Butyricimonas is a key gut microbiome component for predicting postoperative recurrence of esophageal cancer.

BACKGROUND: Recently, intestinal bacteria have attracted attention as factors affecting the prognosis of patients with cancer. However, the intestinal microbiome is composed of several hundred types of bacteria, necessitating the development of an analytical method that can allow the use of this information as a highly accurate biomarker. In this study, we investigated whether the preoperative intestinal bacterial profile in patients with esophageal cancer who underwent surgery after preoperative chemotherapy could be used as a biomarker of postoperative recurrence of esophageal cancer. METHODS: We determined the gut microbiome of the patients using 16S rRNA metagenome sequencing, followed by statistical analysis. Simultaneously, we performed a machine learning analysis using a random forest model with hyperparameter tuning and compared the data obtained. RESULTS: Statistical and machine learning analyses revealed two common bacterial genera, Butyricimonas and Actinomyces, which were abundant in cases with recurrent esophageal cancer. Butyricimonas primarily produces butyrate, whereas Actinomyces are oral bacteria whose function in the gut is unknown. CONCLUSION: Our results indicate that Butyricimonas spp. may be a biomarker of postoperative recurrence of esophageal cancer. Although the extent of the involvement of these bacteria in immune regulation remains unknown, future research should investigate their presence in other pathological conditions. Such research could potentially lead to a better understanding of the immunological impact of these bacteria on patients with cancer and their application as biomarkers.

How Does the Powder Mixture of Ibuprofen and Caffeine Attenuate the Solubility of Ibuprofen? Comparative Study for the Xanthine Derivatives to Recognize Their Intermolecular Interactions Using Fourier-Transform Infrared (FTIR) Spectra, Differential Scanning Calorimetry (DSC), and X-ray Powder Diffractometry (XRPD).

Molecular interactions between active pharmaceutical ingredients (APIs) and xanthine (XAT) derivatives were analyzed using singular value decomposition (SVD). XAT derivatives were mixed with equimolar amounts of ibuprofen (IBP) and diclofenac (DCF), and their dissolution behaviors were measured using high-performance liquid chromatography. The solubility of IBP decreased in mixtures with caffeine (CFN) and theophylline (TPH), whereas that of DCF increased in mixtures with CFN and TPH. No significant differences were observed between the mixtures of theobromine (TBR) or XAT with IBP and DCF. Mixtures with various molar ratios were analyzed using differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infrared spectroscopy to further explore these interactions. The results were subjected to SVD. This analysis provides valuable insights into the differences in interaction strength and predicted interaction sites between XAT derivatives and APIs based on the combinations that form mixtures. The results also showed the impact of the XAT derivatives on the dissolution behavior of IBP and DCF. Although IBP and DCF were found to form intermolecular interactions with CFN and TPH, these effects resulted in a reduction of the solubility of IBP and an increase in the solubility of DCF. The current approach has the potential to predict various interactions that may occur in different combinations, thereby contributing to a better understanding of the impact of health supplements on pharmaceuticals.

Propionic Acid Groups and Multiple Aromatic Rings Induce Binding of Ketoprofen and Naproxen to the Hydrophobic Core of Bovine Serum Albumin.

Ketoprofen (KP), which causes photosensitivity by interacting with serum albumin (SA), and three drugs, ibuprofen (IBP), naproxen (NPX), and diazepam (DZP), which share the same binding site, were investigated for their interaction with bovine SA (BSA). For KP, DZP, and IBP, where drug-concentration-dependent quenching of BSA-intrinsic fluorescence was observed, a modified Stern-Volmer plot showed that dynamic quenching was dominant for KP and static quenching was dominant for DZP and IBP. However, this alone cannot be compared with NPX. Therefore, by performing singular value decomposition (SVD) fluorescence spectroscopy, we were able to find the behavior of the drug-concentration-dependent Langmuir-type principal component vectors. KSVD obtained by the Langmuir equation showed a high correlation with the static extinction constant V. Therefore, KSVD indicates the association constant of the drug with BSA and it was found that NPX and IBP had higher values than KP. Finally, in the analysis of the temperature factors of amino acid residues in each drug-binding region and Trp residues, KP and NPX significantly reduced these temperature factors whereas DZP and IBP hardly changed them. This result is consistent with the dynamic and static quenching dominance in the total quenching mechanism. Summarizing the results so far, it was shown that penetration into the hydrophobic core inside BSA can be achieved not only by one of the multiple aromatic rings and propionic acid groups but also by the joint effect of both. In this study, SVD enabled us to extract information on drug adsorption to BSA from fluorescence spectra. Furthermore, the application of SVD is expected to make it possible to perform fluorescence analysis for drug binding to proteins without being limited by the fluorescence properties of the drug.

Effects of Local Anesthetics on Liposomal Membranes Determined by Their Inhibitory Activity of Lipid Peroxidation.

In this study, we investigated the effects of drugs on membrane function in which lipid peroxidation was inhibited by the antioxidant Trolox (TRO) in liposomes containing egg yolk lecithin. Local anesthetics (LAs), such as lidocaine (LID) and dibucaine (DIB), were used as model drugs. The effect of LAs on the inhibitory activity of TRO was evaluated by calculating the pI50 from the inhibition constant K calculated by curve fitting. pI50TRO indicates the strength of TRO membrane protective function. pI50LA indicates the strength of LA activity. LAs inhibited lipid peroxidation in a dose-dependent manner and decreased pI50TRO. The effect of DIB on pI50TRO was 1.9 times more than that of LID. This result indicated that LA may improve the fluidity of the membrane, which may facilitate the migration of TRO from the membrane to the liquid phase. As a result, TRO is less likely to suppress lipid peroxidation within the lipid membrane, possibly resulting in a decrease in pI50TRO. The effect of TRO on pI50LA was found to be similar in both, indicating that it did not depend on the type of the model drug. These results suggest that our developed procedure successfully quantified the effects of LAs on lipid membrane functions. We were able to obtain the characteristics of model drugs independent of TRO by simultaneously measuring and analyzing the lipid peroxidation inhibitory activities of TRO and model drugs in liposomes.

Effect of Cyclodextrin Complex Formation on Solubility Changes of Each Drug Due to Intermolecular Interactions between Acidic NSAIDs and Basic H2 Blockers.

One of the solubilization of poorly water-soluble drugs is the use of cyclodextrin (CD)-based inclusion complexes. On the other hand, few studies have investigated how CD functions on the solubility of drugs in the presence of multiple drugs that interact with each other. In this study, we used indomethacin (IND) and diclofenac (DIC) as acidic drugs, famotidine (FAM) and cimetidine (CIM) as basic drugs, and imidazole (IMZ), histidine (HIS), and arginine (ARG) as compounds structurally similar to basic drugs. We attempted to clarify the effect of ß-CD on the solubility change of each drug in the presence of multiple drugs. IND and DIC formed a eutectic mixture in the presence of CIM, IMZ, and ARG, which greatly increased the intrinsic solubility of the drugs as well as their affinity for ß-CD. Furthermore, the addition of high concentrations of ß-CD to the DIC-FAM combination, which causes a decrease in solubility due to the interaction, improved the solubility of FAM, which was decreased in the presence of DIC. These results indicate that ß-CD synergistically improves the solubility of drugs in drug-drug combinations, where the solubility is improved, whereas it effectively improves the dissolution rate of drugs in situations where the solubility is reduced by drug-drug interactions, such as FAM-DIC. This indicates that ß-CD can be used to improve the physicochemical properties of drugs, even when they are administered in combination with drugs that interact with each other.

Interaction mode of hydroxypropyl-ß-cyclodextrin with vaccine adjuvant components Tween 80 and Triton X-100 revealed by fluorescence increasing-quenching analysis.

The nonionic surfactants Tween 80 (Tw80) and Triton X-100 (TX100), which are used as components of adjuvants, were used with bovine serum albumin (BSA) and hydroxfypropyl-ß-cyclodextrin (HP-ß-CD) as model antigens. The interaction patterns of Tw80 and TX100 with the hydrophobic cores of the model antigens were investigated. The fluorescence of 8-anilinonaphthalene-1-sulfonic acid (ANS), a hydrophobic fluorescent probe, was used to evaluate the effect of surfactants on each model antigen. A Hanes Woolf plot was used to analyze the adsorption of ANS to BSA, and an activator-inhibitor model was used to analyze the concentration-dependent increase and decrease of ANS fluorescence intensity. For BSA, TX100 occupies the ANS binding site inside the BSA hydrophobic core, while Tw80 does not contribute to the ANS binding site in the hydrophobic core. For HP-ß-CD, the ANS concentration required for analyzable fluorescence intensity extended to the range where ANS concentration-dependent quenching was not negligible. Using the activator inhibitor model, we were able to separate the activators and inhibitors of ANS fluorescence and evaluate the affinity of ANS for HP-ß-CD and surfactants. The results obtained showed that TX100 provided a hydrophobic environment to the ANS while being encapsulated by HP-ß-CD, while Tw80 did not interact with HP-ß-CD and provided a hydrophobic environment to the ANS independently of each other. The interpretations obtained were corroborated by the determination of the CMC of TX100 and Tw80, the effect of salt on ANS fluorescence, and 1H-NMR and ROESY. In summary, the results showed that the large hydrophilic head of Tween, composed of sorbitan and PEG chains, floated in the aqueous phase like a balloon, while Triton pierced the hydrophobic core of the antigen like a spear. In both BSA and HP-ß-CD model antigens, TX100 impinged on the hydrophobic core.

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.

Uniformity and Efficacy of Dry Powders Delivered to the Lungs of a Mycobacterial-Surrogate Rat Model of Tuberculosis.

PURPOSE: Pulmonary administration of dry drug powder is a considered promising strategy in the treatment of various lung diseases such as tuberculosis and is more effective than systemic medication. However, in the pre-clinical study phase, there is a lack of devices for effective delivery of dry powders to the lungs of small rodents. In this study, an administration device which utilizes Venturi effect to deliver dry powders to the lungs homogeneously was developed. METHODS: A Venturi-effect administration device which synchronizes with breathes by use of a ventilator and aerosolizes the dry powders was created. Pulmonary distribution of inhalable dry powders prepared by spray-drying poly(lactic-co-glycolic) acid and an antituberculosis agent rifampicin and anti-tuberculosis effect of the powders on mycobacteria infected rats by administration with the Venturi-effect administration device and a conventional insufflation device were evaluated. RESULTS: Homogeneous distribution of the dry powders in the lung was achieved by the Venturi-effect administration device due to efficient and recurring aerosolization of loaded dry powders while synchronizing with breathes. Amount of rifampicin delivered to the lungs by the Venturi-effect administration device was three times higher than that by a conventional insufflation device, demonstrating three times greater antimycobacterial activity. CONCLUSIONS: The Venturi-effect administration device aerosolized inhalable antituberculosis dry powders efficiently, achieved uniform pulmonary distribution, and aided the dry powders to exert antituberculosis activity on lung-residing mycobacteria.

Enthalpy-Entropy Compensation in the Structure-Dependent Effect of Nonsteroidal Anti-inflammatory Drugs on the Aqueous Solubility of Diltiazem.

Certain combinations of acidic and basic drugs can cause significant changes in physicochemical properties through the formation of ionic liquids, eutectic mixtures, or deep eutectic solvents. In particular, combining indomethacin and lidocaine is known to result in apparent increases in both the partition coefficients (hydrophobicity) and aqueous solubilities (hydrophilicity). The physicochemical interactions between drugs change the water solubility of the drugs and affect the bio-availability of active pharmaceutical ingredients. Therefore, we need to clarify the mechanism of changes of water solubility of drugs through the physicochemical interactions. In the present study, we identified a thermodynamic factor that regulates the dissolution of a basic drug, in the presence of various acidic nonsteroidal anti-inflammatory drugs. The results demonstrated that enthalpy-entropy compensation plays a key role in the dissolution of drug mixtures and that relevant thermodynamic conditions should be considered.

Narrow-band Imaging Examination of Microvascular Architecture of Subcapsular Hepatic Tumors.

BACKGROUND: Intraoperative ultrasonography is the golden standard method for evaluation of liver tumors during hepatectomy. However, in laparoscopic surgery, accurate assessment of tumors may be difficult, particularly if the lesion is located nearby the liver surface because of the challenges in handling the intraoperative ultrasound and the lack of tactile sensation. In this study, we demonstrate the preliminary results of examining the microvascular architecture of subcapsular hepatic tumors using laparoscopic narrow-band imaging (NBI) to distinguish between malignant and benign tumors. MATERIALS AND METHODS: Thirty-five lesions were examined by NBI during laparoscopic hepatectomy for the presence of abnormal microvasculature on the liver surface in relation to hepatic tumors from January 2016 to August 2018. The microvascular findings were correlated with tumor localization and pathological diagnosis. RESULTS: The 35 examined nodules included 11 hepatocellular carcinoma, 18 colorectal liver metastasis, and six benign nodules. The mean tumor diameter was 26.3 (3-70) mm, and the distance from the liver surface to the tumor was 0.5 (0-5) mm. Microvessels on the liver surface were clearly visualized by NBI, consistent with malignant tumor localization. The tumors were thoroughly examined for the presence of three pathological microvascular features (enlargement, tortuosity, and heterogeneity). Abnormal microvascular patterns were found in 90.9% of hepatocellular carcinoma and 77.8% of colorectal liver metastasis, whereas neither normal sites nor benign lesions displayed microvascular abnormality. CONCLUSIONS: This study suggests that observing the microvessel image on the liver surface by NBI could be useful in tumor localization and differentiation between benign and malignant lesions.

Minimally invasive esophagectomy and radical lymph node dissection without recurrent laryngeal nerve paralysis.

BACKGROUND: We introduce a novel operative technique to dissect lymph nodes adjacent to the recurrent laryngeal nerve, referred to as the "native tissue preservation" technique. Using this technique, there was no damage to the recurrent laryngeal nerve, which is maintained in its anatomical position. METHODS: From September 2016 to December 2018, minimally invasive esophagectomy was performed in the left lateral decubitus position in 87 patients with esophageal cancer. The native tissue preservation technique for lymphadenectomy around the recurrent laryngeal nerve was used, and all patients were evaluated for recurrent laryngeal nerve paralysis. RESULTS: Minimally invasive esophagectomy was completed in all patients without conversion to thoracotomy. Although an extended lymphadenectomy was performed in all patients, there were no grade II or higher complications (Clavien-Dindo classification) and no incidence of recurrent laryngeal nerve paralysis. CONCLUSION: The native tissue preservation technique may reduce the incidence of recurrent laryngeal nerve paralysis after minimally invasive esophagectomy with radical lymph node dissection.

Determination of the surgical margin in laparoscopic liver resections using infrared indocyanine green fluorescence.

PURPOSE: Laparoscopic liver resection is increasingly used to treat patients with hepatic tumor. However, during laparoscopic resection, information obtained by palpation using laparoscopic forceps or from intraoperative ultrasonography is extremely limited, which may pose a risk for positive surgical margins. This study aimed to investigate the feasibility and clinical application of near-infrared (NIR) fluorescence imaging to guide laparoscopic liver resection of a liver tumor and secure the surgical margins. METHODS: A preliminary study in 25 patients was conducted. NIR imaging was used intraoperatively during laparoscopic liver resection. The liver tumors were preoperatively labeled by intravenously injecting the patients with indocyanine green dye (0.5 mg/kg), an NIR fluorescence agent. During the surgical procedure, the PINPOINT Endoscopic Fluorescence Imaging System was used to assess the surgical margin by using real-time endoscopic high-definition visible and NIR fluorescence imaging. RESULTS: All tumors were identified and resected laparoscopically by using the PINPOINT system, and all resections successfully secured the surgical margin. The pathological findings of all tumors indicated negative margins, defined as R0. CONCLUSIONS: This technique showed the potential to improve the intraoperative identification and demarcation of tumors. Its use could potentially reduce the number of positive resection margins.

[Present and Future of Navigation Surgery in Hepatobiliary and Pancreatic Surgery].

Hepatobiliary and pancreatic surgery is recognized as technically demanding due to the complicated local anatomy and diverse anatomical variation that require precise techniques. Therefore, preoperative simulation to understand the detailed local anatomy and intraoperative navigation methods for surgical guidance are needed. Intraoperative navigation for anatomical hepatectomy originated with dye injection into the dominant portal pedicle under intraoperative ultrasound guidance to identify hepatic segments, which was reported by Makuuchi et al in 1985. In recent years, with advancing medical technology, newer medical devices that promote the safety and reliability of various surgical procedures have been developed. In this article, we will discuss the current state and future prospects of intraoperative navigation in hepatobiliary and pancreatic surgery.

Thoracoscopic and hand assisted laparoscopic esophagectomy with radical lymph node dissection for esophageal squamous cell carcinoma in the left lateral decubitus position: a single center retrospective analysis of 654 patients.

BACKGROUND: The rates of thoracoscopic esophagectomy performed in the prone and left lateral decubitus positions are similar in Japan. We retrospectively reviewed short- and long-term outcomes of thoracoscopic esophagectomy for esophageal cancer performed in the left lateral decubitus position. METHODS: Between 1996 and 2015, 654 patients with esophageal cancer underwent thoracoscopic esophagectomy in the left lateral decubitus position. Patients were divided into early (1996-2008) and late groups (2009-2015, with standardization of the procedure and formalized training), and their clinical outcomes reviewed. RESULTS: The completion rate of thoracoscopic esophagectomy was 99.5%, and the procedure was converted to thoracotomy in three patients, due to hemorrhage. The mean intrathoracic operative time, intrathoracic blood loss, and number of dissected mediastinal lymph nodes were 205.0 min, 127.3 mL, and 24.7, respectively. Postoperative complications included pneumonia (8.5%), anastomotic leakage (7.5%), and recurrent nerve paralysis (3.5%). Postoperative (30d) mortality was 4/654 (0.61%) due to anastomotic leak and pneumonia. The five year overall survival rate was 70%. A comparison of the 289 early- and 365 late-study period cases revealed significant differences in mean intrathoracic blood loss (174.0 vs. 94.2 mL), number of mediastinal lymph nodes dissected (20.0 vs. 28.4), hospital length of stay (33.4 vs. 20.0 days, p < 0.001), and postoperative anastomotic leakage (14% vs. 1.6%, p < 0.0001). CONCLUSIONS: Standardization of the procedure for thoracoscopic esophagectomy in the left lateral decubitus position, with a standardized clinical pathway for perioperative care led to significant improvements in surgical outcomes.

Routes for virtually guided endoscopic liver resection of subdiaphragmatic liver tumors.

PURPOSE: Laparoscopic and thoracoscopic/laparoscopic hepatectomy is a safe procedure that has potential advantages over open surgery. However, deeply positioned liver tumors require expert laparoscopic and thoracoscopic/laparoscopic hepatectomy techniques. Using simulated preoperative three-dimensional virtual endoscopy (P3DVE) guidance, we demonstrate herein that a thoracoscopic approach (TA), thoracoscopic-laparoscopic approach (TLA), and laparoscopic approach (LA) are all feasible and safe routes for performing pure laparoscopic and thoracoscopic/laparoscopic resection of liver tumors located in the 4a, 7, and 8 liver subdiaphragmatic areas. METHODS: Thirty-eight patients underwent laparoscopic and thoracoscopic/laparoscopic partial liver resection (TA 13 cases, TLA two cases, and LA 23 cases) of the subdiaphragmatic area at Showa University Hospital. All surgical approaches were preoperatively determined based on preoperative 3D virtual endoscopic simulation (P3DVES) visualization and findings using the image processing software SYNAPSE VINCENT(®). RESULTS: Laparoscopic and thoracoscopic/laparoscopic liver resection was successfully performed for all cases under P3DVE instruction. The mean operative times using TA, TLA, and LA approaches were 193, 185, and 190 min, respectively. Mean blood loss during TA, TLA, and LA was 179, 138, and 73 g, respectively. No patients required conversion to open surgery, and there were no deaths, although there were three cases of Clavien-Dindo grade I in TA along with three cases of grade I and one case of grade II in LA. CONCLUSIONS: TA, TLA, and LA routes performed under P3DVE instruction are feasible and safe to perform for pure laparoscopic and thoracoscopic/laparoscopic liver resection in selected patients with lesions located in the hepatic subdiaphragmatic area.

Quantification of crystallinity during indomethacin crystalline transformation from α- to γ-polymorphic forms and of the thermodynamic contribution to dissolution in aqueous buffer and solutions of solubilizer.

The thermodynamic properties and dissolution of indomethacin (INM) were analyzed as models for poorly water-soluble drugs. Physical mixtures of the most stable γ-form and metastable α-form of INM at various proportions were prepared, and their individual signal intensities proportional to their mole fractions were observed using X-ray powder diffraction and Fourier transform infrared spectrometry at standard temperature. The endothermic signals of the α-form, with a melting point of 426 K, and that of the γ-form, with a melting point of 433 K, were obtained by differential scanning calorimetry (DSC). Furthermore, an exothermic DSC peak of the α/γ-phase transition at approximately 428 K was obtained. As we computed the melting entropy of the α-form and that of its transformation, the frequency of the transition was quantitatively determined, which indicated the maximum of the α/γ-phase transition at an α-form proportion of 68%. Subsequently, the thermodynamic contributions of the α- and γ-forms were analyzed using a Van't Hoff plot for solubility in aqueous solutions at pH 6.8. The dissolution enthalpies for α- and γ-forms were 28.2 and 31.2 kJ mol-1, respectively, which are in agreement with the quantitative contribution predicted by the product of the temperature and melting entropy. The contribution of melting entropy was conserved in different dissolution processes with aqueous solvents containing lidocaine, diltiazem, l-carnosine, and aspartame as solubilizers; their γ-form Setschenow coefficients were -39.6, +82.9, -17.3, and +23.2, whereas those of the α-form were -39.7, +80.4, -16.7, and +22.7, respectively. We conclude that the dissolution ability of the solid state and solubilizers indicate their additivity independently.

Long-Term Outcomes of Carbon Dioxide Insufflation in Thoracoscopic Esophagectomy After Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma: A Retrospective Cohort Study.

BACKGROUND: Thoracoscopic esophagectomy (TE) with carbon dioxide (CO2) insufflation is increasingly performed for esophageal cancer; however, there is limited evidence of the long-term outcomes of CO2 insufflation on postoperative survival. OBJECTIVES: We investigated the long-term outcomes of TE with or without CO2 insufflation. METHODS: We enrolled 182 patients who underwent TE for esophageal cancer between January 2003 and October 2013 and categorized them into two groups: with and without CO2 insufflation. The primary endpoint was five-year overall survival (5y-OS). Secondary endpoints included long-term outcomes, such as five-year relapse-free survival (5y-RFS) and five-year cancer-specific survival (5y-CSS), and short-term outcomes, such as surgical and non-surgical complications and reoperation within 30 days. RESULTS: Follow-up until death or the five-year postoperative period was 98.9% (median follow-up duration was six years in survivors). After adjusting for age, sex, and yield pathologic tumor, node, and metastasis (TNM) stage, we found no significant differences in 5y-OS (HR 1.12, 95% CI 0.66-1.91), 5y-RFS (HR 1.12, 95% CI 0.67-1.83), or 5y-CSS rates (HR 1.00, 95% CI 0.57-1.75). For short-term outcomes, significant intergroup differences in operation time (p=0.02), blood loss (p<0.001), postoperative length of stay (p<0.001), and incidence of atelectasis (p=0.004) were observed. The results of the sensitivity analysis were similar to the main results. CONCLUSIONS: In thoracoscopic procedures, CO2 insufflation significantly improved short-term outcomes, and it appears that the recurrence risk of esophageal cancer may not impact the long-term prognosis. While the influence of CO2 insufflation in thoracoscopic esophageal surgery remains unclear, our study suggests that the long-term prognosis is not compromised in other thoracic surgeries.

Maximum Efficacy of Immune Checkpoint Inhibitors Occurs in Esophageal Cancer Patients With a Low Neutrophil-to-Lymphocyte Ratio and Good Performance Status Prior to Treatment.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) play an important role in the treatment of esophageal cancer (EC). However, few patients achieve long-term survival, and some patients develop serious immune-related adverse events (irAEs). Reliable predictive biomarkers of efficacy and safety need to be established in order to improve efficacy. We retrospectively analyzed the outcomes of nivolumab monotherapy on EC at Showa University, Department of Medicine, to identify biomarkers and characteristics of patients who benefit from ICI monotherapy. PATIENTS AND METHODS: Eighty-six patients with EC who received nivolumab monotherapy were included in the present study. Patient characteristics, efficacy, and safety were analyzed. A multivariable analysis evaluated the correlation among overall survival (OS), progression-free survival (PFS), best overall response (BOR), irAEs, and the following variables: sex, age, performance status (PS), neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP) level, albumin level, and body-mass index before treatment. RESULTS: Median PFS was 3.1 months, and median OS was 9.0 months. In multivariable analysis, pretreatment PS, NLR, and sex were significantly correlated with OS and PFS. NLR <3.3 predicted longer survival (median OS 17.5 vs. 6.4 months for NLR ≥3.3; p<0.001). Median OS was 10.6 months for PS 0-1 and 1.3 months for PS 2-3 (p<0.001). NLR remained significantly predictive in the PS 0-1 group. The development of irAEs was significantly associated with increased OS and PFS. CONCLUSION: Patients with low NLR and good PS before treatment may maximize the benefits of ICIs. A low NLR may be an indicator of higher immunocompetence for anti-tumor immunity, suggesting that NLR may be a convenient predictive biomarker in daily practice.

Optimization of the stability constants of the ternary system of diclofenac/famotidine/ß-cyclodextrin by nonlinear least-squares method using theoretical equations.

This study aimed to establish a new method for determining the stability constants of drug/ß-cyclodextrin (ß-CD) complexes when multiple drugs interacting with each other coexist in the solution of complexation. The basic drug famotidine (FAM) and the acidic drug diclofenac (DIC) were used as model drugs, their solubility decreasing owing to their mutual interaction. The dissolution of both FAM and DIC was characterized by AL-type phase solubility diagrams in the presence of the other's 1:1 complex with ß-CD. When the stability constant was calculated from the slope of the phase solubility diagram using the conventional phase solubility diagram method, it was modified in the presence of the other drug. However, by performing optimization calculations that considered the interactions between the drug/ß-CD complex and the drug, drug/ß-CD complexes, and drugs, we were able to accurately calculate the stability constant of DIC/ß-CD and FAM/ß-CD complexes even in the presence of FAM and DIC, respectively. The results of the solubility profile indicated that various molecular species, which are attributed to drug-drug and drug/ß-CD interactions, interfere with the values of the dissolution rate constants and saturated concentration in the solubility profiles.

Thoracoscopic esophageal drainage for tracheal compression due to mucocele after esophagogastric bypass: a case report.

BACKGROUND: Esophagogastric bypass is performed for esophageal strictures. Mucus retention, known as mucocele, sometimes occurs at the stricture oral side of the remnant esophagus. It is often asymptomatic and is expected to be naturally decompressed, but it may cause respiratory failure depending on the case. Herein, we report a case in which we successfully performed thoracoscopic esophageal drainage as emergency airway management due to tracheal compression by a mucocele after esophagogastric bypass for unresectable esophageal cancer with esophagobronchial fistula. CASE PRESENTATION: A 56-year-old man underwent esophageal bypass surgery for an unresectable esophageal carcinoma with an esophagobronchial fistula following chemotherapy and radiation therapy. Nine months after bypass surgery, he experienced severe dyspnea due to tracheal compression caused by mucus retention on the oral side of the esophageal tumor. We planned thoracoscopic surgery for mucus retention drainage through the right thoracic cavity to secure the airway as an emergency procedure under general anesthesia. Intubation can be performed safely by guiding bronchoscopy in the semi-supine position. Upper esophageal dilation was observed on the cranial side of the azygos arch. We dissected the mediastinal pleura of the upper thoracic esophagus and exposed its wall. A 12-Fr silicone drain was placed in the esophagus through the right chest wall and 120 ml of white fluid was aspirated. He was discharged 9 days after surgery without complications and resumed treatment with an immune checkpoint inhibitor 23 days after surgery. Thereafter, he continued chemotherapy for esophageal cancer, but died of tumor progression and lung metastasis 35 months after bypass surgery and 25 months after thoracoscopic surgery. CONCLUSIONS: Thoracoscopic esophageal drainage could be performed safely as emergency airway management, shorten the period of discontinuance, and allow cancer treatment to be resumed promptly. We believe that this thoracoscopic procedure is an effective and less invasive method if the percutaneous approach is difficult.