Successful application of lorlatinib in a 23-year-old patient with anaplastic lymphoma kinase (ALK)-positive lung cancer and multiple brain metastases.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive lung cancer has a better long-term prognosis with ALK-inhibitor than other lung cancers. However, resistance to ALK-inhibitors and the control of metastases in the central nervous system (CNS) remain to be a challenge in the management of ALK-positive lung cancer. CASE: We present the case of a 23-year-old man who developed multiple brain metastases while receiving alectinib treatment for ALK-positive lung cancer. After 3 months of lorlatinib initiation, brain metastases disappeared, and complete response (CR) was maintained. CONCLUSION: While lorlatinib can be used as first line therapy, this drug may be considered as second line or later option for patients with multiple brain metastases if the patient has already been treated with other ALK-inhibitors since lorlatinib is thought to have good CNS penetration. This treatment option should be verified by further research.

Traumatic sigmoid colon rupture due to breast cancer metastasis: a case report.

The metastasis of breast cancer to the gastrointestinal tract is rare. Herein, we presented the case of an 85-year-old woman who had a history of invasive lobular carcinoma and experienced complete colon rupture due to relatively low-energy trauma. The patient underwent bilateral total mastectomy and axillary dissection following preoperative chemotherapy 6 years ago. She had a local recurrence 2 years after the surgery and underwent chemotherapy. Subsequently, the cancer metastasized to the thoracolumbar area and retroperitoneum. In addition, the patient fell from a height of 30 cm while hanging laundry and her abdomen hit a hose reel. Emergency surgery was performed, and the entire circumference of the sigmoid colon was ruptured. The ruptured colon lesion was resected, and the stump was closed. A double-barrel transverse colostomy was created as it was impossible to lift the stump up to the abdominal wall. Histopathological examination revealed the invasive lobular carcinoma metastasis and a linitis plastica-like change of the colon wall, which probably consequently weakened. In addition, minimal trauma can damage the gastrointestinal tract that had invasive lobular carcinoma metastasis.

Enzyme-linked immunosorbent assay using thin-layered microfluidics with perfect capture of the target protein.

We developed a process for enzyme-linked immunosorbent assay on a glass microchip via the use of a thin-layered microfluidic channel. This channel possesses a high aspect ratio (width/depth ∼200) and has an antibody layer immobilized directly on the channel surface. A depth of several microns and an excessive width and length (mm scale) of the channel provide a large-volume capacity (102 nL) and maximum capture efficiency of the analyte for a high level of detection sensitivity (102 pg mL-1). The developed reusable immunosensor has demonstrated high-performance characteristics by requiring less than 50 µL of sample and providing analysis in less than 25 min. This new method could impact the development of point-of-care devices for biomedical applications.

Nanofluidic analytical system integrated with nanochannel open/close valves for enzyme-linked immunosorbent assay.

There have been significant advances in the field of nanofluidics, and novel technologies such as single-cell analysis have been demonstrated. Despite the evident advantages of nanofluidics, fluid control in nanochannels for complicated analyses is extremely difficult because the fluids are currently manipulated by maintaining the balance of driving pressure. To address this issue, the use of valves will be essential. Our group previously developed a nanochannel open/close valve utilizing glass deformation, but this has not yet been integrated into nanofluidic devices for analytical applications. In the present study, a nanofluidic analytical system integrated with multiple nanochannel open/close valves was developed. This system consists of eight pneumatic pumps, seven nanochannel open/close valves combined with piezoelectric actuators, and an ultra-high sensitivity detector for non-fluorescent molecules. For simultaneous actuation of multiple valves, a device holder was designed that prevented deformation of the entire device caused by operating the valves. A system was subsequently devised to align each valve and actuator with a precision of better than 20 µm to permit the operation of valves. The developed analytical system was verified by analyzing IL-6 molecules using an enzyme-linked immunosorbent assay. Fluid operations such as sample injection, pL-level aliquot sampling and flow switching were accomplished in this device simply by opening/closing specific valves, and a sample consisting of approximately 1500 IL-6 molecules was successfully detected. This study is expected to significantly improve the usability of nanofluidic analytical devices and lead to the realization of sophisticated analytical techniques such as single-cell proteomics.

Accelerated protein digestion and separation with picoliter volume utilizing nanofluidics.

Single cell analyses can provide critical biological insight into cellular heterogeneity. In particular, the proteome, which governs cell functions, is much more difficult to analyze because it is principally impossible to amplify proteins compared to nucleic acids. The most promising approach to single cell proteomics is based on the liquid chromatography mass spectrometry (LC-MS) platform. However, pretreatments before MS detection have two critical issues for single cell analysis: analyte loss as a result of adsorption and artifacts due to the duration of analysis. This is a serious problem because single cells have a limited number of protein molecules and a small volume. To solve these issues, we developed an integrated nanofluidic device to manipulate samples on a femtoliter to picoliter (fL-pL) scale to achieve high-throughput analysis via suppressing analyte loss. This device can perform tryptic digestion, chromatographic separation, and non-labeled detection with high consistency. In addition, we introduced an open/close valve by physical deformation of glass on a nanometer scale to independently modify the nanochannel surfaces and control sample aliquots. The injection system equipped with this valve achieved an injection volume of 1.0 ± 0.1 pL. By using this integrated device, we found that the chromatogram of bulk-digestion for 12 hours resembled that of 15 min-digestion in the nanochannel, which indicated that these conditions reached a similar state of digestion. Therefore, an integrated device for ultra-fast protein analysis was developed on a 1 pL scale for the first time.

The evaluation of the postoperative quality of life in patients undergoing radical gastrectomy for esophagogastric junction cancer using the Postgastrectomy Syndrome Assessment Scale-45: a nationwide multi-institutional study.

PURPOSE: This retrospective nationwide survey investigated the quality of life (QOL) of patients with esophagogastric junction cancer after gastrectomy using the Postgastrectomy Syndrome Assessment Scale-45. METHODS: The Postgastrectomy Syndrome Assessment Scale-45 comprises 45 questions classified into symptoms, living status, and QOL domains. A total of 1950 gastrectomized patients with upper-third gastric or esophagogastric junction cancer returned the completed forms. Among them, 224 eligible patients with esophagogastric junction cancer were selected, including 86, 120, and 18 patients who underwent total gastrectomy, proximal gastrectomy (reconstruction-esophagogastrostomy: 56; double-tract method: 51), and other procedures, respectively. RESULTS: The postoperative period was significantly shorter (47 ± 30 vs. 34 ± 30 months, p = 0.002), and the rates of early-stage disease and minimally invasive approaches significantly higher (both p < 0.001) in the proximal gastrectomy group than in the total gastrectomy group. Despite advantageous background factors for proximal gastrectomy, the postoperative QOL did not differ markedly between the groups. Compared to patients who underwent reconstruction with the double-tract method, patients who underwent esophagogastrostomy had significantly larger remnant stomachs but a similar QOL. CONCLUSION: Even with total gastrectomy, a postoperative QOL comparable to that with proximal gastrectomy can be maintained. Clarifying the optimal reconstruction methods for proximal gastrectomy for esophagogastric junction cancer is warranted. TRIAL REGISTRATION: This study was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; registration number: 000032221).

Gene expression signatures as candidate biomarkers of response to PD-1 blockade in non-small cell lung cancers.

Although anti-PD-1/PD-L1 monotherapy has achieved clinical success in non-small cell lung cancer (NSCLC), definitive predictive biomarkers remain to be elucidated. In this study, we performed whole-transcriptome sequencing of pretreatment tumor tissue samples and pretreatment and on-treatment whole blood samples (WB) samples obtained from a clinically annotated cohort of NSCLC patients (n = 40) treated with nivolumab (anti-PD-1) monotherapy. Using a single-sample gene set enrichment scoring method, we found that the tumors of responders with lung adenocarcinoma (LUAD, n = 20) are inherently immunogenic to promote antitumor immunity, whereas those with lung squamous cell carcinoma (LUSC, n = 18) have a less immunosuppressive tumor microenvironment. These findings suggested that nivolumab may function as a molecular targeted agent in LUAD and as an immunomodulating agent in LUSC. In addition, our study explains why the reliability of PD-L1 expression on tumor cells as a predictive biomarker for the response to nivolumab monotherapy is quite different between LUAD and LUSC.

Association of immune-related pneumonitis with clinical benefit of anti-programmed cell death-1 monotherapy in advanced non-small cell lung cancer.

BACKGROUND: The association between the development of checkpoint inhibitor pneumonitis (CIP) with tumor response and survival has remained unclear so far. The aim of the present study was to evaluate the association between CIP and the clinical efficacy of anti-programmed cell death-1 antibody in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Between January 2016 and August 2019, 203 advanced NSCLC patients were administered with nivolumab or pembrolizumab. Comparisons were made between patients with and without CIP. We evaluated the time-to-treatment failure (TTF), progression-free survival (PFS), and overall survival (OS). RESULTS: CIP was observed in 28 (14%) patients. CIP was associated with a longer PFS (18.9 months [95% confidence interval, CI: 8.7 months-not reached] vs. 3.9 months [95% CI: 3.4-5.1 months, p < 0.01]) and longer OS (27.4 [95% CI: 20.7 months-not reached] vs. 14.8 months [95% CI: 11.2-17.9 months, p = 0.003]). Most patients discontinued the immune checkpoint inhibitor (ICI) treatment when they developed CIP. Seven patients (25%) lived for more than 300 days from treatment discontinuation and did not show any long-term tumor growth after treatment discontinuation. CONCLUSION: CIP was associated with prolonged PFS and OS. Additionally, 25% of CIP patients did not show any tumor growth for long periods after treatment discontinuation. Careful management of CIP can help in obtaining the best clinical efficacy from anti-PD-1 antibody.

Relationship between Programmed Cell Death Protein Ligand 1 Expression and Immune-related Adverse Events in Non-small-cell Lung Cancer Patients Treated with Pembrolizumab.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). A correlation between the development of irAEs and efficacy has been suggested; however, it is unclear whether there is a relationship between programmed death ligand 1 (PD-L1) expression and the development of these events. METHODS: We performed a retrospective study of advanced or metastatic non-small cell lung cancer (NSCLC) patients who were treated with pembrolizumab monotherapy at our institution between May 2015 and April 2018 (n = 44). Patients were categorized into two groups, specifically those with irAEs (irAE group) or without (non-irAE group), and we evaluated the objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Predictors of irAEs were examined by multivariate analysis. RESULTS: irAEs of any grade occurred in 31 (70.5%) patients. The median PFS was 10.9 months in the irAE group versus 3.7 months in the non-irAE group (P < 0.001). ORR and DCR were also higher in the irAE group than in the non-irAE group. Furthermore, high PD-L1 expression (≥50%) was a predictive factor of irAE based on logistic regression (P = 0.004). CONCLUSIONS: In patients with advanced NSCLC treated with pembrolizumab monotherapy, ORR, DCR, and PFS were significantly better in the irAE group than in the non-irAE group. High PD-L1 expression, at the time of pretreatment, was identified as an independent predictor of irAE development. We believe that more careful management of irAEs for individuals with high PD-L1 expression is needed to improve clinical benefits. Further, PD-L1 expression might be useful for ICI risk management.

Advances in Label-Free Detections for Nanofluidic Analytical Devices.

Nanofluidics, a discipline of science and engineering of fluids confined to structures at the 1-1000 nm scale, has experienced significant growth over the past decade. Nanofluidics have offered fascinating platforms for chemical and biological analyses by exploiting the unique characteristics of liquids and molecules confined in nanospaces; however, the difficulty to detect molecules in extremely small spaces hampers the practical applications of nanofluidic devices. Laser-induced fluorescence microscopy with single-molecule sensitivity has been so far a major detection method in nanofluidics, but issues arising from labeling and photobleaching limit its application. Recently, numerous label-free detection methods have been developed to identify and determine the number of molecules, as well as provide chemical, conformational, and kinetic information of molecules. This review focuses on label-free detection techniques designed for nanofluidics; these techniques are divided into two groups: optical and electrical/electrochemical detection methods. In this review, we discuss on the developed nanofluidic device architectures, elucidate the mechanisms by which the utilization of nanofluidics in manipulating molecules and controlling light-matter interactions enhances the capabilities of biological and chemical analyses, and highlight new research directions in the field of detections in nanofluidics.

Malignant peripheral nerve sheath tumour of the oesophagus: a case report.

BACKGROUND: Malignant peripheral nerve sheath tumour (MPNST) is a very rare disease, and its pathogenesis is unknown. There are few reports of MPNST of the oesophagus. We report a case of an MPNST that was diagnosed and resected. CASE PRESENTATION: A 30-year-old female presented with dysphagia. She had been aware of the dysphagia approximately 6 months before presentation. The chest X-ray showed shadows in the right mediastinum. Barium fluoroscopy revealed a semicircular raised lesion in the lower oesophagus. Upper gastrointestinal endoscopy revealed a type 1 oesophageal tumour centred on the posterior wall 26-35 cm from the incisors. The surface was ulcerated, and the tumour was exposed. The affected area showed no iodine uptake. The EUS showed an isoechoic mass. The CT scan showed a mass of 71 × 61 × 55 mm in the beginning of the lower oesophagus with low density mass and swelling of the right recurrent nerve lymph node to 12 mm. On FDG-PET, the tumour showed an SUVmax of 11.05, and no abnormal accumulation was found in lymph nodes or other organs. The MRI showed a hyperintense mass on the T2WI, which had prolonged contrast enhancement, and no findings of invasion into surrounding tissue were found. The patient underwent right thoracotomy and open thoracic oesophagectomy. The affected lymph node was tumour negative by rapid pathological diagnosis during the operation. Histologically, spindle cells with different-sized nuclei were mixed throughout the tissue. Some regions showed nuclear polymorphism or a storiform pattern, and locally, there were approximately 7 mitoses/10 HPFs. The margin was relatively clear, but spindle-shaped tumour cells infiltrated the surrounding interstitium and basal myoepithelium, and the patient was diagnosed with MPNST. In this case, the postoperative course was good, and 16 months after the operation, the patient is currently under observation at the outpatient stage without recurrence. CONCLUSIONS: MPNST in the oesophagus is a relatively rare disease. Diagnosis before treatment is sometimes difficult, but the prognosis is good if radical resection is possible.

Ultrasensitive detection of nonlabelled bovine serum albumin using photothermal optical phase shift detection with UV excitation.

Ultrasensitive detection of nonlabelled bovine serum albumin is performed in micro/nanofluidic chips using a photothermal optical phase shift (POPS) detection system. Currently, micro- and nanofluidics allow the analysis of various single cells, and their targets of interest are shifting from nucleic acids to proteins. Previously, our group developed photothermal detection techniques for the sensitive detection of nonfluorescent molecules. For example, we developed a thermal lens microscope (TLM) with ultrahigh sensitivity at the single-molecule level and a POPS detector that is applicable to nanochannels smaller than the wavelength of light. The POPS detector also realized the detection of nonlabelled proteins in nanochannels, although its detection sensitivity is less than that of the TLM in microchannels due to insufficient background light reduction. To overcome this problem, we developed a new POPS detector using relay optics for further reduction of the background light. In addition, heat transfer from the sample solution to the nanochannel wall was thoroughly investigated to achieve ultrahigh sensitivity. The limit of detection (LOD) obtained with the new POPS detector is 30 molecules in 1.0 fL. Considering this LOD, the performance of the new POPS detector is comparable with that of the TLM. Owing to the applicability of the POPS detector for sensitive detection even in nanochannels or single-µm channels, which cannot be realized with the TLM, combinations of the POPS detector and separation techniques employing unique nanochannel properties will contribute to advances in single-cell proteomics in the future.

Association Between Skin Reaction and Clinical Benefit in Patients Treated with Anti-Programmed Cell Death 1 Monotherapy for Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Anti-programmed cell death 1 antibody is a standard therapy for advanced non-small cell lung cancer (NSCLC). However, immune-related adverse events (irAEs), such as skin reactions, are frequently observed. Although skin reactions are associated with clinical efficacy in melanoma, this association in advanced NSCLC and predictors of irAEs remain unclear. Accordingly, this study identified potential correlations of skin reactions with clinical efficacy and clinical predictors of development of skin reactions. SUBJECTS, MATERIALS, AND METHODS: We retrospectively surveyed patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital (n = 155) during January 2016 to April 2018. Treatment efficacy was evaluated in patients with and without skin reactions, and associated predictive markers were determined. A 6-week landmark analysis was conducted to assess the clinical benefit of early skin reactions. RESULTS: Skin reactions were observed in 51 patients with a median time to onset of 6.4 weeks. The overall response rate (ORR) was significantly higher in patients with skin reactions (57% vs. 19%, p < .001). Median progression-free survival (PFS) durations of 12.9 and 3.5 months and overall survival durations of not reached and 11.4 months were observed in patients with and without skin reactions, respectively. In the 6-week landmark analysis, the ORR was significantly higher in patients with skin reactions, and skin reactions were significantly associated with increased PFS. A multivariate analysis identified pre-existing rheumatoid factor (RF) as an independent predictor of skin reactions. CONCLUSION: Skin reactions appeared beneficial in patients treated with nivolumab/pembrolizumab for advanced NSCLC and could be predicted by pre-existing RF. Further large-scale validations studies are warranted. IMPLICATIONS FOR PRACTICE: This single-institutional medical record review that included 155 patients with advanced non-small cell lung cancer who were treated with nivolumab or pembrolizumab monotherapy revealed that overall response rate and progression-free survival were significantly better in patients with skin reactions. Pre-existing rheumatoid factor was an independent predictor of skin reactions.

Enzyme-linked immunosorbent assay utilizing thin-layered microfluidics.

A rapid and sensitive enzyme-linked immunosorbent assay (ELISA) is required for on-site clinical diagnosis. Previously, a microfluidic ELISA in which antibody-immobilized beads are packed in a microchannel for a high surface-to-volume (S/V) ratio was developed, but utilizing beads led to complicated fluidic operation. Recently, we have reported nanofluidic ELISA that utilizes antibody-immobilized glass nanochannels (102-103 nm) to achieve a high S/V ratio without beads, enabling even single-molecule detection, but it is not applicable to clinical diagnosis owing to its fL sample volume, much smaller than the nL-µL sample volume in clinical diagnosis. Here, we propose an antibody-immobilized, thin-layered microfluidic channel as a novel platform. Based on the method of nanofluidic ELISA, the channel width was expanded from 103 nm to 100 mm to expand the volume of the reaction field to 102 nL, while the channel depth (103 nm) was maintained to retain the high S/V ratio. A device design which incorporates a taper-shaped interface between the thin-layered channel and the microchannel for sample injection was proposed, and the uniform introduction of the sample into the high-aspect-ratio (width/depth ∼ 200) channel was experimentally confirmed. For the proof of concept, a thin-layered ELISA device with the same S/V ratio as the bead-based ELISA format was designed and fabricated. By measuring a standard C-reactive protein solution, the working principle was verified. The limit of detection was 34 ng mL-1, which was comparable to that of bead-based ELISA. We believe that the thin-layered ELISA can contribute to medicine and biology as a novel platform for sensitive and rapid ELISA.

Femtoliter Gradient Elution System for Liquid Chromatography Utilizing Extended Nanofluidics.

A gradient system was developed for the separation of proteins on a femtoliter scale utilizing nanofluidic channels. In the history of chromatography, miniaturization of the separation column has been important for efficient separation and downsizing of instruments. Previously, our group developed a small and highly efficient chromatography system utilizing nanofluidic channels, although a flexible design of the gradient was difficult and separation of proteins was not achieved. Here, we propose a flexible gradient system using standard HPLC pumps and an auxiliary mixer with a simple sample injection system. In contrast to our previous sample injection system using pressure balance, the system enables a femtoliter-scale sample injection which is compatible with gradient elution using HPLC pumps. The system was carefully designed, verified for sample injection and gradient elution, and finally applied to the separation of proteins from model and real samples. This femtoliter-scale, efficient separation system will contribute to omics studies at the single-cell level.

Association of low body surface area with dose reduction and/or discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: a pilot study.

BACKGROUND: We have often encountered adverse events requiring dose reduction and/or discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis. OBJECTIVES: The objectives of this study were to clarify the incidence of dose reduction and/or discontinuation following the commercialization of nintedanib and to investigate predictors of dose reduction and/or discontinuation of nintedanib at our hospital. METHODS: We retrospectively identified 25 patients who had received nintedanib 150 mg twice daily at Sendai Kousei Hospital and categorized them into two groups according to whether they had or had not required dose reduction and/or discontinuation and sought to identify predictors of dose reduction and/or discontinuation. RESULTS: Seventeen patients developed adverse events, which included diarrhea (n=10, 44%), hepatotoxicity (n=7, 28%), and anorexia (n=2, 16%). No adverse event-related deaths occurred during the study period. Patients who required dose reduction and/or discontinuation were significantly older than those who did not (72 years vs 67 years; P=0.047). Body surface area (BSA) was significantly lower in the group that needed dose reduction and/or discontinuation than in the group that did not (1.63 m2 vs. 1.78 m2; P=0.028). Multivariate logistic regression revealed that the association of low BSA with dose reduction and/or discontinuation was statistically significant. CONCLUSIONS: A low BSA was associated with dose reduction and/or discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis. Further studies in larger patient samples are needed to validate these findings.

Profiling Preexisting Antibodies in Patients Treated With Anti-PD-1 Therapy for Advanced Non-Small Cell Lung Cancer.

Importance: Administration of anti-programmed cell death protein 1 (anti-PD-1) is now standard therapy in advanced non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors, including anti-PD-1, have not been assessed in patients with subclinical disease with advanced NSCLC, and no useful clinical biomarkers have been associated with immune-related adverse events (irAEs) among these patients treated with anti-PD-1. Objective: To assess the safety and efficacy of anti-PD-1 treatment in patients with subclinical disease with advanced NSCLC and with or without preexisting autoimmune markers, including rheumatoid factor, antinuclear antibody, antithyroglobulin, and antithyroid peroxidase; and to assess potential clinical biomarkers that may be meaningfully and conveniently associated with clinical benefit or with irAEs following anti-PD-1 treatment. Design, Setting, and Participants: This medical records analysis retrospectively evaluated 137 patients who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital in Japan between January 2016 and January 2018. Treatment efficacy and irAEs were evaluated along with candidate factors that may be associated with irAEs. Exposures: Absence or presence of specific autoimmune markers and antibodies before treatment. Main Outcomes and Measures: Preexisting antibodies and autoimmune markers, progression-free survival (PFS), and irAEs. Results: Of 137 patients with advanced NSCLC, 105 were men, the median age was 68 (range, 36-88) years, 99 underwent nivolumab monotherapy, 38 underwent pembrolizumab monotherapy, and 134 had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median PFS was 6.5 (95% CI, 4.4-12.9) months among patients with examined preexisting antibodies and 3.5 (95% CI, 2.4-4.1) months among patients without, suggesting significantly better prognosis in the former. The hazard ratio for disease progression or death in the presence of the examined preexisting antibodies was 0.53 (95% CI, 0.36-0.79; P = .002). The PFS was significantly longer among patients with any preexisting antibodies than among those without. The examined preexisting antibodies (48 patients [73%]) and rheumatoid factor (26 patients [39%]) were more common among patients who developed irAEs. Multivariate analysis indicated that the presence of the examined preexisting antibodies was independently associated with irAEs (odds ratio, 3.25; 95% CI, 1.59-6.65; P = .001). Skin reactions were more frequent among patients with preexisting rheumatoid factor (47% vs 24%, P = .02), whereas thyroid dysfunction was more frequent among patients with preexisting antithyroid antibodies (20% vs 1%, P < .001). Conclusions and Relevance: The presence of the examined preexisting antibodies was associated with clinical benefit and with the development of irAEs in patients with NSCLC treated with nivolumab or pembrolizumab. Thus, the presence of these autoimmune markers may help determine the risk-benefit ratio for individual patients with NSCLC, maximizing therapeutic benefits while minimizing irAEs.

[A Case of Ascending Colon Cancer Recurrence with Para-Aortic Lymph Node Metastases That Was Successfully Treated with Resection and Adjuvant Chemotherapy].

A laparoscopy-assisted right hemicolectomy and D3 lymph node dissection were performed to treat a 60-year-old woman with ascending colon cancer. Microscopically, the resected specimen was diagnosed as adenocarcinoma(tub1>tub2, pSS, pN1, M0). Adjuvant chemotherapy using UFT/UZEL was administered for 6 months. Enlarged para-aortic lymph nodes were identified by follow-up CT 2 years post operation, and a para-aortic lymph node dissection was performed. Microscopic examination revealed that the #216 b1 int lymph node contained poorly differentiated metastatic adenocarcinoma. After 36 courses of FOLFOX as adjuvant chemotherapy, the chemotherapy was discontinued because of an adverse event. She has remained well without recurrence for 5 years after the second surgery. There have been reports of survival improvements by surgical resections in patients with solitary para-aorta lymph node metastases of colorectal cancer. These observations suggest that the surgical therapy may have contributed to the improved prognosis in the present case.

Association of Immune-Related Adverse Events with Clinical Benefit in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Nivolumab.

BACKGROUND: Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study aimed to evaluate whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We conducted a retrospective study of patients who received nivolumab monotherapy at Sendai Kousei Hospital (n = 70). The patients were categorized into two groups based on the incidence of irAEs: those with irAEs (irAE group) or those without (non-irAE group). Treatment efficacy was evaluated in each group. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were determined. RESULTS: The objective response rate was 57% in the irAE group versus 12% in the non-irAE group. Median progression-free survival was 12.0 months in the irAE versus 3.6 months in the non-irAE group. The incidence of both irAEs and pre-existing antithyroid antibody was significantly higher in responders than in nonresponders. Multivariate analysis identified incidence of irAEs and pre-existing antithyroid antibody as an independent predictor of treatment response. CONCLUSION: Objective response rate and progression-free survival were significantly better in the irAE than in the non-irAE group in patients with advanced NSCLC treated with nivolumab monotherapy. The development of irAEs was associated with clinical efficacy, and the presence of pre-existing antithyroid antibody might be correlated with treatment response to nivolumab monotherapy. IMPLICATIONS FOR PRACTICE: Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study evaluted whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer. Results showed that the objective response rate and progression-free survival were significantly better in the patients who developed irAEs than in the patients who did not develop irAEs, and the incidence of irAEs and positivity for antithyroid antibody at pretreatment were independent predictors of treatment response of nivolumab monotherapy. Therefore, the development of irAEs predicts clinical benefit and suggests that cautious management of irAEs can lead to achieving maximum clinical benefit from nivolumab monotherapy.

A single-molecule ELISA device utilizing nanofluidics.

Single molecule analysis is desired in many areas that require the analysis of ultra-small volume and/or extremely low concentration samples (e.g., single-cell biology, medicine diagnosis, virus detection, etc.). Due to the ultra-small volume or concentration, the sample contains only single or countable analyte molecules. Thus, specific single molecules should be precisely processed and detected for analysis. However, except nucleic acids, most molecules are difficult to amplify, and a new analytical methodology for specific single molecules is thus essential. For this, efficient chemical processing and detection, which are important analytical elements, should be developed. Here, we report a single-molecule ELISA (enzyme-linked immunosorbent assay) device utilizing micro/nanofluidic technology. Both chemical processing and detection were integrated into an ultra-small space (102 nm in size), and the integration allowed precise processing (∼100% capture) and detection of a specific single molecule (protein) for the first time. This new concept and enabling technology represent a significant innovation in analytical chemistry and will have a large impact on general biology and medicine.