariatric surgery resulted in the significant improvement in the eGFRcys values of Japanese patients with morbid obesity, particularly those with pre-CKD (eGFRcys ≥ 60 ml/min/1.73 m2), while the eGFRcys values of CKD patients (< 60 ml/min/1.73 m2) were not ameliorated by surgery.

Feasibility of Laparoscopic Resection of Gastrointestinal Stromal Tumor of the Stomach.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Complete surgical resection of localized GISTs is the only chance of cure for patients. Laparoscopic resections (LAP) have been widely accepted as a reasonable approach to treat gastric GISTs. The current study compares operative outcomes of laparoscopic and open resection of gastric GISTs. MATERIALS AND METHODS: We retrospectively reviewed patients with primary gastric GISTs who underwent surgical resection between 2003 and 2015. RESULTS: Of a total of 89 patients, 24 (27%) patients underwent open resection (OPEN), and 65 (73%) underwent LAP. LAP or OPEN did not differ with respect to gender, body mass index, and age. Median blood loss was significantly lower in LAP than in OPEN resection (32.5 mL versus 100 mL, P < .01). Both tumor location and median operative time were comparable between LAP and OPEN (108 versus 108 min, P = .93). Median tumor size in OPEN was significantly larger than LAP tumors (6.5 versus 3.8 cm, P < .01). LAP resection yielded a shorter hospital stay (3.0 versus 6.0 days P < .01) and lower 30-day readmission rate (17% versus 0%; P < .01). Complication rates were 9% after LAP and 12% after OPEN (P = .652). Two patients in each group died during the study period. Kaplan-Meier analysis for overall survival showed no significant difference between LAP and OPEN (P = .23). CONCLUSIONS: LAP of gastric GISTs resulted in similar operative time and survival rate, but shorter hospital stay compared with open resection. Consequently, whenever possible, the laparoscopic approach should be preferably used for treatment of gastric GISTs. However, advanced tumor stage might dictate the need for open procedure with expected worse results.

A Comparison of the Bariatric Procedures that Are Performed in the Treatment of Super Morbid Obesity.

BACKGROUND: We have experienced numerous cases of super morbid obesity (SMO), defined by a BMI of ≥50 kg/m2, in which laparoscopic sleeve gastrectomy (LSG) was not able to achieve a sufficient weight loss effect. However, the most appropriate procedure for the treatment of SMO has not yet been established. METHODS: The subjects included 248 successive patients who underwent surgery at our hospital from June 2006 to December 2012. We divided the subjects into an SMO group (BMI, 50 to <70 kg/m2) and a morbid obesity (MO) group (BMI, 35 to <50 kg/m2). The subjects underwent LSG, LSG with duodenojejunal bypass (LSG/DJB), or laparoscopic Roux-en-Y gastric bypass (LRYGB). The weight loss effects, safety of surgery, and metabolic profile changes were compared. RESULTS: Sixty-two subjects were classified into the SMO group (25%). The percent excess weight loss (%EWL) after LSG among the patients in the SMO group was not significantly different from that of patients who underwent other procedures. LSG was associated with a significantly lower success rate in terms of weight loss (%EWL ≥ 50%), in comparison to the weight loss at 1 year after LRYGB and at 2 years after LSG/DJB and LRYGB. Among the patients in the MO group, the %EWL and the rate of successful weight loss did not differ to a statistically significant extent. CONCLUSION: This study demonstrated that in patients with SMO, LSG/DJB and LRYGB can achieve superior weight loss effects in comparison to LSG.

LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum.

Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a putative serine protease inhibitor encoded by serine protease inhibitor Kazal-type 5 (SPINK5). It is strongly expressed in differentiated keratinocytes in normal skin but expression is markedly reduced or absent in Netherton syndrome (NS), a severe ichthyosis caused by SPINK5 mutations. At present, however, both the precise intracellular localization and biological roles of LEKTI are not known. To understand the functional role of LEKTI, we examined the localization of LEKTI together with kallikrein (KLK)7 and KLK5, possible targets of LEKTI, in the human epidermis, by confocal laser scanning microscopy and immunoelectron microscopy. In normal skin, LEKTI, KLK7, and KLK5 were all found in the lamellar granule (LG) system, but were separately localized. LEKTI was expressed earlier than KLK7 and KLK5. In NS skin, LEKTI was absent and an abnormal split in the superficial stratum granulosum was seen in three of four cases. Collectively, these results suggest that in normal skin the LG system transports and secretes LEKTI earlier than KLK7 and KLK5 preventing premature loss of stratum corneum integrity/cohesion. Our data provide new insights into the biological functions of LG and the pathogenesis of NS.