Efficacy and safety of add-on mirogabalin to conventional therapy for the treatment of peripheral neuropathic pain after thoracic surgery: the multicenter, randomized, open-label ADMIT-NeP study.

BACKGROUND: For chronic pain after thoracic surgery, optimal timing of its diagnosis and effective treatment remains unresolved, although several treatment options are currently available. We examined the efficacy and safety of mirogabalin, in combination with conventional pain therapy (nonsteroidal anti-inflammatory drugs and/or acetaminophen), for treating peripheral neuropathic pain (NeP) after thoracic surgery. METHODS: In this multicenter, randomized, open-label, parallel-group study, patients with peripheral NeP were randomly assigned 1:1 to mirogabalin as add-on to conventional therapy or conventional treatment alone. RESULTS: Of 131 patients of consent obtained, 128 were randomized (mirogabalin add-on group, 63 patients; conventional treatment group, 65 patients). The least squares mean changes (95% confidence interval [CI]) in Visual Analogue Scale (VAS) score for pain intensity at rest from baseline to Week 8 (primary endpoint) were - 51.3 (- 54.9, - 47.7) mm in the mirogabalin add-on group and - 47.7 (- 51.2, - 44.2) mm in the conventional group (between-group difference: - 3.6 [95% CI: - 8.7, 1.5], P = 0.161). However, in patients with Self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) score (used for the screening of NeP) ≥ 12 at baseline, the greater the S-LANSS score at baseline, the greater the decrease in VAS score in the mirogabalin add-on group, while no such trend was observed in the conventional treatment group (post hoc analysis). This between-group difference in trends was statistically significant (interaction P value = 0.014). Chronic pain was recorded in 7.9% vs. 16.9% of patients (P = 0.171) at Week 12 in the mirogabalin add-on vs. conventional treatment groups, respectively. Regarding activities of daily living (ADL) and quality of life (QOL), changes in Pain Disability Assessment Scale score and the EQ-5D-5L index value from baseline to Week 8 showed significant improvement in the mirogabalin add-on group vs. conventional treatment group (P < 0.001). The most common adverse events (AEs) in the mirogabalin add-on group were dizziness (12.7%), somnolence (7.9%), and urticaria (3.2%). Most AEs were mild or moderate in severity. CONCLUSIONS: Addition of mirogabalin to conventional therapy did not result in significant improvement in pain intensity based on VAS scores, but did result in significant improvement in ADL and QOL in patients with peripheral NeP after thoracic surgery. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs071200053 (registered 17/11/2020).

Long-term outcomes and early recurrence after resection for metachronous pulmonary metastases from colorectal cancer.

PURPOSE: Properly selecting patients for aggressive curative resection for pulmonary metastases (PMs) from colorectal cancer (CRC) is desirable. We purposed to clarify prognostic factors and risk factors for early recurrence after metachronous PM resection. METHODS: Clinical data of 151 patients who underwent R0 resection for metachronous PMs from CRC at two institutions between 2008 and 2021 were reviewed. RESULTS: Seventy-six patients (50.3%) were male, and the median age was 71 (42-91) years. The numbers of colon/rectal cancers were 76/75, with pStage I/II/III/IV/unknown in 15/34/86/13/3. The duration from primary surgery to PM was 19.7 (1.0-106.4) months. The follow-up period was 41.9 (0.3-156.2) months. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 75.1%, 53.7%, and 51.1%, and the 1-, 3-, and 5-year overall survival (OS) rates were 97.7%, 87.5%, and 68.2%. On multivariate analysis, lymph node metastasis of the primary lesion (HR 1.683, 95%CI 1.003-2.824, p = 0.049) was an independent predictor of poor RFS, and history of resection for extrapulmonary metastasis (e-PM) (HR 2.328, 95%CI 1.139-4.761, p = 0.021) was an independent predictor of poor OS. Patients who experienced early recurrence (< 6 months) after PM resection showed poorer OS than others (3-year OS 50.8% vs. 90.2%, p = 0.002). On multivariate analysis, e-PM was an independent predictor of early recurrence after PM resection (OR 3.989, 95%CI 1.002-15.885, p = 0.049). CONCLUSION: Since a history of e-PM was a predictor of early recurrence and poor OS after R0 resection for PM, surgical treatment of patients with a history of e-PM should be considered carefully.

A single-arm, phase 2 study of adjuvant chemotherapy with oral tegafur-uracil for pathologically lymphovascular invasion positive stage IA non-small cell lung cancer: LOGIK0602 study.

BACKGROUND: Lymphovascular invasion (LVI), which includes vascular or lymphatic invasions, is a representative prognostic factor even in patients with resected stage IA non-small cell lung cancer (NSCLC). Because tegafur-uracil is effective on cancers with LVI, we conducted a multi-center single-arm phase II study to estimate the efficacy of adjuvant tegafur-uracil in patients with LVI-positive stage IA NSCLC. METHODS: Patients with completely resected LVI-positive stage IA NSCLC were registered. LVI was diagnosed by consensus of two of three pathologists. Adjuvant chemotherapy consisted of 2 years of oral tegafur-uracil at 250 mg/m2/day. Fifty-five patients from 7 institutions were enrolled from June 2007 to September 2012. RESULTS: Among the 52 eligible patients, 36 (69.2%) completed the treatment course. There were 39 male and 13 female patients. The observation period was calculated as 562 to 3107 days using the reverse Kaplan-Meier method. The 5-year overall and relapse free survival rates were 94.2 and 88.5% respectively, which were significantly better than that of any other studies conducted on patients with LVI-positive stage IA NSCLC. Notably, the overall survival rate was 15% better than that of our prior retrospective study. The retrospective analysis of stage IA NSCLC patients who had received an operation in the same period revealed that the 5-year overall survival rate of the LVI positive group was 73.6% when adjuvant chemotherapy was not applied. Among 55 safety analysis sets, 4 cases of grade 3 hepatic function disorder (9.1%) and 5 cases of grade 2 anorexia (10.9%) were most frequently observed. No grade 4 adverse effects were encountered. CONCLUSION: A 2-year course of oral tegafur-uracil administration is feasible and might have a significant benefit in the adjuvant treatment of LVI-positive stage IA NSCLC. TRIAL REGISTRATION: UMIN identifier: UMIN000005921 ; Date of enrolment of the first participant to the trial: 19 June 2007; Date of registration: 5 July 2011 (retrospectively registered).

Double stenting with silicone and metallic stents for malignant airway stenosis.

For severe malignant airway stenosis, there are several types of commercially available airway stents, and each has its own advantages and disadvantages. We herein describe the safety and efficacy of combination stenting with silicone and metallic stents for patients with extended malignant airway stenosis. Seven patients with malignant airway stenosis were treated via combination stenting with a silicone stent and a metallic stent for extended airway stenosis from the central to peripheral airways. Five patients were diagnosed with advanced esophageal cancer, two of whom had tracheoesophageal fistulas. One patient had adenoid cystic carcinoma, and another had mediastinal tumor. There were no specific complications related to the double stenting. Combination stenting with silicone and metallic stents proved to be a safe option for patients with severe, extended, and complicated malignant airway stenosis.

Ratio of C-reactive protein to albumin is a prognostic factor for operable non-small-cell lung cancer in elderly patients.

PURPOSE: The aim of this retrospective study was to evaluate inflammation-based scoring as a prognostic factor for operable non-small-cell lung cancer (NSCLC) in elderly patients. METHODS: We collected preoperative data from 108 patients aged above 80 years with NSCLC. Inflammation-based scoring systems, including the C-reactive protein to albumin ratio (CAR) and the Glasgow prognostic score (GPS), as well as other clinicopathological factors, were evaluated as potential prognostic factors. RESULTS: The median patient age was 82 (range 80-93) years and the 5-year overall and disease-specific survival rates were 49.7 and 73.9%, respectively. The cut-off value for CAR was calculated using a receiver operator characteristics analysis and patients were dichotomized accordingly. Patients with a low CAR had significantly higher overall survival than those with a high CAR (<0.028; 65.2% vs. ≥0.028; 31.0%, respectively; p < 0.01). In univariate analysis, female gender, a low Charlson comorbidity index of 0 or 1 and a low CAR were significantly identified in overall survival. On multivariate analysis, a low CAR (p = 0.03, hazard ratio: 2.13, 95% confidence interval 1.074-4.295) was identified as a significant prognostic factor. CONCLUSIONS: The preoperative CAR is a useful predictor of overall survival and could be a simple prognostic tool to help identify resectable NSCLC in elderly patients.

Surgery or stereotactic body radiotherapy for elderly stage I lung cancer? A propensity score matching analysis.

PURPOSE: The aim of this study was to compare the outcomes of surgery and stereotactic body radiotherapy (SBRT) for elderly clinical stage I non-small cell lung cancer (NSCLC) patients. METHODS: Patients ≥80 years of age with clinical stage I NSCLC between August 2008 and December 2014 were treated either surgery or SBRT. Propensity score matching was performed to reduce bias in various clinicopathological factors. RESULTS: Surgery was performed in 57 cases and SBRT in 41 cases. In the surgery group, the operations included 34 lobectomies and 23 sublobar resections. In the SBRT group, 27 cases were given 48 Gy in 4 fractions, and 14 were given 60 Gy in 10 fractions. Similar characteristics were identified in age (82 years), gender (male:female ratio 2:1), tumor size (2.2 cm), carcinoembryonic antigen (3.6 ng/ml), Charlson comorbidity index (1), Glasgow prognostic scale (0), and forced expiratory volume in 1 s (1.7 L) after matching. Before matching, the 5-year overall survival (OS) in surgery (68.3%) was significantly better than that in SBRT (47.4%, p = 0.02), and the 5-year disease-specific survival (DSS) (94.1%, 78.2%, p = 0.17) was not significantly different between the groups. The difference in the 5-year OS became non-significant between the matched pairs (57.0%, 49.1%, p = 0.56). CONCLUSIONS: The outcomes of surgery and SBRT for elderly patients with the early stage NSCLC were roughly the same.

[Anastomotic Airway Complications after Lung Transplantation].

Anastomotic airway complications still remain an important issue after lung transplantation. Most of the complications are stenosis and anastomotic leakage. Stent insertion is one option for the stenosis. We review the anastomotic airway complications and report our recent experience of stent insertion using 3-dimensional printed airway model.

Giant benign intrathoracic schwannoma: a decade-long progression towards fatality.

BACKGROUND: Intrathoracic neurogenic tumors arise from sympathetic nerve trunks and intercostal nerves; more than 90% are benign. Schwannomas are the most common histological variety, but fatalities due to giant schwannomas are rare. CASE PRESENTATION: We report a case of a 65-year-old woman who presented with chest pain and cough. Computed tomography (CT) revealed a large left chest wall mass of 130-mm in size, and the patient was referred to our department. Tumor biopsy was performed under local anesthesia, and a diagnosis of schwannoma was made. Ten years previously, a 30-mm tumor had been noted in the left third intercostal space by a previous doctor, but follow-up had been interrupted owing to depressive disorder. Although we planned to perform intercostal artery embolization followed by chest wall tumor resection, the patient did not consent to surgery due to uncontrolled depression. After four months, she developed respiratory failure caused by compression due to an enlarged tumor and died. Autopsy also revealed a benign schwannoma with no malignant findings. CONCLUSIONS: Although schwannomas are benign tumors, there are some very rare cases in which they can become huge and life-threatening. Therefore, a benign tumor should not be neglected, and if surgery is not possible at the time of diagnosis, a regular follow up is necessary, in order not to miss the right timing for surgery.

[A patient with small cell lung cancer who developed a drug eruption due to concomitant therapy with carboplatin and etoposide].

We describe a case of a 69-year-old male patient with small cell lung cancer who developed a drug eruption due to concomitant therapy with carboplatin and etoposide. During simultaneous therapy with carboplatin and etoposide and radiotherapy, moderate drug eruption developed on the 11th day of the treatment. In a drug-induced lymphocyte stimulation assay, a negative result was confirmed for carboplatin, however, the responsiveness to etoposide could not be determined due to test drug-derived lymphocytic impairment. In the second course, irinotecan was administered instead of etoposide, and no drug eruption was observed. Thus, there was a high likelihood that the drug eruption observed in this case may have been caused by an allergic response to etoposide or its additives. Since some reports have demonstrated that the incidence of hypersensitivities, including drug eruption, to etoposide would increase in a dose-dependent manner, further accumulation and investigation of clinical data are required.

Three-dimensional (3D) bronchial tree model for bronchial resection with pulmonary segmentectomy.

There has been an increase in pulmonary segmentectomy procedures because of increased numbers of individuals with small lung cancer. However, it is difficult to identify the correct bronchus during surgery even with pre-operative three-dimensional (3D) computed tomography. We investigated using a 3D-printed model of the bronchi to prepare for bronchus resection during pulmonary segmentectomy. The model was useful to determine pre-operatively which bronchus should be transected, and being composed of a soft material it could be mobilized similarly to the actual bronchus during surgery. This simulation can increase surgeons' confidence to identify the correct bronchus during pulmonary segmentectomy.

Adenocarcinoma arising from an enteric cyst of the posterior mediastinum.

Mediastinal enteric cysts are rare congenital thoracic cysts. The majority of mediastinal enteric cysts occur in infants, while they are rare in adults. Although most of these cysts are benign, surgical resection is sometimes performed, and malignant changes found in enteric cysts are rare. A 52-year-old man was incidentally discovered to have a posterior mediastinal mass and we excised the mass thoracoscopically. Histopathological findings showed an enteric cyst with adenocarcinoma. Comparing the pathological and magnetic resonance imaging (MRI) findings, MRI would help to detect malignant changes in such cysts. Although malignant changes found in mediastinal enteric cysts are extremely rare, clinicians should always keep in mind that those cysts have malignant potential and careful evaluation of MRI would be a clue for surgical indication.

Is Pleurectomy/Decortication Superior to Extrapleural Pneumonectomy for Patients with Malignant Pleural Mesothelioma? A Single-Institutional Experience.

PURPOSE: This study was performed to compare the outcome of pleurectomy/decortication (P/D) with that of extrapleural pneumonectomy (EPP) for patients with malignant pleural mesothelioma (MPM). METHODS: Patients with MPM underwent either P/D or EPP from August 2008 to December 2014. Various clinicopathological factors were analyzed to identify differences between the two procedures. RESULTS: P/D was performed in nine patients and EPP in 30 patients. Most of the patients' background characteristics were not significantly different between the groups. The surgery time (680 vs. 586 min, p = 0.0034) and bleeding volume (4050 vs. 2110 mL, p = 0.002) were significantly greater in P/D than in EPP; however, grade ≥3 complications (44% vs. 33%, p = 0.54) and length of postoperative hospital stay (29 vs. 37 days, p = 0.26) were not significantly different. The median survival time and 2- and 3-year survival rates in all patients were 16.7 months, 28.5%, and 15.3%, respectively. The median survival time and 2- and 3-year survival in the P/D and EPP groups were 22.5 months, 43.8%, and 43.8% and 16.5 months, 24.0%, and 14.4%, respectively (p = 0.13). CONCLUSION: Survival of patients with MPM remains poor despite multidisciplinary treatment. P/D is comparable with EPP and could be a safe and another surgical treatment for patients with MPM.

Stage IA non-small cell lung cancer: vessel invasion is a poor prognostic factor and a new target of adjuvant chemotherapy.

This study reports the efficacy of adjuvant chemotherapy in stage IA non-small cell lung cancer (NSCLC) with vessel invasion (Vi). We sub-divided 322 patients with surgically resected pathological stage IA NSCLC into two groups according to Vi [non-Vi (n=237) and Vi (n=85)]. Both groups were compared with regard to age, gender, performance status, smoking habits, serum carcinoembryonic antigen level, extent of surgery, tumour size, histopathology, recurrence sites, and survival. The overall 5-year survival rates of non-Vi and Vi groups were 89.6% and 71.8% (P<0.001), respectively. Distant metastasis was observed more frequently in the Vi group (P<0.001, risk ratio: 9.06). Univariate and multivariable analyses identified poor performance status, squamous cell carcinoma, tumour size>or=15 mm and Vi as poor prognostic factors (P<0.05). The overall 5-year survival rate of stage IA Vi group nearly overlapped with that of patients with stage IB NSCLC. Retrospectively, oral uracil-tegafur chemotherapy increased the overall 5-year survival rate of stage IA Vi group by more than 25% (P=0.036). In conclusion, vessel invasion is a poor prognostic factor in patients with stage IA NSCLC. Prognosis of patients with Vi-stage IA NSCLC is similar to that of patients with stage IB NSCLC and is improved significantly by postoperative oral uracil-tegafur chemotherapy. Our preliminary study suggests that stage IA Vi group benefits from adjuvant chemotherapy.

Temporary bypass for superior vena cava reconstruction with Anthron bypass tubeTM.

Total superior vena cava (SVC) clamping for SVC replacement or repair can be used in thoracic surgery. A bypass technique is an option to avoid hemodynamic instability and cerebral venous hypertension and hypoperfusion. The present report describes a venous bypass technique using Anthron bypass tubeTM for total SVC clamping. Indications for this procedure include the need for a temporary bypass between the brachiocephalic vein and atrium for complete tumor resection. This procedure allows the surgeons sufficient time to complete replacement of SVC or partial resection of SVC without adverse effects. Further, it is a relatively simple procedure requiring minimal time.

Avoiding completion pneumonectomy by omentopexy for bronchial dehiscence.

A 56-year-old man underwent right upper sleeve lobectomy with mediastinal lymph node dissection after induction chemoradiotherapy (CRT) for advanced non-small cell lung cancer (NSCLC). The patient developed anastomotic dehiscence 11 days postoperatively. A fistula measuring 10 mm in diameter was found around the transition region between cartilage and membranous portions of the bronchus. To avoid completion right pneumonectomy, omentopexy was performed to cover the bronchial dehiscence and facilitate healing. The patient's condition improved after a redo operation with surveillance bronchoscopy to check the anastomotic status. Omentopexy may be a feasible treatment option for bronchial dehiscence and could help to avoid completion pneumonectomy (CP).

Single lung retrieval from a donor supported by a left ventricular assist device.

The number of patients who need cardiac support with a left ventricular assist device (LVAD) has increased over the last decade. However, the number of reports of organ retrieval from donors with an LVAD is still small. Successful lung retrieval for single lung transplantation was performed from a donor on LVAD support. This required special care not to injure the heart, great vessels, and the device, particularly the outflow conduit, because of significant conglutination around the device. A right single lung transplantation was performed successfully, with no postoperative complications. This means that patients on an LVAD could be potential donors for lung transplantation.

Transplantation of bioengineered rat lungs recellularized with endothelial and adipose-derived stromal cells.

Bioengineered lungs consisting of a decellularized lung scaffold that is repopulated with a patient's own cells could provide desperately needed donor organs in the future. This approach has been tested in rats, and has been partially explored in porcine and human lungs. However, existing bioengineered lungs are fragile, in part because of their immature vascular structure. Herein, we report the application of adipose-derived stem/stromal cells (ASCs) for engineering the pulmonary vasculature in a decellularized rat lung scaffold. We found that pre-seeded ASCs differentiated into pericytes and stabilized the endothelial cell (EC) monolayer in nascent pulmonary vessels, thereby contributing to EC survival in the regenerated lungs. The ASC-mediated stabilization of the ECs clearly reduced vascular permeability and suppressed alveolar hemorrhage in an orthotopic transplant model for up to 3 h after extubation. Fibroblast growth factor 9, a mesenchyme-targeting growth factor, enhanced ASC differentiation into pericytes but overstimulated their proliferation, causing a partial obstruction of the vasculature in the regenerated lung. ASCs may therefore provide a promising cell source for vascular regeneration in bioengineered lungs, though additional work is needed to optimize the growth factor or hormone milieu for organ culture.

Is early postoperative administration of pregabalin beneficial for patients with lung cancer?-randomized control trial.

BACKGROUND: Post-thoracotomy pain is an obstacle for lung-cancer patients even after introduction of less invasive surgical procedures. The aim of this prospective study was to evaluate if early postoperative administration of pregabalin is beneficial for patients with non-small cell lung cancer (NSCLC). METHODS: We conducted a randomized open control trial. Patients with NSCLC were allocated randomly to epidural and nonsteroidal anti-inflammatory drug (NSAID) use for analgesia (control group) or pregabalin use (pregabalin group). Primary endpoint was the frequency of additional administration of a NSAID. Secondary endpoints were intensity of ongoing pain, frequency of neuropathic pain, and pain catastrophizing. RESULTS: Seventy-two patients were registered and allocated. Thirty-four cases in the control group and 33 in the pregabalin group were assessed. Age, sex, body mass index (BMI), type of surgical procedure, type of lymph-node dissection, operation time, bleeding, duration of chest-tube insertion, and postoperative hospital stay between the two groups was not significantly different. Frequency of additional NSAID use between the control group (2±4 suppositories) and pregabalin group (2±3 suppositories) was not significantly different (P=0.62). Numeric Rating Scale (NRS) for the intensity of ongoing pain, frequency of neuropathic pain, and Pain Catastrophizing Scale (PCS) between each group were not significantly different at any time until 3 months after surgery. CONCLUSIONS: Early postoperative administration of pregabalin is not beneficial for patients with NSCLC.

Overexpression of the adiponectin gene mimics the metabolic and stress resistance effects of calorie restriction, but not the anti-tumor effect.

Adiponectin (Adipoq), a peptide hormone secreted from the white adipose tissue, may play a role in the anti-aging and/or anti-tumor effects of calorie restriction (CR). We analyzed metabolic traits in Adipoq gene-overexpressing mice fed ad libitum with a regular diet (RD) or a high-fat diet (HFD), or fed 30% CR of RD initiated at 12 weeks of age. Adipoq-RD and -HFD mice at 6 months of age showed reduced blood glucose and insulin concentrations, and thus increased insulin sensitivity, compared with WT mice fed a RD or a HFD. In the epididymal white adipose tissue in Adipoq mice, senescence-like changes such as upregulation of p53 protein and of biomarkers of inflammation, Cd68 and Ccl2 mRNA, were ameliorated compared with WT-RD and WT-HFD mouse tissues. Resistance to stress induced by lipopolysaccharide was also strengthened in Adipoq mice compared with WT mice. These metabolic changes and stress resistance were also noted in the WT-CR mice, suggesting that Adipoq plays a part in the effect of CR. In contrast, in an allograft tumor growth model, tumor growth was not inhibited in Adipoq mice. The present findings suggest that Adipoq plays a part in the anti-aging, but not in the anti-tumor, effects of CR.

Intratracheal Administration of Recombinant Human Keratinocyte Growth Factor Promotes Alveolar Epithelial Cell Proliferation during Compensatory Lung Growth in Rat.

Keratinocyte growth factor (KGF) is considered to be one of the most important mitogens for lung epithelial cells. The objectives of this study were to confirm the effectiveness of intratracheal injection of recombinant human KGF (rhKGF) during compensatory lung growth and to optimize the instillation protocol. Here, trilobectomy in adult rat was performed, followed by intratracheal rhKGF instillation with low (0.4 mg/kg) and high (4 mg/kg) doses at various time-points. The proliferation of alveolar cells was assessed by the immunostaining for proliferating cell nuclear antigen (PCNA) in the residual lung. We also investigated other immunohistochemical parameters such as KGF, KGF receptor and surfactant protein A as well as terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Consequently, intratracheal single injection of rhKGF in high dose group significantly increased PCNA labeling index (LI) of alveolar cells in the remaining lung. Surprisingly, there was no difference in PCNA LI between low and high doses of rhKGF with daily injection, and PCNA LI reached a plateau level with 2 days-consecutive administration (about 60%). Our results indicate that even at low dose, daily intratracheal injection is effective to maintain high proliferative states during the early phase of compensatory lung growth.