Non-metastatic hip fractures surgery in patients with active cancer: benefit and risk.

PURPOSE: Although rare, non-metastatic proximal femoral fracture (PFF) can develop in patients with active cancer. However, little data are available regarding the risks and benefits of surgical treatment in such patients. The purpose of his study was to investigate the risks and benefits of surgical treatment of PFF in patients with and without cancer. METHODS: We retrospectively examined the medical records of all patients treated for PFF, excluding those with pathological fracture, at our hospital from July 2013 to December 2020. The patients were divided into two groups; The active cancer group and the standard group. We investigated in both groups about surgical and medical complications during the perioperative period, walking ability two weeks postoperatively, and one-year postoperative mortality rate. RESULT: After the inclusion and exclusion criteria, 39 patients in the active cancer group and 331 patients in the standard group were finally investigated. There were no statistically significant differences between the two groups. The complication rate did not appear statistical significance between two groups (16.7% in active cancer group vs 10.7% in standard group: p = 0.272). Walking ability was also similar in two groups. Mortality rate at one year was significantly higher in the active cancer group. (41.2% in active cancer group vs 6.0% in standard group: p < 0.05). CONCLUSION: Although the active cancer group had a higher mortality rate at one year, which was influenced by the prognosis of the cancer, the benefits of surgical intervention, such as regaining walking ability, were the same in patients with and without active cancer.

NTRK2 expression in gastrointestinal stromal tumors with a special emphasis on the clinicopathological and prognostic impacts.

Gastrointestinal stromal tumors (GISTs) are typically characterized by activating mutations of the KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type GIST. We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases, and all pan-trk positive cases showed diffuse and strong expression of c-kit. Interestingly, all of these cases showed only trkB but not trkA/trkC expression. Cap analysis of gene expression (CAGE) analysis identified increased number of genes whose promoters were activated in pan-trk/trkB positive GISTs. Imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in any of trkB positive GISTs, despite higher mRNA expression. TrkB expression was found in duodenal GISTs and more than half of small intestinal GISTs, and this subset of cases showed poor prognosis. However, there was not clear difference in clinical outcomes according to the trkB expression status in small intestinal GISTs. These findings may provide a possible hypothesis for trkB overexpression contributing to the tumorigenesis and aggressive clinical outcome in GISTs of duodenal origin.

Analysis of Quadriceps Muscle Tightness as a Risk Factor for Osgood-Schlatter Disease: A Prospective Cohort Study.

Background: The prevalence of Osgood-Schlatter disease (OSD) is unknown. Tightness of the quadriceps femoris has been reported to be a risk factor for OSD. Hypothesis: Quadriceps muscle tightness would not contribute to the development of OSD. Study Design: Cohort study; Level of evidence, 2. Methods: We enrolled 150 Japanese male junior high school soccer players (N = 300 knees), with a mean age at first examination of 12.5 years (range, 12-13 years). All players were assessed annually and evaluated for 2 years. Ten players (n = 14 knees) had a history of OSD before the first medical examination. After excluding these 10 players (n = 20 knees), the remaining 140 players (n = 280 knees) were included in this prospective analysis. Age at the time of starting soccer, history of injury (including OSD and time missed), height, weight, annual increase in height, body mass index (BMI), straight-leg raise angle, heel-buttock distance (HBD), and ultrasound images of the tibial tuberosity (maturity and morphology) were compared between players who developed OSD and those who did not. Results: OSD was identified in 8 knees of 6 players, with an incidence of 2.9% of knees (8/280) and 4.3% of players (6/140). Univariate analysis revealed significant differences between the OSD and non-OSD groups regarding BMI (17.1 ± 1 kg/m2 vs 18.5 ± 1.6 kg/m2, respectively; P = .018), HBD (1.5 ± 1.6 cm vs 4.8 ± 4.5 cm; P < .001), and stage of tibial tuberosity maturity (P < .001). The maturity of the tibial tuberosity was the only independent risk factor for the development of OSD in multivariate logistic regression analysis (odds ratio, 9.848 [95% CI, 3.297-29.41]; P < .001). Conclusion: Study findings indicated that quadriceps muscle tightness did not contribute to the development of OSD.

A retrospective analysis of the prognosis of Japanese patients with sarcoma brain metastasis.

BACKGROUND: Bone and soft tissue sarcomas are rare tumors and extremely rarely metastasize to the brain. Previous studies have examined the characteristics and poor prognostic factors in cases of sarcoma brain metastasis (BM). Due to the rarity of cases of BM from sarcoma, limited data exist concerning the prognostic factors and treatment strategies. METHODS: A retrospective single-center study was performed on sarcoma patients with BM. The clinicopathological characteristics and treatment options for BM of sarcoma were investigated to identify predictive prognostic factors. RESULTS: Between 2006 and 2021, 32 patients treated for newly diagnosed BM at our hospital were retrieved among 3133 bone and soft tissue sarcoma patients via our database. The most common symptom was headache (34%), and the most common histological subtypes were alveolar soft part sarcoma (ASPS) and undifferentiated pleomorphic sarcoma (25%). Non-ASPS (p = 0.022), presence of lung metastasis (p = 0.046), a short duration between initial metastasis, and the diagnosis of brain metastasis (p = 0.020), and the absence of stereotactic radiosurgery for BM (p = 0.0094) were significantly correlated with a poor prognosis. CONCLUSIONS: In conclusion, the prognosis of patients with brain metastases of sarcomas is still dismal, but it is necessary to be aware of the factors associated with a relatively favorable prognosis and to select treatment options appropriately.

Quadratus lumborum muscle strain in a youth soccer player: a case report.

Case: We report a case of quadratus lumborum muscle strain that occurred in a 16-year-old soccer player during a game. According to a video recording of the game, the injury occurred when the leg landed just after kicking the ball with the same leg while dribbling. The mechanism was suspected to be right lateral flexion of the trunk while the pelvis was simultaneously forced to tilt backward. The injury healed and he was able to return to competition 3 weeks later.Conclusion: This is the first report of a sports-related quadratus lumborum muscle strain.

Establishment of Rapid and Accurate Screening System for Molecular Target Therapy of Osteosarcoma.

Introduction Comprehensive analyses using clinical sequences subcategorized osteosarcoma (OS) into several groups according to the activated signaling pathways. Mutually exclusive co-occurrences of gene amplification (PDGFRA/KIT/KDR, VEGFA/CCND3, and MDM2/CDK4) have been identified in approximately 40% of OS, representing candidate subsets for clinical evaluation of additional therapeutic options. Thus, it would be desirable to evaluate the specific gene amplification before starting therapy in patients with OS. Materials and Methods This is a retrospective study. We examined 13 cases of clinical OS samples using NanoString-based copy number variation (CNV) analysis. Decalcification and chemotherapeutic effects on this analysis were also assessed. Results First, the accuracy of this system was validated by showing that amplification/deletion data obtained from this system using various types of cancer cell lines almost perfectly matched to that from the Cancer Cell Line Encyclopedia (CCLE). We identified potentially actionable alterations in CDK4/MDM2 amplification in 10% of samples and potential additional therapeutic targets (PDGFRA/KIT/KDR and VEGFA/CCND3) in 20% of samples, which is consistent with the reported frequencies. Furthermore, this assay could identify these potential therapeutic targets regardless of the sample status (frozen vs formalin-fixed paraffin-embedded [FFPE] tissues). Conclusion We established a NanoString-based rapid and cost-effective method with a short turnaround time (TAT) to examine gene amplification status in OS. This CNV analysis using FFPE samples is recommended where the histological evaluation of viable tumor cells is possible, especially for tumors after chemotherapy with higher chemotherapeutic effects.

SRC Family Kinase Inhibition Targets YES1 and YAP1 as Primary Drivers of Lung Cancer and as Mediators of Acquired Resistance to ALK and Epidermal Growth Factor Receptor Inhibitors.

PURPOSE: The identification of novel oncogenic driver alterations and novel mechanisms of acquired resistance (AR) is the key for further development of personalized therapy. The current study investigates the potential role of YES1 amplification as a primary driver of tumorigenesis and of YES1/YAP1 amplifications as mediators of AR to ALK and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). METHODS: Models of ectopic expression were established and characterized for YES1 and YAP1 in human bronchial epithelial cells and ALK fusion-positive (ALK+) and EGFR-mutant lung adenocarcinoma cell lines. MSK-IMPACT data for all lung adenocarcinoma cases and for ALK and EGFR TKI AR cases were surveyed for YES1 and YAP1 amplification. RESULTS: We report response to SRC family kinase (SFK) inhibition in a patient whose lung cancer exhibited YES1 amplification, without any well-established primary driver alteration, suggesting that YES1 amplification can also function as a primary oncogenic driver. To investigate the possibility of YES1 as a primary driver in tumorigenesis, we established preclinical models of YES1 overexpression using human bronchial epithelial cells and normal human breast epithelial cells. We showed that YES1 overexpression conferred sensitivity to SFK TKIs and promoted EGF-independent growth in a YAP1-dependent manner. Analysis of clinical genomic sequencing data from cases of AR to EGFR and ALK inhibitors revealed acquired amplification of YAP1 in four cases. EGFR-mutant and ALK fusion-positive cells overexpressing YES1 or YAP1 were resistant to EGFR and ALK TKIs, respectively, but were sensitive to dual inhibition of the primary driver and YES1. CONCLUSION: Our results demonstrate the therapeutic potential of SFK inhibition in primary tumorigenesis and AR driven by YES1/YAP1 signaling.

Molecular and clinicopathological analysis revealed an immuno-checkpoint inhibitor as a potential therapeutic target in a subset of high-grade myxofibrosarcoma.

This study aimed to identify differences in genetic alterations between low- and high-grade lesions in myxofibrosarcoma (MFS) and to examine the efficacy of immune checkpoint inhibitors in 45 patients with MFS. First, genetic differences between low- and high-grade components within the same tumor were analyzed in 11 cases using next-generation sequencing. Based on the obtained data, Sanger sequencing was performed for TP53 mutations in the remaining 34 patients. Loss of heterozygosity (LOH) analysis was performed at the TP53 and RB1 loci. Immunohistochemistry was performed for FGFR3, KIT, MET, programmed death receptor ligand 1 (PD-L1), CD8, FOXP3, and mismatch repair proteins. The microsatellite instability status was also evaluated in all cases. TP53 deleterious mutations and LOH at TP53 and RB1 loci were detected significantly more frequently in high-grade than in low-grade MFS (P = 0.0423, 0.0455, and 0.0455, respectively). LOH at the RB1 locus was significantly associated with shorter recurrence-free survival in both univariate and multivariate analyses. TP53 alterations, such as mutation and LOH, were more frequently observed in low-grade areas within high-grade MFS than in pure low-grade MFS. The positive PD-L1 expression rate was 35.6% (16/45), and all these 16 cases were high-grade. A high density of both CD8+ and FOXP3+ tumor-infiltrating lymphocytes was associated with PD-L1 positivity. LOH at the RB1 locus was identified an independent adverse prognostic factor for recurrence-free survival in patients with MFS. Immune checkpoint inhibitors may be a therapeutic option for a subset of high-grade MFS.

Immunological status of peripheral blood is associated with prognosis in patients with bone and soft-tissue sarcoma.

Immune-checkpoint inhibitors have shown promising antitumor effects against certain types of cancer. However, specific immune-checkpoint inhibitors for patients with sarcoma have yet to be identified, whereas the immunological status of peripheral blood in patients with bone sarcoma and soft-tissue sarcoma (STS) remains unknown. In addition, it is unclear whether the immunological status from the peripheral blood could be used as a prognostic indicator. Therefore, the present study aimed to clarify the immunological status of peripheral blood samples derived from patients with bone sarcoma and STS. Immune monitoring was performed using the peripheral blood samples of 61 patients with no metastasis of high-grade sarcoma. A total of 25 patients with metastatic sarcoma were used for comparison. A total of 41 immune cell subsets were analyzed using multicolor-flow cytometry. The patients that did not have metastasis demonstrated higher quantities of monocytic myeloid-derived suppressor cells (M-MDSCs) and T cell immunoglobulin and mucin domain-3 (Tim-3)+ CD8+ T cells, which were significantly associated with poor disease-free survival (DFS) time, while higher quantities of NKG2D+ CD8+ T cells were significantly associated with improved DFS time. Multivariate Cox regression analysis demonstrated that the number of Tim-3+ CD8+ T cells was associated with lower DFS time. A significant association was also found between the number of M-MDSCs and progression-free survival (PFS) time in patients with metastasis. The results suggested the occurrence of immune surveillance, which indicated that the host immune reaction against cancer existed in patients with bone sarcoma and STS. Notably, a high number of M-MDSCs was associated with both DFS and PFS time, suggesting a strong prognostic value. The data suggested that the immune status of peripheral blood was associated with the prognosis in patients with sarcoma, as previously reported in patients with other cancer types. In summary, the results may assist with the development of novel strategies for sarcoma treatment, based on the use of biomarkers or immunotherapy.

IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant bone tumor. However, the therapeutic results of the advanced cases at the first visit were still extremely poor. Therefore, more effective therapeutic options based on molecular profiling of OS are needed. In this study, we investigated the functions of endoplasmic reticulum (ER) stress activities in OS and elucidated whether ER stress inhibitors could exert antitumor effects. The expression of 84 key genes associated with unfolded protein response (UPR) was assessed in four OS cells (143B, MG63, U2OS and KHOS) by RT2 Profiler PCR Arrays. Based on results, we performed both siRNA and inhibitor assays focusing on IRE1α-XBP1 and PERK pathways. All OS cell lines showed resistance to PERK inhibitors. Furthermore, ATF4 and EIF2A inhibition by siRNA did not affect the survival of OS cell lines. On the other hand, IRE1α-XBP1 inhibition by toyocamycin suppressed OS cell growth (IC50: < 0.075 µM) and cell viability was suppressed in all OS cell lines by silencing XBP1 expression. The expression of XBP1s and XBP1u in OS cell lines and OS surgical samples were confirmed using qPCR. In MG63 and U2OS, toyocamycin decreased the expression level of XBP1s induced by tunicamycin. On the other hand, in 143B and KHOS, stimulation by toyocamycin did not clearly change the expression level of XBP1s induced by tunicamycin. However, morphological apoptotic changes and caspase activation were observed in these two cell lines. Inhibition of the IRE1α-XBP1s pathway is expected to be a promising new target for OS.

Allele-Specific Role of ERBB2 in the Oncogenic Function of EGFR L861Q in EGFR-Mutant Lung Cancers.

INTRODUCTION: Unlike common EGFR mutations, many less common EGFR mutations remain poorly characterized in terms of oncogenic function and drug sensitivity. Here, we characterize the subset of lung adenocarcinoma harboring EGFR L861Q through both preclinical and clinical investigations. METHODS: We reviewed clinical and genomic data from patients with EGFR-mutant lung cancer. We established cells expressing EGFR mutations and performed functional analysis of L861Q in comparison with common EGFR mutations. RESULTS: Among the patients with lung cancer, 3.4% (47 of 1367) possess an EGFR L861Q mutation. Of the patients with L861Q, 23.4% (11 of 47) had a concurrent exon 18 mutation (typically involving G719). In vitro studies revealed that the oncogenic activity of L861Q is dependent on asymmetric dimerization. Cells expressing L861Q were less sensitive to EGFR-specific inhibitors compared with cells expressing L858R but were similarly sensitive to pan-ERBB inhibitors. In cells expressing L861Q, ERBB2 phosphorylation was markedly higher compared with cells expressing L858R, and an enhanced interaction between EGFR and ERBB2 was observed in coimmunoprecipitation studies. In addition, treatment with osimertinib enhanced expression of the antiapoptotic protein MCL1, and knockdown of ERBB2 suppressed the expression of MCL1 in L861Q, raising the possibility of differential allele-specific cross-phosphorylation of ERBB2. Moreover, compared with EGFR-specific inhibitors, pan-ERBB inhibitors exerted superior growth inhibitory effects on cells expressing compound L861Q/G719X mutations. CONCLUSIONS: Our results suggest that ERBB2 plays a previously unrecognized role in EGFR L861Q-driven tumorigenesis, and pan-ERBB inhibitors are likely to be more effective than selective EGFR tyrosine kinase inhibitors in this setting.

Preoperative denosumab treatment with curettage may be a risk factor for recurrence of giant cell tumor of bone.

PURPOSE: Giant cell tumor of bone (GCTB) is a local aggressive bone tumor, histologically classified as intermediate malignancy. Recently, the RANKL inhibitor, denosumab, was developed as a novel and effective treatment option for GCTB. Since the risk of preoperative use of denosumab with curettage had been previously reported, this study aimed to investigate the relationship between recurrences and clinicopathological features associated with adjuvant denosumab treatment in GCTB. METHODS: A total of 87 GCTB cases were treated at our institution. We reviewed 66 patients with conventional-type GCTB occurring in the extremities and analyzed 78 surgical treatments, including curettages and resections, with clinicopathological features and denosumab treatment. RESULTS: GCTB lesions, including 66 primary and 12 recurring, underwent surgical treatment like curettage and resection. Recurrence-free survivals in 78 GCTB surgeries were 78.7% in 3 years and 71.9% in 5 years. In the resected cases of GCTBs, there was no recurrence either with or without denosumab. In curettage cases, 3-year recurrence-free survivals were 0.0% (n = 3) in preoperative treatment of denosumab, 66.7% (n = 6) in postoperative treatment, and 76.6% (n = 43) in no treatment. Interestingly, three preoperative treatment cases demonstrated low MIB-1 index despite 100% recurrence. The other clinicopathological factors did not contribute much to the risk of recurrence in curettage cases. CONCLUSION: Our findings revealed the use of denosumab in GCTB, prior to curettage, to possibly increase the risk of local recurrence. Together with previous reports, our finding might provide information for beneficial treatment of GCTB.

Pre-operative hemoglobin level and use of sedative-hypnotics are independent risk factors for post-operative delirium following total knee arthroplasty.

BACKGROUND: Delirium is a well-known complication following surgery, especially with the increasing age of patients undergoing surgery. The increasing demands resulting from a prolonged healthy life expectancy has resulted in more arthroplasties despite their age and existing comorbidities. The purpose of this study is to explore the various risk factors that may contribute to delirium in unilateral and bilateral total knee arthroplasties in the elderly population. METHODS: 170 patients who underwent unilateral or bilateral total knee arthroplasties were analyzed retrospectively for delirium. Age, sex, comorbidities, use of sedative-hypnotics, peri-operative blood loss, pre- and post-operative laboratory blood test results were investigated and analyzed. RESULTS: The incidence of post-operative delirium was 6.5% (11 out of 170 patients) with a mean age of 79.5 (± 6.9) years, compared to 73.0 (± 9.0) years in the non-delirium group. Higher age, use of sedative-hypnotics, low pre-operative Hb and Ht, low post-operative Hb, Ht and BUN were observed in the delirium group. Multivariate logistic regression analysis identified that the use of sedative-hypnotics and pre-operative Hb level were independent risk factors for post-operative delirium after TKA. The odds ratios for the use of sedative-hypnotics and pre-operative Hb level were 4.6 and 0.53, respectively. Receiver operating characteristic curve analysis showed that pre-operative Hb of less than 11.1 g/dL was a predictor for the development of delirium, with a sensitivity of 54.6% and a specificity of 91.6%. CONCLUSION: Patients with a pre-operative Hb level of < 11.1 g/dL or those using sedative-hypnotics are associated with post-operative delirium. Peri-operative management and preventative measures are therefore needed to reduce the risks of post-operative delirium in such patients.

MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by ROS1 Fusions.

PURPOSE: ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes. EXPERIMENTAL DESIGN: ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines. RESULTS: Eight of the 75 patients with a ROS1 fusion had a concurrent MAPK pathway alteration and this correlated with shorter overall survival. In addition, the induction of ROS1 fusions stimulated activation of MEK/ERK signaling with minimal effects on AKT signaling, suggesting the importance of the MAPK pathway in driving ROS1 fusion-positive cancers. Of 8 patients, 2 patients harbored novel in-frame deletions in MEK1 (MEK1delE41_L54) and MEKK1 (MEKK1delH907_C916) that were acquired after ROS1 TKIs, and 2 patients harbored NF1 loss-of-function mutations. Expression of MEK1del or MEKK1del, and knockdown of NF1 in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del. CONCLUSIONS: We demonstrate that downstream activation of the MAPK pathway can mediate of innate acquired resistance to ROS1 TKIs and that patients harboring ROS1 fusion and concurrent downstream MAPK pathway alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations.

Tumor Analyses Reveal Squamous Transformation and Off-Target Alterations As Early Resistance Mechanisms to First-line Osimertinib in EGFR-Mutant Lung Cancer.

PURPOSE: Patterns of resistance to first-line osimertinib are not well-established and have primarily been evaluated using plasma assays, which cannot detect histologic transformation and have differential sensitivity for copy number changes and chromosomal rearrangements. EXPERIMENTAL DESIGN: To characterize mechanisms of resistance to osimertinib, patients with metastatic EGFR-mutant lung cancers who received osimertinib at Memorial Sloan Kettering Cancer Center and had next-generation sequencing performed on tumor tissue before osimertinib initiation and after progression were identified. RESULTS: Among 62 patients who met eligibility criteria, histologic transformation, primarily squamous transformation, was identified in 15% of first-line osimertinib cases and 14% of later-line cases. Nineteen percent (5/27) of patients treated with first-line osimertinib had off-target genetic resistance (2 MET amplification, 1 KRAS mutation, 1 RET fusion, and 1 BRAF fusion) whereas 4% (1/27) had an acquired EGFR mutation (EGFR G724S). Patients with squamous transformation exhibited considerable genomic complexity; acquired PIK3CA mutation, chromosome 3q amplification, and FGF amplification were all seen. Patients with transformation had shorter time on osimertinib and shorter survival compared with patients with on-target resistance. Initial EGFR sensitizing mutation, time on osimertinib treatment, and line of therapy also influenced resistance mechanism that emerged. The compound mutation EGFR S768 + V769L and the mutation MET H1094Y were identified and validated as resistance mechanisms with potential treatment options. CONCLUSIONS: Histologic transformation and other off-target molecular alterations are frequent early emerging resistance mechanisms to osimertinib and are associated with poor clinical outcomes.See related commentary by Piotrowska and Hata, p. 2441.

Efficacy and safety of eradication therapy for elderly patients with helicobacter pylori infection.

Helicobacter pylori (H. pylori) is the most prevalent chronic bacterial infection and is associated with chronic gastritis, peptic ulcer disease, and gastric adenocarcinoma. Although eradication therapy is widely performed for H. pylori infection, adverse events (AEs) are of particular concern in the elderly. This study investigated the efficacy and safety of H. pylori eradication therapy for elderly patients.Retrospective investigation of 1271 cases (median age: 61 years, 730 male) of H. pylori infection was performed to compare clinical indications and outcomes among the younger group (<65 years old), elderly group (65-74 years old), and super-elderly group (>75 years old).Chronic gastritis (77.0%) and gastric and/or duodenal ulcer (16.4%) were the most frequent indications for eradication therapy in the cohort. The respective eradication and AE rates for the first and second treatment regimens were 92.1% (1044 of 1133 cases) and 9.1% (103 of 1133 cases) and 84.2% (123 of 146 cases) and 8.9% (13 of 146 cases). No significant differences were detected for eradication rate or AE frequency between the super-elderly group and the other groups. Prior to therapy, the super-elderly group had significantly less frequent chronic gastritis than the other groups but more frequent gastric or duodenal ulcer and post-gastric cancer treatment (all P < .001), indicating a reluctance for clinicians to treat very old patients, possibly due to unfounded concerns of complications.Triple therapy for H. pylori eradication is effective and safe, even for elderly patients.

Positioning the femoral bone socket and the tibial bone tunnel using a rectangular retro-dilator in anterior cruciate ligament reconstruction.

PURPOSE: The purpose of this study was to evaluate the positions of femoral bone sockets and tibial bone tunnels made with the rectangular retro-dilator (RRD), which we manufactured for anterior cruciate ligament reconstruction (ACLR) with a bone-patella tendon-bone (BPTB) graft which is fixed into the rectangular bone socket and tunnel made at anatomical ACL insertion sites. METHODS: 42 patients who had undergone ACLR with BPTB using the RRD were evaluated to assess bone socket and tunnel positions by the quadrant method and Magnussen classification using three-dimensional (3-D) CT. Intra-operative complications were also investigated in all patients. RESULTS: 3-D CT of the operated knee joints using the RRD showed that the bone socket and tunnel were placed in anatomical positions. In the quadrant method, the mean position of the femoral bone socket aperture was located at 22.0 ± 4.2% along the Blumensaat's line, and 37.4 ± 7.2% across the posterior condylar rim. The mean positions of the tibial bone tunnel aperture were 37.7 ± 5.2% and 46.1 ± 2.2% antero-posteriorly and medio-laterally, respectively. In addition, according to the Magnussen classification, 39 cases were evaluated as type 1, and almost all were located behind the lateral intercondylar ridge (also known as the resident's ridge). 3 cases were classified as type 2, which overlapped with the resident's ridge. A partial fracture of BPTB bone fragment was observed in 2 patients, but no serious complications including neurovascular injury were observed. CONCLUSION: The study indicates that the use of RRD achieves a safe anatomical reconstruction of the ACL.

Acquired BRAF Rearrangements Induce Secondary Resistance to EGFR therapy in EGFR-Mutated Lung Cancers.

INTRODUCTION: Multiple genetic mechanisms have been identified in EGFR-mutant lung cancers as mediators of acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs), but many cases still lack a known mechanism. METHODS: To identify novel mechanisms of AR, we performed targeted large panel sequencing of samples from 374 consecutive patients with metastatic EGFR-mutant lung cancer, including 174 post-TKI samples, of which 38 also had a matched pre-TKI sample. Alterations hypothesized to confer AR were introduced into drug-sensitive EGFR-mutant lung cancer cell lines (H1975, HCC827, and PC9) by using clustered regularly interspaced short palindromic repeats/Cas9 genome editing. MSK-LX138cl, a cell line with EGFR exon 19 deletion (ex19del) and praja ring finger ubiquitin ligase 2 gene (PJA2)/BRAF fusion, was generated from an EGFR TKI-resistant patient sample. RESULTS: We identified four patients (2.3%) with a BRAF fusion (three with acylglycerol kinase gene (AGK)/BRAF and one with PJA2/BRAF) in samples obtained at AR to EGFR TKI therapy (two posterlotinib samples and two posterlotinib and postosimertinib samples). Pre-TKI samples were available for two of four patients and both were negative for BRAF fusion. Induction of AGK/BRAF fusion in H1975 (L858R + T790M), PC9 (ex19del) and HCC827 (ex19del) cells increased phosphorylation of BRAF, MEK1/2, ERK1/2, and signal transducer and activator of transcription 3 and conferred resistance to growth inhibition by osimertinib. MEK inhibition with trametinib synergized with osimertinib to block growth. Alternately, a pan-RAF inhibitor as a single agent blocked growth of all cell lines with mutant EGFR and BRAF fusion. CONCLUSION: BRAF fusion is a mechanism of AR to EGFR TKI therapy in approximately 2% of patients. Combined inhibition of EGFR and MEK (with osimertinib and trametinib) or BRAF (with a pan-RAF inhibitor) are potential therapeutic strategies that should be explored.

Hepatic Angiosarcoma with Kasabach-Merritt Phenomenon: A Case Report and Review of the Literature.

A 76-year-old woman was referred to our hospital due to massive gingival bleeding following teeth extraction. Laboratory findings suggested disseminated intravascular coagulopathy (DIC). Enhanced computed tomography and magnetic resonance imaging disclosed multiple hypervascular liver masses of 2-6 cm in diameter, the largest of which displaying an irregular enhancement pattern. We considered that her DIC was caused by the multiple liver masses and commenced repeated erythrocyte/fresh frozen plasma infusión and gabexate mesilate administration. However, the DIC proved uncontrollable and trans-arterial embolization could not be attempted. The patient eventually died 4 months after admission due to spontaneous hepatic tumor rupture and hepatic failure. Post-mortem hepatic tumor biopsy led to a final diagnosis of hepatic angiosarcoma with Kasabach-Merritt phenomenon (KMP). Among the 7 cases of hepatic angiosarcoma representing KMP found in the literature, mortality occurred within 4 months of the appearance of bleeding tendency primarily due to abdominal bleeding and hepatic failure. The possibility of hepatic angiosarcoma should be considered in patients with DIC and hypervascular liver tumors. Since treatment is uncertain and prognosis is poor, novel diagnostic and therapeutic advances are needed for angiosarcoma.