Using singular value decomposition to analyze drug/ß-cyclodextrin mixtures: insights from X-ray powder diffraction patterns.

The article discusses the use of mathematical models and linear algebra to understand the crystalline structures and interconversion pathways of drug complexes with ß-cyclodextrin (ß-CD). It involved the preparation and analysis of mixtures of indomethacin, diclofenac, famotidine, and cimetidine with ß-CD using techniques such as differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and proton nuclear magnetic resonance (1H-NMR). Singular value decomposition (SVD) analysis is used to identify the presence of different polymorphs in the mixtures of these drugs and ß-CD, determine interconversion pathways, and distinguish between different forms. In general, linear algebra or artificial intelligence (AI) is used to approximate the contribution of distinguishable entities to various phenomena. We expected linear algebra to completely reveal all eight entities present in the diffractogram dataset. However, after performing the SVD procedure, we found that only six independent basis functions were extracted, and the entities of the INM α-form and the CIM B-form were not included. It is considered that this is due to that data processing is limited to revealing only six or seven independent factors, as it is a small world. The authors caution that these may not always reproduce or approach reality in complicated real-world situations.

Stabilization of the Metastable α-Form of Indomethacin Induced by the Addition of 2-Hydroxypropyl-ß-Cyclodextrin, Causing Supersaturation (Spring) and Its Sustaining Deployment (Parachute).

The purpose of this study is to find that a small amount of 2-Hydroxypropyl-ß-cyclodextrin (HP-ß-CD) can produce a parachute effect on indomethacin (INM). From the examination of dissolution curves and concentration after several days, the supersaturation of INM was observed for the mixtures containing HP-ß-CD at a molar ratio ≤ 0.5, and the sustained deployment of supersaturation was found not only in equimolar mixtures but also in mixtures with a shortage of HP-ß-CD. In the solid state, it was compared the physical properties of INM/HP-ß-CD mixtures using two different mixing methods and determined the stoichiometry of INM and HP-ß-CD. Differential scanning calorimetry (DSC) revealed that the polymorphs of INM were converted by HP-ß-CD into an amorphous state. Furthermore, X-ray powder diffraction (XRPD) and DSC-XRPD demonstrated that INM crystals from the INM/HP-ß-CD mixture prepared from an EtOH solution were metastable. In conclusion, these phenomena may be considered the "spring" and "parachute" effects of mixtures with a shortage of HP-ß-CD, as they depended on the presence of the metastable α-form of INM. The addition of 1/3 to 1/20 equivalents of HP-ß-CD to INM enhanced INM solubility.

Non-incisional pleurectomy/decortication for malignant pleural mesothelioma.

OBJECTIVE: Pleurectomy/decortication has been preferably employed as a curative-intent surgery for malignant pleural mesothelioma. However, visceral pleurectomy during pleurectomy/decortication provides technical challenges. For visceral pleurectomy, pleural incisions are commonly made to create a dissection plane between the visceral pleura and the lung parenchyma, which may cause tumor dissemination and may not allow en bloc complete resection of the entire pleura. To overcome such potential disadvantages, we have developed a novel surgical technique without any pleural incision (non-incisional pleurectomy/decortication) to achieve en bloc removal of the entire pleura. METHODS: A total of 36 consecutive patients who underwent non-incisional pleurectomy/decortication for malignant pleural mesothelioma from January 2017 through December 2020 in our institute were retrospectively reviewed to assess the feasibility. RESULTS: Macroscopic complete resection was achieved in 31 patients (86.1%) with non-incisional pleurectomy/decortication. In the majority of patients (n = 29), en bloc complete resection of the entire pleura was achieved (without pleural laceration in 10 and with some pleural laceration in 19 patients). The total operation time and the duration of visceral pleurectomy were significantly shorter as compared with those for conventional pleurectomy/decortication (median, 350 versus 506 min [P = 0.011], and 43 versus 97 min [P < 0.001], respectively). Among 36 patients who underwent non-incisional pleurectomy/decortication, postoperative complications developed in 13 patients (36.1%), and one patient died on the postoperative day 95 caused by aggressive tumor progression of residual tumor. CONCLUSIONS: Non-incisional pleurectomy/decortication is a fast and feasible technique to achieve en bloc macroscopic complete resection for malignant pleural mesothelioma.

Novel technique to repair a bronchopleural fistula after esophagectomy using wide intercostal muscle flap fixed by azygos vein and bronchus: a case report.

BACKGROUND: Post-esophagectomy bronchopleural fistulas can be life-threatening in patients who are exhausted, for example, by surgical stress and pleural infection; therefore, establishment of a reliable surgical procedure is extremely important. We here report a novel procedure entailing muscle flap closure for bronchopleural fistula. CASE PRESENTATION: A 64-year-old man developed a right bronchopleural fistula after esophagectomy. Because he was exhausted by surgical stress and malnourished, we considered reliable surgical closure of the fistula essential. Intraoperatively, it was found to connect with the membranous portion of the right main bronchus. We decided to close the fistula with a pedicled fourth and fifth intercostal muscle flap. After separating the intercostal muscles near the angle of the rib, we passed a muscle flap between the azygos vein and bronchus and sutured it securely to the fistula. The postoperative course was uneventful, and there was no thoracic infection. Postoperative bronchoscopy confirmed the muscle flap had securely closed the fistula. CONCLUSIONS: The route and suturing technique of the intercostal muscle flap to a fistula are important, especially in exhausted patients.

Relationship Between Phase Solubility Diagrams and Crystalline Structures During Dissolution of Cimetidine/Cyclodextrin Complex Crystals.

Cyclodextrins (CDs) form complex crystals with drugs and improve physicochemical properties of drugs. However, only few reports have summarized relationships between crystal structures of drug/CD and dissolution behavior. In this study, we developed cimetidine (CIM)/CD complex crystals to achieve sustained drug release and investigated the relationship between the dissolution behavior of CIM/CD complexes and their crystal structures. CIM and 3 types of CDs (α-, ß-, and γ-CD) formed a complex crystal when subjected to solvent mixing. The CIM/CD complexes had a highly reduced dissolution rate compared to that of the physical mixture of CIM and CD. ß-CD improved the solubility of CIM, whereas γ-CD decreased its solubility. Based on the phase solubility diagram, CIM and α-, ß-, and γ-CD indicated A-type positive (AP) and AL deviation, and B-type limited solubility (BS) profiles, respectively. In γ-CD, the saturated concentration of CIM decreased owing to the formation of a low-solubility complex with CIM. CIM/α-CD formed cage-type crystals, and CIM/ß-CD and CIM/γ-CD formed channel-type crystals. The dissolution rate constant (k) of CIM/α-CD and CIM/ß-CD were 0.045 and 0.04 h-1, respectively. CIM/γ-CD and CIM/ß-CD displayed channel-type crystals; however, the channel-type crystals of CIM/γ-CD were stabilized by the presence of additional water molecules.

Prognostic impact of PD-L1 expression in correlation with neutrophil-to-lymphocyte ratio in squamous cell carcinoma of the lung.

The prognostic impact of tumoral programmed death-ligand 1 (PD-L1) expression in correlation with neutrophil-to-lymphocyte ratio (NLR) was retrospectively assessed in 83 patients with completely resected stage I squamous cell carcinoma of the lung, as PD-L1 is a potent regulator of cancer immunity and NLR is a potential surrogate of immune status. Forty-three patients (51.8%) had tumor with positive PD-L1 expression. There was no significant correlation between PD-L1 expression and NLR. PD-L1-positivity failed to provide a significant prognostic impact (overall survival [OS] rate at 5 years, 53.0% in PD-L1-positive patients versus 70.1% in PD-L1-negative patients; P = 0.117). Among NLR-low (<2.2) patients, however, PD-L1-positivity was significantly correlated with a poor prognosis (OS rate at 5 years, 46.1% versus 86.0%; P = 0.020). In contrast, among NLR-high (≥2.2) patients, PD-L1-positivity provided no prognostic impact (P = 0.680). When NLR status and tumoral PD-L1 status were combined, "NLR-low and PD-L1-negative" was a significant and independent factor to predict a favorable recurrence-free survival (hazard ratio, 0.237 [95% confidence interval, 0.083 to 0.674]; P = 0.007) and OS (hazard ratio, 0.260 [0.091 to 0.745]; P = 0.012). These results suggest the prognostic impact of tumoral PD-L1 expression might be influenced by the status of NLR.

Difficulty of treatment for pleural epithelioid hemangioendothelioma: a report of a case.

We herein report the case of a 62-year-old man who underwent extrapleural pneumonectomy (EPP) for pleural epithelial hemangioendothelioma (EHE) diagnosed by a pleural biopsy. Pre-operative computed tomography revealed diffuse pleural thickening and pleural effusion in the right thoracic cavity, although metastasis to neither the lymph nodes nor distant organs was detected. We decided to perform EPP based on surgical findings that the tumor had invaded the lung parenchyma. A pathological examination revealed tumor invasion of the lung parenchyma, blood vessel, pericardium, diaphragm and bronchial wall. Despite aggressive treatment, tumor recurrence was detected about 1 month after surgery. Although we controlled the tumor progression using pazopanib, the patient ultimately died 3.5 months after the operation. Pleural EHE is a very rare disease that has a poor prognosis due to its high malignant potential. It is important to formulate strategies matched to individual cases based on disease progression and invasiveness of treatment.

What is the best treatment strategy for primary spontaneous pneumothorax? A retrospective study.

BACKGROUND: Several treatment strategies are available for primary spontaneous pneumothorax (PSP). Surgical procedures are also performed in patients with PSP without an absolute indication for surgery. This study was performed to investigate the best treatment strategy for PSP by comparison of the recurrence rate. MATERIALS AND METHODS: From January 2006 to December 2013, 149 patients with PSP aged ≤50 years were treated in our institution. We reviewed the recurrence rate of PSP for each treatment strategy and evaluated the association between the recurrence rate of PSP with the clinicopathological characteristics. We also compared the surgery and non-surgery groups. RESULTS: A significant difference in the PSP recurrence rate was found between the surgery and non-surgery groups (22% vs. 52%, respectively; p < 0.001), patients aged ≥22 and < 22 years (16% vs. 44%, respectively; p < 0.001), and smokers and nonsmokers (13% vs. 43%, respectively; p < 0.001). There were also significant differences in the multivariate analysis (p < 0.001, p = 0.050, and p = 0.001, respectively). In the surgery group, the PSP recurrence rate was significantly different between patients aged ≥22 and < 22 years (7% vs. 38%, respectively; p < 0.001) and smokers and nonsmokers (5% vs. 33%, respectively; p = 0.002). No significant differences were found in the non-surgery group. CONCLUSIONS: In the surgical treatment of PSP, it is desirable that smokers stop using tobacco and that patients are ≥22 years old. Moreover, when surgery is being considered, the best timing seems to be when air leakage is present because the air leakage sites can be resected.

[A Case Report of Luminal A Male Inflammatory Breast Cancer that Was Difficult to Treat Because of Trousseau Syndrome].

This report describes the case of a 67-year-old male with inflammatory breast cancer. He had noticed a left breast mass about seven years previously, but he had ignored it. He then visited our hospital 4 months previously when multiple small masses occurred in the left front chest wall. The tumor was diagnosed as skin metastasis of breast cancer by skin biopsy and he was referred to our department. The tumor cells were positive for estrogen receptor and progesterone receptor, and negative for HER2/neu, and the Ki67 expression was 10-15%. The subtype of his breast cancer was luminal A type. It had secondary inflammatory breast cancer and preceded chemotherapy. Also, as the veins in the lower extremity were filled with thrombus, we gave him an anticoagulant (Edoxaban), but due to the malignant hyper coagulable state (Trousseau syndrome) a CV port could not be implanted. 3 courses of docetaxel every 3 weeks failed to control the disease. Since an obstruction of the right iliac artery was newly observed, the anticoagulant was changed to cilostazol and rivaroxaban, but left second finger and fourth finger necrosis occurred due to peripheral circulatory failure. The condition of the disease was stabilized by FEC (5-FU, epirubicin, cyclophosphamide) therapy, but it became difficult to secure the blood vessel. Without constructing a CV port because of the thrombus, chemotherapy was changed to S-1 oral administration, and strength to the chest wall Modulated radiotherapy intensity modulated radiation therapy (IMRT) was performed. Although the tumor was reduced, the condition of the whole body gradually weakened and the patient died a year and a half after the start of the treatment. This case of inflammatory luminal in male breast cancer that caused thrombus was difficult to treat. Thrombosis in advanced cancer patients is often pointed out, but since male breast cancer patients tend to take a long time to visit the hospital after becoming aware of the mass and arrive at an advanced state, it is necessary to notify the public of the existence of male breast cancer.

Salvage surgery combined with descending aorta resection for lung cancer.

BACKGROUND: Recent retrospective studies have shown that salvage surgery can improve survival with acceptable adverse events, and this procedure has been adapted for lung cancer. However, there are no reports demonstrating the efficacy of salvage surgery combined with aortic resection. CASE PRESENTATION: A 73-year-old man had received definitive concurrent chemoradiotherapy (carboplatin/paclitaxel, 70 Gy) for lung cancer originated from the left upper lobe and infiltrating the thoracic aorta (cT4N1M0 stage IIIA). Although the tumor has shrunk significantly (ycT4N0M0 stage IIIA), radiation pneumonitis occurred. Due to the steroid therapy, radiation pneumonitis was relieved; however, re-enlargement of the primary tumor was observed during steroid tapering. Nonetheless, the lymphatic and distant metastases were controlled. Moreover, aortic invasion was localized to the periphery of the third branch, and the tumor was considered to be resectable. Intraoperatively, we observed macroscopic evidence of aortic invasion in the periphery of the third branch; thus, left upper lobectomy combined with descending aorta resection was performed under partial extracorporeal circulation. The patient is currently active without any recurrence 21 months post-surgery. CONCLUSIONS: No clear consensus exists regarding salvage surgery combined with aortic resection for primary lung cancer. However, we believe that this surgery may improve the survival of carefully selected patients.

Prognostic factors of advanced or postoperative recurrent non-small cell lung cancer targeted with immune check point inhibitors.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) for non-small cell lung cancer (NSCLC) have been established as one of standard therapy, the prognostic factors of ICIs remain unclear, aside from the programed cell death-ligand 1 (PD-L1) expression of tumor cells. The aim of this study was to determine the prognostic factors of ICIs. METHODS: We analyzed the clinicopathological data of 44 cases of advanced NSCLC targeted with ICIs in our hospital, between February 2016 and February 2018, in order to determine the prognostic factors of ICIs. We also reviewed the literature regarding ICIs. RESULT: We retrospectively analyzed the 44 cases (26 nivolumab and 18 pembrolizumab cases). These patients were 38 men and 6 women, comprising 13 cases of adenocarcinoma, 29 squamous cell carcinoma and 2 unclassified types. Seven patients were using first-line therapy and while the others were using second-line therapy or later. Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) mutations were negative in all the cases. The response rate and disease control rate were 20.5% and 51.3%, respectively. The median progression-free survival time and median survival time were 146 days and 257 days, respectively. We observed five severe adverse effects (AEs) (three cases of interstitial pneumonia, one of liver dysfunction and one of adrenal failure), that were resolved by steroid pulse therapy. In multivariate analyses, the Eastern Cooperative Oncology Group performance status (ECOG PS), pathological type, standardized uptake value (SUV) on positron emission tomography (PET), white blood cell (WBC) count, neutrophil, neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH) and albumin were independently prognostic factors. There were no significant differences in the prognosis between nivolumab and pembrolizumab. CONCLUSIONS: ICIs were effective in 44 treated NSCLC cases. Our analysis suggests that while ICIs are effective in treating patients, candidates must be carefully selected and cautiously observed.

Fenestration without rib resection for postoperative bronchopleural fistula.

BACKGROUND: Fenestration is performed in patients with bronchopleural fistula to avoid a life-threatening situation. However, usually, this procedure is required 9-cm mean length of the incision with rib resection. CASE PRESENTATION: A 73-year-old man underwent right lower lobectomy with lymph node dissection (ND2a-2) for primary lung cancer (cT1cN2M0 Stage IIIA) with combined pulmonary fibrosis and emphysema. He developed a bronchopleural fistula on postoperative day 20, and we performed emergency fenestration without rib resection using a Lap-protector. The patient reported minimal pain postoperatively. As the rapid deterioration of the general condition due to the recurrence of the tumor was observed at the time of his 1-year postoperative follow-up, closing of the thoracic cavity was abandoned. However, using this fenestration, the control of infection in the thoracic cavity could be sufficiently performed without complications such as pain and pneumonia, and his routine activities were unaffected postoperatively. CONCLUSION: Compared with conventional method, fenestration without rib resection using a Lap-protector is a more convenient and painless technique for postoperative bronchopleural fistula.

Return to work after surgical treatment for malignant pleural mesothelioma: report of a case.

We report the case of a 56-year-old woman who underwent pleural biopsy to identify the cause of the right pleural effusion. The pathological diagnosis was epithelial malignant pleural mesothelioma. The patient worked as a junior high school teacher and strongly hoped for continuing work. Thus, we performed pleurectomy/decortication (P/D) as a curative surgery. The operative findings showed pleural thickening that in the lower lobe of the lung. Thus, peeling of the lower lobe was performed. Pleural biopsy was only performed on the upper and middle lobes. As a result, the operation was limited P/D. The pathological findings showed a small number of mesothelioma cells in the upper and middle lobes. The patient received four courses of cisplatin plus pemetrexed systemic chemotherapy after surgery. Continuous maintenance chemotherapy using pemetrexed has been performed until the time of writing. At present, she has continued her work for 6 years after the operation and has extended her retirement age without recurrence.

Extended pleurectomy decortication for thymoma with pleural dissemination.

Complete resection is the mainstay of treatment for thymoma. Even for advanced-stage thymoma with pleural dissemination, complete resection with extrapleural pneumonectomy may provide a favorable prognosis. Pleurectomy decortication, a lung-sparing surgery, has been preferably employed in recent years as an alternative surgical procedure for malignant pleural mesothelioma. However, little has been reported about pleurectomy decortication for other malignant tumors with pleural dissemination. Here, we present the first case of thymoma with pleural dissemination for which complete en bloc resection was achieved with extended pleurectomy decortication.

Detection of circulating tumor cells with a novel microfluidic system in malignant pleural mesothelioma.

Detection of rare tumor cells circulating in the blood (CTCs) presents technical challenges. CellSearch, the only approved system for clinical use, fails to capture epithelial cell adhesion molecule-negative CTCs such as malignant pleural mesothelioma (MPM). We have developed a novel microfluidic device (CTC-chip) in which any Ab to capture CTCs is conjugated. The CTC-chip was coated with an Ab against podoplanin that is abundantly expressed on MPM. Circulating tumor cell-detection performance was evaluated in experimental models in which MPM cells were spiked in blood sampled from a healthy volunteer and in clinical samples drawn from MPM patients. The CTC-chip showed superior CTC-detection performance over CellSearch in experimental models (sensitivity, 63.3%-64.5% vs 0%-1.1%; P < .001) and in clinical samples (CTC-positivity, 68.8% vs 6.3%; P < .001). A receiver operating characteristic (ROC) analysis showed that the CTC test provided a significant diagnostic performance in discrimination of unresectable disease from resectable disease (area under the ROC curve, 0.851; P = .003). The higher CTC count (≥2 cells/mL) was significantly associated with a poor prognosis (P = .030). The novel CTC-chip enabled sensitive detection of CTCs, which provided significant diagnostic and prognostic information in MPM.

Effect of erlotinib plus bevacizumab on brain metastases in patients with non-small cell lung cancer.

BACKGROUND: The standard therapy for brain metastasis (BM) in non-small cell lung cancer (NSCLC) is radiation therapy (RT), although it is associated with complications such as leukoencephalopathy. In the current report, we retrospectively review data from eight patients who had NSCLC and harbored epidermal growth factor receptor (EGFR) mutations, and who were received erlotinib plus bevacizumab (E+B) as first-line therapy for BM. METHODS: Patients were given E+B as first therapy for BM until August 2017 at our institution. Patients receiving local therapy for BM, such as surgery or radiotherapy, were excluded. Patients were administered erlotinib orally (once daily at 150 mg/body) plus bevacizumab by intravenous infusion (15 mg/kg on day 1 of a 21- or 28-day cycle). RESULTS: Eight NSCLC patients who were diagnosed with BM received E+B, including 2 men and 6 women with a median age of 65 years (range, 46-84 years). Four patients had an L858R EGFR mutation, while the other four had an exon 19 deletion. Seven patients had a partial response to E+B treatment, and one had a complete response. The 2-year survival rate was 62.5%. Three patients who were pre-treated with gefitinib had an E+B treatment duration of less than 1 year. At the time of this analysis, four patients had BM-related neurologic symptoms and multiple BMs, and were still receiving E+B with no evidence of treatment failure after more than 1 year. CONCLUSIONS: E+B can be used as first-line therapy for BM, even in patients with BM-related neurologic symptoms and multiple BMs.

Complete resection of an anterior mediastinal tumor by total arch replacement and pulmonary artery trunk plasty with a pericardial patch: A case report.

INTRODUCTION: Patients with undiagnosed anterior mediastinal tumors commonly undergo surgery for diagnosis and treatment. However, determining the optimal therapeutic strategy is difficult for tumors with substantial invasion, such as lesions touching the aortic arch (AA). CASE PRESENTATION: A 76-year-old man of Asian descent presented to our hospital because chest computed tomography (CT) revealed an anterior mediastinal tumor. This tumor surrounded the left subclavian vein and touched the AA. We suspected the tumor to be malignant. We therefore decided to resect the tumor with preparation for total arch replacement (TAR). The operation was performed in three steps. First, we performed a mediastinal sternotomy. However, the tumor had invaded the subclavian vein, so we resected this vein after adding a transmanubrial approach. However, because of invading the AA we needed next step. Second, we shifted the patient to the right lateral decubitus position. We performed partial resection of the left upper lobe and exfoliated the distal AA. Third, we shifted the patient to the dorsal position and implanted an artificial cardiopulmonary device, after which we performed TAR, and pulmonary artery (PA) trunk plasty with a pericardial patch. The operation was successful, with no major adverse events. Pathologically, the tumor was diagnosed as diffuse large B-cell lymphoma. DISCUSSION: If oncologically complete resection is preferable for tumors with substantial invasion, complete resection should be attempted even if the surgery is difficult. CONCLUSION: We performed complete resection of an anterior mediastinal tumor with TAR and PA trunk plasty using a pericardial patch.

Outcomes of patients undergoing surgery for thymic carcinoma: a single-center experience.

BACKGROUND: Thymic carcinoma is uncommon, presents locally at an advanced stage, and behaves aggressively. The optimum treatment for advanced thymic carcinoma is controversial. We retrospectively reviewed our institutional experience with patients with thymic carcinoma. METHODS: We analyzed the clinical data of six patients who underwent total thymectomy for thymic carcinoma at our institution from 2006 to 2016. Variables analyzed included sex, age, histological classification, Masaoka staging, postoperative treatment, and recurrence. RESULTS: The clinical characteristics of the six patients with thymic carcinoma (median age, 56 years; five men and one woman) were as follows: squamous cell carcinoma (n=5); sarcomatoid carcinoma (n=1); Masaoka stages II (n=1), III (n=2), IVa (n=1), and IVb (n=2). Four patients underwent combined pulmonary resection (66.7%) as a component of en bloc resection due to suspicion of pulmonary invasion. Four patients (66.7%) received postoperative therapy, and complete resection was achieved for four patients. There were no perioperative deaths. One patient experienced a recurrence. CONCLUSIONS: Complete resection for thymic cancer improved the prognosis of our patients, indicating that robust studies will be required to confirm our findings.