Real-time estimation of the remaining surgery duration for cataract surgery using deep convolutional neural networks and long short-term memory.

PURPOSE: Estimating the surgery length has the potential to be utilized as skill assessment, surgical training, or efficient surgical facility utilization especially if it is done in real-time as a remaining surgery duration (RSD). Surgical length reflects a certain level of efficiency and mastery of the surgeon in a well-standardized surgery such as cataract surgery. In this paper, we design and develop a real-time RSD estimation method for cataract surgery that does not require manual labeling and is transferable with minimum fine-tuning. METHODS: A regression method consisting of convolutional neural networks (CNNs) and long short-term memory (LSTM) is designed for RSD estimation. The model is firstly trained and evaluated for the single main surgeon with a large number of surgeries. Then, the fine-tuning strategy is used to transfer the model to the data of the other two surgeons. Mean Absolute Error (MAE in seconds) was used to evaluate the performance of the RSD estimation. The proposed method is compared with the naïve method which is based on the statistic of the historical data. A transferability experiment is also set to demonstrate the generalizability of the method. RESULT: The mean surgical time for the sample videos was 318.7 s (s) (standard deviation 83.4 s) for the main surgeon for the initial training. In our experiments, the lowest MAE of 19.4 s (equal to about 6.4% of the mean surgical time) is achieved by our best-trained model for the independent test data of the main target surgeon. It reduces the MAE by 35.5 s (-10.2%) compared to the naïve method. The fine-tuning strategy transfers the model trained for the main target to the data of other surgeons with only a small number of training data (20% of the pre-training). The MAEs for the other two surgeons are 28.3 s and 30.6 s with the fine-tuning model, which decreased by -8.1 s and -7.5 s than the Per-surgeon model (average declining of -7.8 s and 1.3% of video duration). External validation study with Cataract-101 outperformed 3 reported methods of TimeLSTM, RSDNet, and CataNet. CONCLUSION: An approach to build a pre-trained model for estimating RSD estimation based on a single surgeon and then transfer to other surgeons demonstrated both low prediction error and good transferability with minimum fine-tuning videos.

CD169+ sinus macrophages in regional lymph nodes do not predict mismatch-repair status of patients with colorectal cancer.

AIMS: Mismatch-repair deficiency and microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC) is treated with programmed death (PD)-1 antibody regardless of PD-ligand (L)1 expression in tumor cells. We previously found that abundant CD169+ macrophages in regional lymph node (RLN) sinuses and CD8+ tumor-infiltrating lymphocytes (TILs) positively correlated in CRC and were associated with a favorable prognosis. However, associations between dMMR/MSI-H CRC and CD8+ TILs or prognoses vary among studies. In this study, we attempted to compare the association between MMR status, CD169+ macrophages in RLNs, CD8+ TILs, PD-L1 scores, and prognoses in CRC. METHODS AND RESULTS: We immunostained 83 surgically resected CRC tumors that we previously analyzed for MMR proteins, and identified 9 that were dMMR. The number of CD169+ macrophages in RLNs and CD8+ TILs significantly correlated with overall survival, whereas MMR status did not. The number of cells positive for the TIL markers CD3, CD4, CD8, and TIA-1, and macrophage markers CD68 and CD169 in RLNs did not significantly differ between groups according to MMR status. Furthermore, combined positive scores (CPS) for PD-L1 expression in five of nine dMMR CRCs were all <1. We found that dMMR in CRC did not correlate with numbers of CD169+ macrophages in RLNs or CD8+ TILs. CONCLUSIONS: CRC with CD169+ macrophages in RLNs and abundant CD8+ TILs indicates a better prognosis and it should be immunologically classified as a different antitumor group from dMMR CRC.

A Case of L-Asparaginase-Induced Severe Hepatic Steatosis With Decreased Serum Cholinesterase Levels.

L-asparaginase (L-Asp) is a useful antileukemic agent for acute lymphoblastic leukemia (ALL); however, it often causes severe liver injury with marked fatty liver. Here, we present a case of L-Asp-induced fatty liver disease in a 21-year-old female patient with ALL. Serum cholinesterase levels, which are usually elevated in fatty liver, decrease at the onset of liver injury. After treatment with L-carnitine and vitamin B complex, the liver injury rapidly improved, resulting in the patient being able to continue subsequent chemotherapy.

Novel Inhibitor for Downstream Targeting of Transforming Growth Factor-ß Signaling to Suppress Epithelial to Mesenchymal Transition and Cell Migration.

Cancer metastasis accounts for most of the mortality associated with solid tumors. However, antimetastatic drugs are not available on the market. One of the important biological events leading to metastasis is the epithelial to mesenchymal transition (EMT) induced by cytokines, namely transforming growth-factor-ß (TGF-ß). Although several classes of inhibitors targeting TGF-ß and its receptor have been developed, they have shown profound clinical side effects. We focused on our synthetic compound, HPH-15, which has shown anti-fibrotic activity via the blockade of the TGF-ß Smad-dependent signaling. In this study, 10 µM of HPH-15 was found to exhibit anti-cell migration and anti-EMT activities in non-small-cell lung cancer (NSCLC) cells. Although higher concentrations are required, the anti-EMT activity of HPH-15 has also been observed in 3D-cultured NSCLC cells. A mechanistic study showed that HPH-15 inhibits downstream TGF-ß signaling. This downstream inhibition blocks the expression of cytokines such as TGF-ß, leading to the next cycle of Smad-dependent and -independent signaling. HPH-15 has AMPK-activation activity, but a relationship between AMPK activation and anti-EMT/cell migration was not observed. Taken together, HPH-15 may lead to the development of antimetastatic drugs with a new mechanism of action.

Classification of PD-L1 expression in various cancers and macrophages based on immunohistocytological analysis.

Programmed death (PD)-1/PD-ligand 1 (PD-L1) antibodies have shown an intense clinical effect in some patients with PD-L1+ tumors, and their applications have rapidly expanded to various cancer types with or without the application of new companion diagnostics (CDx) with a lower cutoff value and inclusion of macrophage evaluation. However, the pathological background explaining the difference in the cutoff value remains unknown. To address this, we evaluated tissue array samples from 231 patients with lung adenocarcinoma, 186 with lung squamous cell carcinoma, and 38 with renal cell carcinoma (RCC) who were not receiving PD-1/PD-L1 antibodies to investigate the relationship between PD-L1 expression on tumor cells and CD8+ T-cell infiltration in tumor tissues. PD-L1 expression in RCC was clearly lower than that in non-small-cell lung cancer (NSCLC) tissue, whereas CD8+ T-cell infiltration was low in all cancers. We next analyzed PD-L1 expression by interferon (α, ß, and γ) and LPS stimulation in both macrophages and 41 cancer cell lines derived from various organs and histological types. The PD-L1 expression patterns were classified into three types, which differed depending on each organ or tissue type. Interestingly, NSCLC cell lines showed highly diverse PD-L1 expression patterns compared with RCC cell lines. Conversely, PD-L1 expression was stronger and more prolonged in macrophages than in typical cell lines. Here, we revealed the diversity of the PD-L1 expression patterns in tumor cells and macrophages, demonstrating the pathological and cytological significance of the transition of cutoff values in PD-L1 CDx for PD-1/PD-L1 antibody administration.

Amakusamine from a Psammocinia sp. Sponge: Isolation, Synthesis, and SAR Study on the Inhibition of RANKL-Induced Formation of Multinuclear Osteoclasts.

A simple methylenedioxy dibromoindole alkaloid, amakusamine (1), was isolated from a marine sponge of the genus Psammocinia, and its structure was determined from spectroscopic data, time-dependent density-functional theory calculations, and synthesis. Compound 1 inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts with an IC50 value of 10.5 µM in RAW264 cells. The structure-activity relationship of 1 was also investigated with synthetic derivatives.

Detection of cancer cells in whole blood using a dynamic deformable microfilter and a nucleic acid aptamer.

Cancer cell count in the blood of cancer patients is extremely low. If these cells are easily detectable, cancer diagnosis may be possible by simply using a blood test, thus reducing patient burden. This study aimed to develop a cancer detection device by combining a microfilter that can be dynamically deformed and a nucleic acid aptamer that has a specific binding ability to cancer cells for easy detection. The cancer detection device was fabricated by photolithography, electroforming, and three-dimensional printing. The cancer cell detection ability of the fabricated device was evaluated using 1 mL of blood samples spiked with different concentrations of cancer cells. The lowest concentration of cancer cells in the blood was 5 cancer cells/1 mL blood. The fabricated microfilters specifically detected cancer cells in the blood successfully at exceedingly low concentrations. Moreover, the cancer detection experiment results using human whole blood revealed that cancer detection could be performed with higher accuracy using the fabricated cancer detection device compared to pre-existing cancer detection equipment (e.g., CellSearch system, Veridex). These findings provide important insights into the use of cancer cells in the blood as a diagnostic approach for cancer.

Efficacy of oral levofloxacin monotherapy against low-risk FN in patients with malignant lymphoma who received chemotherapy using the CHOP regimen.

The safety and feasibility of oral fluoroquinolone monotherapy in patients with low-risk febrile neutropenia (FN) were demonstrated in recent studies. Levofloxacin (LVFX) is a commonly prescribed antibiotic; however, evidence for its efficacy against FN is limited. Therefore, in this study, we retrospectively investigated the efficacy of LVFX against low-risk FN in patients with malignant lymphoma at our institution. Treatment success was defined as recovery from fever and neutropenia without alteration of the initial regimen. We recruited 29 patients between January 2013 and December 2018. The median age of the cohort was 64 (range: 21-87) years; 13 (44.8%) were aged over 65 years. In total, 22 patients had diffuse large B-cell lymphoma (DLBCL). Therapy was successful in 24 (82.8%) patients, whereas 5 had treatment failure requiring a change from LVFX to intravenous broad-spectrum antibacterial agents. No deaths related to FN were observed. Two patients required FN-related chemotherapy dose reduction in subsequent cycles. Although this cohort comprised many elderly patients, our study confirmed the efficacy of LVFX in patients with low-risk FN. This may improve the treatment of low-risk FN and malignant lymphoma.

Severe Hemorrhagic Cystitis Caused by Cyclophosphamide and Capecitabine Therapy in Breast Cancer Patients: Two Case Reports and Literature Review.

Combined oral cyclophosphamide and capecitabine (XC) chemotherapy is used for metastatic breast cancer (MBC) patients. We report herein two MBC patients who developed severe hemorrhagic cystitis after XC therapy. Case 1: A 67-year-old woman with MBC had received XC therapy for 2.5 years. After a sudden onset of lower abdominal pain and gross hematuria, cystoscopy revealed a urinary bladder mucosa showing diffuse dilation of the capillaries and a large blood clot. A total dose of 60.8 g cyclophosphamide had been given and the XC regimen was discontinued immediately. The patient experienced frequent episodes of bladder tamponade over 18 months and underwent continuous bladder irrigation and cystoscopic fulguration. Hyperbaric oxygen therapy (HBOT) provided only temporary relief and the patient subsequently developed hemorrhagic shock. A bilateral ureterostomy was eventually performed. Case 2: A 65-year-old woman with MBC was given XC for 3 years, but this was discontinued after she developed new lung lesions. The patient was given a total dose of 78.4 g of cyclophosphamide. A month later, the patient complained of intermittent gross hematuria, which progressed to persistent macroscopic hematuria for 1 week. She underwent continuous bladder irrigation with saline, without an improvement in her bladder tamponade. Subsequently, the bleeding ceased completely after HBOT. Some MBC cases can be controlled for a long time with XC therapy. For those cases, we need to realize that severe hemorrhagic cystitis may occur. Even at a low dose, requires testing periodically for occult blood in the urine to detect the early stages of cystitis.

Retrospective analysis of the efficacy and safety of eribulin therapy for metastatic breast cancer in daily practice.

BACKGROUND: Evidence of eribulin therapy for metastatic breast cancer (MBC) in clinical practice is not well documented. METHODS: We retrospectively analyzed the safety and efficacy of eribulin in 29 MBC patients from 2011 to 2016 at Fukuoka University Hospital. RESULTS: The median patient age, number of courses, total dose, and relative dose intensity were as follows: 65 years, five courses, 8.6 mg/m2 , and 75%, respectively. One patient achieved a complete response, (CR) six a partial response (PR), eight stable disease (SD) and 14 patients exhibited progressive disease. The objective response rate (ORR: CR + PR) was 24.1%, and the clinical benefit rate (CBR: CR + PR + SD) was 51.7%. The median progression-free survival was 90 days (95% confidence interval [CI] 67-126) and median overall survival was 264 days (95% CI 198-357). In patients who previously received 2-4 regimens, the ORR was 28.5% and the CBR was 57.1%. In patients who received 5-12 regimens, the ORR was 20% and the CBR was 45%. Chemotherapy was administered to 20 patients (69%) after eribulin administration, and the median overall survival rate of cases that achieved greater than a PR was 1088 days. The most frequent treatment-related grade 3/4 adverse events were neutropenia (55.2%), and febrile neutropenia (20.1%). Grade 3 peripheral neuropathy occurred in 13.8% of patients, but was not exacerbated even if present before treatment. CONCLUSION: Eribulin is effective for MBC patients who have received multiple chemotherapies. Neutropenia and febrile neutropenia may develop after heavy prior therapy.

Very rare case of large obstructive myxofibrosarcoma of the right ventricle assessed with multi-diagnostic imaging techniques.

Primary myxofibrosarcoma of the heart is quite rare. We herein present the case of a 56-year-old man who presented with large obstructive myxofibrosarcoma of the right ventricle (RV), as assessed on multi-diagnostic imaging techniques (multidetector row computed tomography, magnetic resonance imaging and positron emission tomography). Most previous cases of cardiac myxofibrosarcoma have been reported in the left atrium and ventricle. In this report, we describe a very rare case of large obstructive myxofibrosarcoma of the RV.

Safety and pharmacokinetic evaluation of repeated intravenous administration of palonosetron 0.75 mg in patients receiving highly or moderately emetogenic chemotherapy.

PURPOSE: The aims of this study were to evaluate the safety, efficacy, and pharmacokinetics of repeated doses of palonosetron 0.75 mg on days 1 and 3 in Japanese patients who received highly or moderately emetogenic chemotherapy. METHODS: Twenty- six patients received palonosetron 0.75 mg intravenously before chemotherapy on days 1 and 3 plus dexamethasone (12-16 mg before chemotherapy on day 1 and 4-8 mg on days 2 and 3). The primary endpoints were safety and pharmacokinetics. Pharmacokinetics were evaluated in a subset of patients (n=6). Complete response and complete protection were evaluated as secondary endpoints. RESULTS: The accumulation ratios for C max and AUClast after the second dose on day 3 were 1.42 and 1.37, respectively. These values were consistent with the theoretical values expected from the half-life of palonosetron on day 1. Almost all of the patients had no nausea or vomiting in the acute phase (complete response (CR) rate, 96.2% [25/26]; CP rate, 92.3% [24/26]). In the delayed phase (24-192 h post-chemotherapy), the complete response and complete protection rates were 76.9% (20/26) and 61.5% (16/26), respectively. Treatment was well tolerated. CONCLUSIONS: This is the first study to report the pharmacokinetics of multiple doses of palonosetron 0.75 mg, given on days 1 and 3, in Japanese patients. Repeated treatment with palonosetron was safe and well tolerated by patients who received highly or moderately emetogenic anticancer chemotherapy.

Desmoplastic small round cell tumors in a young man.

A previously healthy 18-year-old man was admitted to our hospital with abdominal pain in September 2010. We performed a percutaneous biopsy of multiple intrahepatic masses. A diagnosis of desmoplastic small round cell tumors was confirmed based on the presence of a polyphenotypic immunoprofile (positivity for EMA, vimentin, cytokeratin, desmin and WT1) and characteristic EWS-WT1 gene fusion. Because the mass had invaded the mesentery and the disease had disseminated to liver, the patient received palliative chemotherapy with carboplatin, paclitaxel, vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide and irinotecan. The maximal response to the chemotherapy was a partial remission. The patient died 20 months after diagnosis.

Myosin-II-mediated directional migration of Dictyostelium cells in response to cyclic stretching of substratum.

Living cells are constantly subjected to various mechanical stimulations, such as shear flow, osmotic pressure, and hardness of substratum. They must sense the mechanical aspects of their environment and respond appropriately for proper cell function. Cells adhering to substrata must receive and respond to mechanical stimuli from the substrata to decide their shape and/or migrating direction. In response to cyclic stretching of the elastic substratum, intracellular stress fibers in fibroblasts and endothelial, osteosarcoma, and smooth muscle cells are rearranged perpendicular to the stretching direction, and the shape of those cells becomes extended in this new direction. In the case of migrating Dictyostelium cells, cyclic stretching regulates the direction of migration, and not the shape, of the cell. The cells migrate in a direction perpendicular to that of the stretching. However, the molecular mechanisms that induce the directional migration remain unknown. Here, using a microstretching device, we recorded green fluorescent protein (GFP)-myosin-II dynamics in Dictyostelium cells on an elastic substratum under cyclic stretching. Repeated stretching induced myosin II localization equally on both stretching sides in the cells. Although myosin-II-null cells migrated randomly, myosin-II-null cells expressing a variant of myosin II that cannot hydrolyze ATP migrated perpendicular to the stretching. These results indicate that Dictyostelium cells accumulate myosin II at the portion of the cell where a large strain is received and migrate in a direction other than that of the portion where myosin II accumulated. This polarity generation for migration does not require the contraction of actomyosin.