Patient‐derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, ...including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non‐small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO‐PrkdcscidHrhr). Histology of SQ, advanced clinical stage (III‐IV), status of lymph node metastasis (N2‐3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients’ surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next‐generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR‐TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial‐to‐mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR‐TKI resistance.
We successfully established 10 PDX. Next‐generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had EGFR mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR‐TKI resistance.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Numerous studies have focussed on the mechanisms of entry of pesticides into insect body parts such as oral intake, penetration through the integument of the body wall, and inhalation through ...spiracles. However, little is known about how insecticides spread to the points of entry or the paths on the body surface that are used to reach the target sites. In this study, elemental signals of pesticide-mimicking test solutions were tracked and their routes of spreading in experimental insects (Blattella germanica L.) were investigated using NanoSuit (a method of surface modification) and energy dispersive X-ray spectroscopy, combined with high-resolution scanning electron microscopy. When the test solution initially adhered to the dorsal and/or ventral body surface, it tended to spread horizontally to reach lateral plates. Whereas, when the solution directly adhered to the anterior side of the lateral plates, it spread to posterior segments. In this case, however, spreading in the opposite direction (i.e., the solution directly adhered to the posterior side of the lateral plates) was interrupted at a boundary erected by different groups of fine structures; each protrusion was large, and the arrangement was rather dense in the posterior segments. Morphological features of these fine structures and chemical characteristics of the hydrophobic surface substances potentially regulate the strength of the capillary force, which determines pesticide spreading.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Microplastics cause environmental problems. Biodegradable plastics have become popular because they aim to avoid such problems. However, their decomposition in the soil may have an impact. This study ...aims to investigate the effects of biodegradable plastics on the physicochemical properties of soil, specifically the production of CO
2
and N
2
O in the soil and plant growth. Three kinds of biodegradable plastics in the forms of 1) nonwoven fabric sheets made of poly-lactic acid (PLA) and polybutylene-succinate (referred to hereafter as fabric), 2) laminate sheets made of polybutylene adipate terephthalate (PBAT) and pulp (hereafter laminate), and 3) drinking cups made of PLA (hereafter cup), were cut into small pieces (<5 mm), added to soil, then water-holding capacity was determined and incubated aerobically for 4 weeks at 30°C in the dark. Soil and gas samples were collected weekly to measure soil pH, nitrate-nitrogen content, CO
2
, and N
2
O productions. These plastics were also tested in a pot experiment with Komatsuna (Brassica napa var. perviridis). We tested for seed germination, plant growth, leaf color, and fresh weight at harvest. Results showed that the water retention capacity was higher in the fabric plastics as compared to the cup plastics and the control. Soil pH with the fabric plastics dropped during the initial 2 weeks of incubation, then recovered to a similar pH to the control (without plastic). Nitrate contents in the soil with laminate plastics were lower than those in the control, while CO
2
production in the soil with the laminate plastics was higher than that in the control and the other plastics during the incubation period, and even higher than the one of added plastic-C. N
2
O was produced rapidly within 1 week of incubation in the soil with the laminate plastics, and cumulative N
2
O production from incubation was more than that of the control. The seed germination and plant growth tended to be suppressed in the pot experiment with the fabric and laminate plastics. The results indicate that the influence of these biodegradable plastics on soil properties, greenhouse gas production, and plant growth on the kind of plastic and the timing.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Primary malignant melanoma (MM) of the mediastinum is rare, and there is a lack of consensus regarding the preferred treatment because non-cutaneous MM demonstrates an inferior response to systemic ...therapy. Herein, we describe the case of a 73-year-old man with MM of the anterior mediastinum with multiple liver metastases. Even though the size of lesions increased rapidly following diagnosis, nivolumab monotherapy caused remarkable tumor shrinkage. This is the first report of mediastinal MM showing a significant response to nivolumab. We, therefore, suggest that immunotherapy may be one of the treatment options for primary mediastinal MM.
Background
Multitarget kinase inhibitors (m‐TKI), including lenvatinib, are now available as treatment options for radioiodine‐refractory differentiated thyroid cancer (RR‐DTC). However, the optimal ...timing of treatment initiation with m‐TKI in these patients remains to be defined.
Methods
We retrospectively reviewed the clinical records of 30 consecutive patients with RR‐DTC. The relationship between clinical characteristics was evaluated, including tumor growth parameters at pretreatment/post‐treatment and efficacy of lenvatinib.
Results
A total of 26 patients with RR‐DTC treated with lenvatinib were evaluable for response and eligible for analysis. From the results of multivariate analysis, baseline tumor size and tumor‐related symptoms were independent negative prognostic factors for overall survival (OS) and progression‐free survival (PFS). Pretreatment tumor growth parameters were not prognostic for either PFS or OS.
Conclusions
Patients with RR‐DTC with a high tumor burden and tumor‐related symptoms had significantly worse prognosis. Greater tumor reduction after starting lenvatinib may lead to better prognosis, irrespective of pretreatment high tumor growth rate.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Tropomyosin receptor kinase (TRK) inhibitors have demonstrated histology‐agnostic efficacy in patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion. Although responses to TRK ...inhibitors can be dramatic and durable, duration of response may eventually be limited by acquired resistance via several mechanisms, including resistance mutations such as NTRK1‐G595R. Repotrectinib is a second‐generation TRK inhibitor, which is active against NTRK1‐G595R. However, its efficacy against entrectinib‐resistant tumors has not been fully elucidated. In the present study, we established entrectinib‐resistant tumor cells (M3B) in a brain metastasis model inoculated with NTRK1‐rearranged KM12SM cells and examined the sensitivity of M3B cells to repotrectinib. While M3B cells harbored the NTRK1‐G595R mutation, they were unexpectedly resistant to repotrectinib. The resistance was due to extracellular signal–regulated kinase (ERK) reactivation partially mediated by epidermal growth factor receptor (EGFR) activation. We further demonstrate that the triplet combination of repotrectinib, EGFR inhibitor, and MEK inhibitor could sensitize M3B cells in vitro as well as in a brain metastasis model. These results indicate that resistant mutations, such as NTRK1‐G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib‐resistant tumors, thereby causing resistance to second‐generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance.
We explored the resistance mechanism to tropomyosin receptor kinase (TRK) inhibitors. We demonstrated that resistant mutations, such as NTRK1‐G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib‐resistant tumors, thereby causing resistance to entrectinib as well as repotrectinib, and that this resistance could be surmounted by triple inhibitions to TRK, EGFR, and ERK.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Context
Intake of stable iodine helps prevent childhood thyroid cancer in nuclear emergencies, but there is limited case information.
Objective
We identified the intake rate and the factors ...associated with no intake among children who did not take stable iodine after the Fukushima disaster.
Design
Retrospective observational study.
Setting
Data were obtained from thyroid cancer screenings performed from August through November 2017.
Participants
Children in Miharu Town, Fukushima, Japan.
Intervention
No intervention.
Main Outcome Measures
We performed multilevel logistic regression analysis at the regional and individual levels. We qualitatively examined the reasons for no intake of stable iodine based on closed- and open-ended questions.
Results
The rate of distribution was 94.9%, but the intake rate was only 63.5%. Intake was lower in those aged 0 to 2 years compared with those aged ≥3 years (OR, 0.21; 95% CI, 0.11 to 0.36). Parents’ intake was positively associated with their children’s intake (OR, 61.0; 95% CI, 37.9 to 102.9). The variance partition coefficient for regions was 0.021, suggesting that the intake of stable iodine was more likely affected by individual than by regional factors. Closed-ended questions showed that the main reason for avoiding intake was concern about safety. Open-ended questions for other reasons revealed issues related to the distribution method, information about the effects and adverse effects of iodine, and instructions for iodine intake. There were no symptomatic adverse effects claimed to the town.
Conclusions
The distribution and consumption of stable iodine occurred in Miharu Town after the Fukushima disaster. To prepare for future nuclear emergencies, it is important to explain to both children and parents the need for intake of stable iodine, particularly among young children.
The intake rate of stable iodine among children was only 63.5% in Miharu Town after the Fukushima disaster. Factors affecting the intake of stable iodine were identified.
A BRAF V600E mutation is found as driver oncogene in patients with non-small cell lung cancer. Although combined treatment with dabrafenib and trametinib is highly effective, the efficacy of reduced ...doses of the drugs in combination therapy has not yet been reported.
A Japanese man in his mid-sixties was diagnosed with unresectable lung adenocarcinoma and was unresponsive to cytotoxic chemotherapy and immune checkpoint inhibitors. The BRAF V600E mutation was detected by next generation sequencing, and the patient was subjected to treatment with dabrafenib and trametinib in combination. Although the treatment reduced the tumor size, he experienced myalgia and muscle weakness with elevated serum creatine kinase and was diagnosed with rhabdomyolysis induced by dabrafenib and trametinib. After the patient recovered from rhabdomyolysis, the treatment doses of dabrafenib and trametinib were reduced, which prevented further rhabdomyolysis and maintained tumor shrinkage.
The reduction of the doses of dabrafenib and trametinib was effective in the treatment of BRAF V600E-mutant NSCLC, and also prevented the incidence of rhabdomyolysis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prophylactic elective neck dissection (ND) with navigation surgery using radioisotope-based sentinel lymph node biopsy (SLNB) is non-inferior to elective ND in terms of survival but has an advantage ...in postoperative functional disability. We conducted a subgroup analysis to identify predictive factors for false-negative (FN)-SLNB in patients with early oral cavity cancer. This study is a supplementary analysis using the dataset of a previously reported randomized clinical trial on SLN navigation surgery for oral cancers. This study investigated the association of clinical and SLN-related factors with false-negative cases in the SLNB group. From 2011 to 2016, 275 patients were enrolled and randomly assigned to the ND and SLNB study groups, with 134 patients assigned to the SLNB group. In the SLNB group, seven cases with negative SLNs and neck recurrences were judged as FN-SLNBs according to the general definition. The number of detected SLNs with and without adjusting for the propensity score was significantly associated with FNs in the logistic analysis. FN-SLNB was associated with the number of identified SLNs, suggesting the need for careful postoperative monitoring for neck recurrence in patients with one or two identified SLNs after acquiring sufficient experience in the identification technique.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We herein report a 67-year-old woman with malignant lymphomas of the bile duct that developed after regression of a pancreatic head mass. Computed tomography suggested the mass was pancreatic head ...cancer. Endoscopic ultrasonography showed a low-echoic mass with hyperechoic strands resembling autoimmune pancreatitis. Her serum IgG4 concentration was elevated to 674 mg/dL. After the pancreatic head mass spontaneously diminished, three masses were detected in the common bile duct. A biopsy of the major papilla revealed high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangement. Systemic chemotherapy with rituximab plus etoposide, prednisolone, vincristine, cyclophosphamide and doxorubicin resulted in complete remission.
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