[Minimally Invasive Aortic Valve Replacement for Aortic Valve Infective Endocarditis Complicated by Septic Arthritis of the Sternoclavicular Joint:Report of a Case].

A 54-year-old man with a history of atopic dermatitis was admitted to our hospital for persistent fever and multiple arthralgias unresponsive to antibiotics. On the second day of hospitalization, Staphylococcus aureus was detected in the blood culture, and debridement for presumed pyogenic arthritis was performed on the patient's bilateral wrists and right ankle joints. Echocardiography showed evidence of infective endocarditis of the aortic valve. The patient's fever persisted after drainage of multiple joint abscesses, and blood cultures remained positive. A right sternoclavicular joint abscess that had been noted on computed tomography (CT) at the time of admission had not decreased in size on repeat CT performed 10 days post-admission. After additional drainage of the sternoclavicular joint abscess on the 15th day, the patient's fever subsided, and blood culture was negative. On the 29th day, an aortic valve replacement was performed via a right anterior thoracotomy to prevent sternal osteomyelitis. The postoperative course was uneventful, and the patient was discharged on the 35th day after valve surgery. One year after the surgery, he continues to take antibiotics, and recurrence of infection has not been observed.

CEP-1347 Boosts Chk2-Mediated p53 Activation by Ionizing Radiation to Inhibit the Growth of Malignant Brain Tumor Cells.

Radiation therapy continues to be the cornerstone treatment for malignant brain tumors, the majority of which express wild-type p53. Therefore, the identification of drugs that promote the ionizing radiation (IR)-induced activation of p53 is expected to increase the efficacy of radiation therapy for these tumors. The growth inhibitory effects of CEP-1347, a known inhibitor of MDM4 expression, on malignant brain tumor cell lines expressing wild-type p53 were examined, alone or in combination with IR, by dye exclusion and/or colony formation assays. The effects of CEP-1347 on the p53 pathway, alone or in combination with IR, were examined by RT-PCR and Western blot analyses. The combination of CEP-1347 and IR activated p53 in malignant brain tumor cells and inhibited their growth more effectively than either alone. Mechanistically, CEP-1347 and IR each reduced MDM4 expression, while their combination did not result in further decreases. CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. The present results show, for the first time, that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR in addition to inhibiting the expression of MDM4 and, thus, CEP-1347 has potential as a radiosensitizer for malignant brain tumors expressing wild-type p53.

Maediastinal germ cell tumors: analysis using hospital-based cancer registry data in Japan.

OBJECTIVES: Mediastinal germ cell tumors are rare and few large-scale studies on mediastinal germ cell tumors are reported. We aimed to investigate the clinical characteristics and survival outcomes of patients with mediastinum germ cell tumors in Japan. METHODS: A hospital-based cancer registry data in Japan was used to identify and enroll patients diagnosed with mediastinal germ cell tumors in 2012-2013. The datasets were registered from 80 institutions. RESULTS: The selection criteria were met by 123 patients, the majority of whom were male. The median age at diagnosis was 39 years (range 25-89 years) and the most common age groups at diagnosis was 30-39 years, followed by 40-49 years and ≥ 50 years. The histology of non-seminoma (55.3%) was slightly more frequent than that of seminoma (44.7%). The most common histological subtype in non-seminoma was yolk sac tumor, followed by mixed germ cell tumor. The 5-year survival of seminoma and non-seminoma were 96.4% and 57.3%, respectively (p < 0.001). Non-seminomatous mediastinal germ cell tumors, malignant teratomas, mixed germ cell tumors, and yolk sac tumors had comparable survival rates, while those with choriocarcinoma showed the worst prognosis. CONCLUSIONS: This is the first report showing the clinical characteristics and survival outcomes of mediastinal germ cell tumors in Japan using a real-world large cohort database.

Melanocortin Receptor Agonist Bremelanotide Induces Cell Death and Growth Inhibition in Glioblastoma Cells via Suppression of Survivin Expression.

BACKGROUND/AIM: Glioblastoma is the most aggressive form of brain tumor and has a dismal prognosis; therefore, novel therapeutic approaches based on the mechanisms underlying its aggressive nature are urgently required. A growing body of evidence suggests that neurotransmitters play a key role in modulating the biology of glioblastoma; however, the role of melanocortins remains unclear. MATERIALS AND METHODS: The effects of bremelanotide, a melanocortin receptor agonist, alone or in combination with chemotherapeutic agents, on survivin expression and cell viability were investigated in human glioblastoma cell lines. RESULTS: Bremelanotide reduced survivin expression and induced cell death in glioblastoma cells at concentrations that were not toxic to normal human cells, and both of these effects were canceled in the presence of an antagonist of melanocortin receptors 3 and 4. Bremelanotide-induced cell death was prevented by the forced over-expression of survivin in glioblastoma cells, suggesting that bremelanotide induces glioblastoma cell death by inhibiting the expression of survivin. Bremelanotide also promoted cell death induced by chemotherapeutic agents, such as temozolomide and osimertinib. CONCLUSION: The present results identified melanocortin receptors 3 and 4 as novel and viable therapeutic targets for glioblastoma. Activation of these receptors by bremelanotide may inhibit the expression of survivin, thereby sensitizing glioblastoma cells to cell death.

The MDM2-p53 Axis Represents a Therapeutic Vulnerability Unique to Glioma Stem Cells.

The prevention of tumor recurrence by the successful targeting of glioma stem cells endowed with a tumor-initiating capacity is deemed the key to the long-term survival of glioblastoma patients. Glioma stem cells are characterized by their marked therapeutic resistance; however, recent evidence suggests that they have unique vulnerabilities that may be therapeutically targeted. We investigated MDM2 expression levels in glioma stem cells and their non-stem cell counterparts and the effects of the genetic and pharmacological inhibition of MDM2 on the viability of these cells as well as downstream molecular pathways. The results obtained showed that MDM2 expression was substantially higher in glioma stem cells than in their non-stem cell counterparts and also that the inhibition of MDM2, either genetically or pharmacologically, induced a more pronounced activation of the p53 pathway and apoptotic cell death in the former than in the latter. Specifically, the inhibition of MDM2 caused a p53-dependent increase in the expression of BAX and PUMA and a decrease in the expression of survivin, both of which significantly contributed to the apoptotic death of glioma stem cells. The present study identified the MDM2-p53 axis as a novel therapeutic vulnerability, or an Achilles' heel, which is unique to glioma stem cells. Our results, which suggest that non-stem, bulk tumor cells are less sensitive to MDM2 inhibitors, may help guide the selection of glioblastoma patients suitable for MDM2 inhibitor therapy.

Patient characteristics correlate with diagnostic performance of photodynamic diagnostic assisted transurethral resection of bladder tumors: A retrospective, single-center study.

BACKGROUND: Identification of patient subclasses that correlate with the diagnostic performance of photodynamic diagnostic (PDD)-assisted transurethral resection of bladder tumors (TURBT) may improve outcomes. METHODS: Data were extracted from patients that underwent PDD-assisted TURBT at the University of Tsukuba Hospital between 2018 and 2023. Sensitivity and specificity were evaluated based on PDD findings (excluding WL findings) and pathology results. Cluster analysis using uniform manifold approximation and projection and k-means methods was performed, focusing on patients with malignant lesions. RESULTS: A total of 267 patients and 2082 specimens were extracted. Sensitivity was lowest with regard to BCG treatment (53.7 %), followed by flat lesions (57.2 %), urine cytology class ≥ III (62.9 %), and recurrent tumors (64.5 %). In the cluster analysis of 231 patients with malignant lesions, two showed lower sensitivity: Cluster 3 (62.4 %), consisting of patients with recurrent tumors and post-BCG treatment, and Cluster 4 (55.7 %), consisting of patients with primary tumors and urine cytology class ≥ III. Clusters 1 and 2, consisting of patients without BCG treatment and patients with lower urine cytology classes, exhibited higher sensitivities (94.4 % and 87.7 %). Among all clusters, Cluster 4 had the highest proportion of specimens which were negative for both PDD and white light (WL) findings but actually had malignant lesions (20.8 %). CONCLUSIONS: PDD-assisted TURBT sensitivity was lower in subclasses after BCG treatment or with cytology class III or higher. Random biopsy for PDD/WL double-negative lesions may improve diagnostic accuracy in these subclasses.

Outcomes of thoracic endovascular aortic repair using fenestrated stent grafts in patients with thoracic aortic distal arch aneurysms.

OBJECTIVES: Thoracic endovascular aortic repair (TEVAR) for aortic arch aneurysms is challenging because of anatomical restrictions and the presence of cervical branches. Revascularization of the cervical branch is required when conventional commercial stent grafts are used. TEVAR using fenestrated stent grafts (FSG) often does not require additional procedures to revascularize cervical branches. This study aimed to evaluate the features and initial and midterm outcomes of TEVAR using fenestrated stent grafts. METHODS: From April 2007 to December 2016, 101 consecutive patients underwent TEVAR using fenestrated stent grafts for distal aortic arch aneurysms at a single centre. Technical success, complications, freedom from aneurysm-related death, secondary intervention and aneurysm progression were retrospectively investigated. RESULTS: All the patients underwent TEVAR using fenestrated stent grafts. The 30-day mortality rate was zero. Cerebral infarction, access route problems and spinal cord injury occurred in 4, 3 and 2 patients, respectively. Each type of endoleak was observed in 38 of the 101 patients during the course of the study; 20/38 patients had minor type 1 endoleaks at the time of discharge. The endoleak disappeared in 2 patients and showed no significant change in 8 patients; however, the aneurysm expanded over time in 10 patients. Additional treatment was performed in 8 of the 10 patients with type 1 endoleaks and dilatation of the aneurysm. The rate of freedom from aneurysm-related death during the observation period was 98%. CONCLUSIONS: TEVAR with FSG is a simple procedure, with few complications. Additional treatment has been observed to reduce aneurysm-related deaths, even in patients with endoleaks and enlarged aneurysms. Based on this study, the outcomes of endovascular repair of aortic arch aneurysms using a fenestrated stent graft seem acceptable.

Objective Evaluation of Gaze Location Patterns Using Eye Tracking During Cystoscopy and Artificial Intelligence-Assisted Lesion Detection.

Background: The diagnostic accuracy of cystoscopy varies according to the knowledge and experience of the performing physician. In this study, we evaluated the difference in cystoscopic gaze location patterns between medical students and urologists and assessed the differences in their eye movements when simultaneously observing conventional cystoscopic images and images with lesions detected by artificial intelligence (AI). Methodology: Eye-tracking measurements were performed, and observation patterns of participants (24 medical students and 10 urologists) viewing images from routine cystoscopic videos were analyzed. The cystoscopic video was captured preoperatively in a case of initial-onset noninvasive bladder cancer with three low-lying papillary tumors in the posterior, anterior, and neck areas (urothelial carcinoma, high grade, and pTa). The viewpoint coordinates and stop times during observation were obtained using a noncontact type of gaze tracking and gaze measurement system for screen-based gaze tracking. In addition, observation patterns of medical students and urologists during parallel observation of conventional cystoscopic videos and AI-assisted lesion detection videos were compared. Results: Compared with medical students, urologists exhibited a significantly higher degree of stationary gaze entropy when viewing cystoscopic images (p < 0.05), suggesting that urologists with expertise in identifying lesions efficiently observed a broader range of bladder mucosal surfaces on the screen, presumably with the conscious intent of identifying pathologic changes. When the participants observed conventional and AI-assisted lesion detection images side by side, contrary to urologists, medical students showed a higher proportion of attention directed toward AI-detected lesion images. Conclusion: Eye-tracking measurements during cystoscopic image assessment revealed that experienced specialists efficiently observed a wide range of video screens during cystoscopy. In addition, this study revealed how lesion images detected by AI are viewed. Observation patterns of observers' gaze may have implications for assessing and improving proficiency and serving educational purposes. To the best of our knowledge, this is the first study to utilize eye tracking in cystoscopy. University of Tsukuba Hospital, clinical research reference number R02-122.

Retroperitoneal sarcoma: a 10-year follow-up analysis using hospital-based cancer registry data in Japan.

OBJECTIVES: We sought clinical characteristics, survival outcomes, and prognostic factors for overall survival of retroperitoneal sarcoma in Japan. METHODS: A Japanese hospital-based cancer registry database with a pivotal 10-year follow-up was used to identify and enroll patients, registered from 106 institutions, diagnosed with retroperitoneal sarcoma in 2008-2009. Treating hospitals were divided by hospital care volume; high-volume hospitals and low-volume hospitals were defined as ≥ 4 and < 4 cases/year, respectively. RESULTS: A total of 91 men and 97 women were included, with a median age of 64 years. The most common histological type was liposarcoma in 101 patients, followed by leiomyosarcoma in 38 patients. The 5-year and 10-year overall survival rates were 44.1 and 28.3%. The majority of patients (n = 152, 80.9%) were treated at low-volume hospitals. High-volume hospital patients had higher 10-year overall survival rates than low-volume hospital patients (51.2% vs 23.2%, P = 0.026). Multivariate analysis revealed age over 60 years, treatment in low-volume hospitals and chemotherapy were independent predictors of unfavorable survival while treatment with surgery was an independent predictor of favorable survival. CONCLUSIONS: The possibility of surgical removal was suggested to be the most important prognostic factor for retroperitoneal sarcoma. Better survival was shown in patients treated at high-volume hospitals in our series.

Adult genitourinary sarcoma: analysis using hospital-based cancer registry data in Japan.

BACKGROUND: Genitourinary sarcomas are rare in adults and few large-scale studies on adult genitourinary sarcoma are reported. We aimed to elucidate the clinical characteristics, survival outcomes, and prognostic factors for overall survival of adult genitourinary sarcoma in Japan. METHODS: A hospital-based cancer registry data in Japan was used to identify and enroll patients diagnosed with genitourinary sarcoma in 2013. The datasets were registered from 121 institutions. RESULTS: A total of 116 men and 39 women were included, with a median age of 66 years. The most common primary site was the kidney in 47 patients, followed by the paratestis in 36 patients. The most common histological type was liposarcoma in 54 patients, followed by leiomyosarcoma in 25 patients. The 5-year overall survival rates were 57.6%. On univariate analysis, male gender, paratestis as primary organ, and histological subtype of liposarcoma were predictive of favorable survival while primary kidney, bladder, or prostate gland location were predictive of unfavorable survival. On multivariate analysis, primary paratestis was an independent predictor of favorable survival while primary kidney, bladder, or prostate gland were independent predictors of unfavorable survival. CONCLUSIONS: This is the first report showing the clinical characteristics and survival outcomes of adult genitourinary sarcoma in Japan using a real-world large cohort database.

The prognostic impact of treatment centralization in patients with testicular germ cell tumors: analysis of hospital-based cancer registry data in Japan.

BACKGROUND: To identify the prognostic impact of treatment centralization in patients with testicular germ cell tumors (TGCT). METHODS: We used a hospital-based cancer registry data in Japan to extract seminoma and non-seminoma cases that were diagnosed in 2013, histologically confirmed, and received the first course of treatment. To compare the 5-years overall survival (OS) rates of patients stratified by institutional care volume, we performed a Cox proportional hazards regression analysis using inverse probability of treatment weighting (IPTW) method to adjust patient backgrounds. RESULTS: A total of 1767 TGCT patients were identified. The 5-years OS rates for stage II and III TGCT patients treated at low-volume institutions (< 7 cases) were significantly worse than high-volume institutions (≥ 7 cases) (91.2% vs. 83.4%, p = 0.012). Histological stratification revealed that 5-year OS rates for stage II and III seminoma patients in the low-volume group were significantly worse than the high-volume group (93.5% vs. 84.5%, p = 0.041). Multivariate OS analysis using an IPTW-matched cohort showed that institutional care volume was an independent prognostic factor (hazard ratio 2.13 [95% confidence interval: 1.23-3.71], p = 0.0072). CONCLUSION: Our results indicate that stage II and III TGCT patients experience lower survival rates at low-volume institutions and would benefit from treatment centralization.

Athletic Fear Avoidance in Athletes Receiving Rehabilitation for Sport-Related Concussion: A Preliminary Study.

BACKGROUND: Fear avoidance after musculoskeletal injury is avoiding activity due to fear of pain and contributes to persistent symptoms, depression, and disability. Little is known about fear avoidance for sport (athletic fear avoidance) in athletes with sport-related concussion (SRC). HYPOTHESIS: Athletic fear avoidance after SRC would be elevated at the start of rehabilitation, improve over time, and be associated with postconcussion recovery outcomes. STUDY DESIGN: Observational study. LEVEL OF EVIDENCE: Level 4. METHODS: Athletes in rehabilitation after SRC participated. Testing at initial and discharge visits and 6-month follow-up included Athletic Fear Avoidance Questionnaire (AFAQ), Postconcussion Symptom Scale (PCSS), Profile of Mood States (POMS), and Dizziness Handicap Inventory (DHI). Differences were explored in AFAQ score at initial testing based on sex or age (<18 or ≥18 years). Change in questionnaire scores over time was examined. Association of AFAQ score with other questionnaire scores was determined at each timepoint. RESULTS: A total of 48 athletes participated: 28 completed initial testing only (INITIAL ONLY), and 20 completed all testing (LONGITUDINAL). Across cohorts, the mean (SD) AFAQ score at initial testing was 24.3 (7.6) points, with no significant difference by sex or age. AFAQ, PCSS, POMS, and DHI scores improved in LONGITUDINAL; the effect size was large from initial to discharge testing (1.0, 1.0, 1.0, and 1.2, respectively) and variable from discharge to follow-up testing (0.52, -0.34, -0.08, and 0.02, respectively). AFAQ scores increased from discharge to follow-up in 3 athletes and were consistently above the mean value in 2 athletes. AFAQ score was significantly correlated to the other questionnaire scores at each timepoint (range, r = 0.36-0.75). CONCLUSION: Athletic fear avoidance was elevated at the start of SRC rehabilitation, improved over time in most patients, and was associated with postconcussion symptoms, mood, and disability. CLINICAL RELEVANCE: Athletic fear avoidance may impact recovery after SRC.

Antagonizing MDM2 Overexpression Induced by MDM4 Inhibitor CEP-1347 Effectively Reactivates Wild-Type p53 in Malignant Brain Tumor Cells.

The development of MDM4 inhibitors as an approach to reactivating p53 in human cancer is attracting increasing attention; however, whether they affect the function of MDM2 and how they interact with MDM2 inhibitors remain unknown. We addressed this question in the present study using CEP-1347, an inhibitor of MDM4 protein expression. The effects of CEP-1347, the genetic and/or pharmacological inhibition of MDM2, and their combination on the p53 pathway in malignant brain tumor cell lines expressing wild-type p53 were investigated by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 alone or in combination with MDM2 on inhibition were examined by dye exclusion and/or colony formation assays. The treatment of malignant brain tumor cell lines with CEP-1347 markedly increased MDM2 protein expression, while blocking CEP-1347-induced MDM2 overexpression by genetic knockdown augmented the effects of CEP-1347 on the p53 pathway and cell growth. Blocking the MDM2-p53 interaction using the small molecule MDM2 inhibitor RG7112, but not MDM2 knockdown, reduced MDM4 expression. Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest the combination of CEP-1347-induced MDM2 overexpression with the selective inhibition of MDM2's interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells.

Domatinostat Targets the FOXM1-Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents.

The deregulation of the FOXM1 transcription factor is a key molecular alteration in ovarian cancer, contributing to the development and progression of ovarian cancer via activation of the target genes. As such, FOXM1 is a highly attractive therapeutic target in the treatment of ovarian cancer, but there has been no clinically tested FOXM1 inhibitor to date. We investigated in this study the effects of domatinostat, a class I-selective HDAC inhibitor currently in the clinical stage of development as a cancer therapeutic, on the expression of FOXM1 and viability of ovarian cancer cells. Cell viability, as well as protein and mRNA expression of FOXM1 and its transcriptional target survivin, was examined after domatinostat treatment of TOV21G and SKOV3 ovarian cancer cell lines in the absence or presence of cisplatin and paclitaxel. The effect of FOXM1 knockdown on survivin expression and those of genetic and pharmacological inhibition of survivin alone or in combination with the chemotherapeutic agents on cell viability were also examined. Domatinostat reduced the protein and mRNA expression of FOXM1 and survivin and also the viability of ovarian cancer cells alone and in combination with cisplatin or paclitaxel at clinically relevant concentrations. Knockdown experiments showed survivin expression was dependent on FOXM1 in ovarian cancer cells. Survivin inhibition was sufficient to reduce the viability of ovarian cancer cells alone and in combination with the chemotherapeutic agents. Our findings suggest that domatinostat, which effectively targets the FOXM1-survivin axis required for the viability of ovarian cancer cells, is a promising option for the treatment of ovarian cancer.

The Novel MDM4 Inhibitor CEP-1347 Activates the p53 Pathway and Blocks Malignant Meningioma Growth In Vitro and In Vivo.

A significant proportion of meningiomas are clinically aggressive, but there is currently no effective chemotherapy for meningiomas. An increasing number of studies have been conducted to develop targeted therapies, yet none have focused on the p53 pathway as a potential target. In this study, we aimed to determine the in vitro and in vivo effects of CEP-1347, a small-molecule inhibitor of MDM4 with known safety in humans. The effects of CEP-1347 and MDM4 knockdown on the p53 pathway in human meningioma cell lines with and without p53 mutation were examined by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 were examined in vitro and in a mouse xenograft model of meningioma. In vitro, CEP-1347 at clinically relevant concentrations inhibited MDM4 expression, activated the p53 pathway in malignant meningioma cells with wild-type p53, and exhibited preferential growth inhibitory effects on cells expressing wild-type p53, which was mostly mimicked by MDM4 knockdown. CEP-1347 effectively inhibited the growth of malignant meningioma xenografts at a dose that was far lower than the maximum dose that could be safely given to humans. Our findings suggest targeting the p53 pathway with CEP-1347 represents a novel and viable approach to treating aggressive meningiomas.

Givinostat Inhibition of Sp1-dependent MGMT Expression Sensitizes Glioma Stem Cells to Temozolomide.

BACKGROUND/AIM: Givinostat is a pan-histone deacetylase (HDAC) inhibitor that has demonstrated excellent tolerability as well as efficacy in patients with polycythemia vera. Accumulating in vitro and in vivo evidence suggests givinostat is also promising as a therapeutic agent targeting glioma stem cells (GSCs), the cancer stem cells of glioblastoma (GBM) considered responsible for its intractable nature. However, it remains to be shown how givinostat impacts the therapeutic effects of temozolomide, a DNA-alkylating agent and the key component of GBM treatment given not only during postoperative radiotherapy but also thereafter as maintenance chemotherapy. MATERIALS AND METHODS: The effects of givinostat and knockdown of O6-methylguanine-DNA methyltransferase (MGMT) or Sp1 on the mRNA and protein expression of relevant genes in human GSC lines were examined by RT-PCR and western blot analyses. The dye exclusion method was used to evaluate cell viability. RESULTS: Givinostat enhanced the cytotoxic activity of temozolomide in GSC lines expressing MGMT, in which the MGMT expression was shown to contribute to their temozolomide resistance. Givinostat inhibited MGMT expression in GSCs and, in parallel, the expression of Sp1, a transcription factor involved in the control of MGMT promoter activity. Knockdown experiments demonstrated Sp1 expression was indeed required for MGMT expression in GSCs. CONCLUSION: Givinostat, in addition to its own cytotoxic activity, sensitizes GSCs to temozolomide by inhibiting Sp1-dependent MGMT expression in GSCs. Combining givinostat with temozolomide could therefore be a rational therapeutic strategy to effectively eliminate GSCs and thus help overcome the therapy resistance of GBM.

Mild Quadriceps and Hamstring Strength Deficits Do Not Persist After Sport-Related Concussion.

BACKGROUND: Risk for lower extremity musculoskeletal injury increases after sport-related concussion (SRC) and may result from unresolved motor control deficits. Muscle weakness is a deficit that could contribute to musculoskeletal injury risk. HYPOTHESIS: Athletes with SRC will demonstrate quadriceps and hamstring muscle weakness at the time of return to sport and 30 days later compared with controls. STUDY DESIGN: Prospective matched cohort. LEVEL OF EVIDENCE: Level 3. METHODS: A total of 31 athletes with SRC (CONCUSSION) were matched by sex, age, and activity level to controls (CONTROL). Testing was conducted at initial assessment and 30 days later; initial assessment in CONCUSSION occurred when cleared for return to play. Isokinetic testing assessed quadriceps and hamstring strength of the dominant and nondominant legs at 60 and 180 deg/s. Peak torque values were normalized to body mass (N-m/kg). Data were analyzed with repeated measures general linear models (group × time), and effect sizes were calculated. RESULTS: Analysis at 60 deg/s included 26 matched pairs (15 male per group) and at 180 deg/s included 30 matched pairs (17 males per group). Time from concussion to initial assessment was 21.3 (7.8) mean (standard deviation) days. No significant interactions or main effects were detected (P > 0.05). Across muscle groups, legs, and testing speeds, effect sizes at initial assessment were small (d = 0.117 to 0.353), equating to a strength deficit in CONCUSSION of 0.04 to 0.18 N-m/kg, and effect sizes were further reduced at 30-day follow-up (d = -0.191 to 0.252). CONCLUSION: In athletes with SRC, quadriceps and hamstring strength were decreased only minimally at return to play compared with controls and the difference lessened over 30 days. CLINICAL RELEVANCE: Strength deficits may not be a major contributor to increased lower extremity musculoskeletal injury risk after SRC. Strength training could be implemented before return to play after SRC to mitigate any strength deficits.

Clinical decisions by the molecular tumor board on comprehensive genomic profiling tests in Japan: A retrospective observational study.

BACKGROUND: A paradigm shift has occurred in cancer chemotherapy from tumor-specific treatment with cytotoxic agents to personalized medicine with molecular-targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary-sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions. METHODS: This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations. RESULTS: The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden-high (TMB-H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non-small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%). CONCLUSION: The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine.

[Elderly Advanced Breast Cancer Effectively Treated with Locoregional Therapy-A Case Report].

We report a case of advanced breast cancer in an elderly patient effectively treated with locoregional therapy. The patient was an 81-year-old woman who presented with an increasing right breast lump. The tumor was 55 mm in diameter, accompanied by fixation to pectoral muscle. A core needle biopsy for right breast tumor led to a diagnosis of mucinous carcinoma, positive for estrogen receptor(ER)and progesterone receptor(PgR), negative for HER2/neu. The Ki-67 positive cell index was 10%. A bone scintigraphy revealed multiple bone metastases, so, we confirmed the diagnosis as T4cN2aM1, Stage Ⅳ. She initiated endocrine therapy by letrozole. By changing the endocrine therapy to toremifene followed by fulvestrant, the therapy achieved a partial response. However, the size of the primary tumor increased accompanied by bleeding, and surgical resection of the right breast was performed for local control. The locoregional surgery was effective, improving the patient's quality of life. She was administered lapatinib as anti-HER2 therapy in addition to the endocrine therapy. Two years and 6 months after surgery, there has been no worsening of bone metastasis or appearance of visceral metastasis.

[Recurrent Breast Cancer with Bone Metastasis Effectively Treated with Abemaciclib plus Endocrine Therapy-A Case Report].

We report a case of recurrent breast cancer with bone metastasis in a premenopausal woman. A 46-year-old woman underwent mastectomy for right breast cancer 6 years ago. Histopathological diagnosis was invasive ductal carcinoma, T2N3aM0, stage ⅢC. She received adjuvant chemotherapy and irradiation followed by tamoxifen. Four and a half years after surgery, serum tumor marker levels elevated, and bone metastasis in the sacral region was revealed by PET-CT scan. After suppressing ovarian function with LH-RH agonist, we switched the endocrine therapy from tamoxifen to letrozole with a CDK4/6 inhibitor. Five months after starting administration of abemaciclib, the bone metastasis disappeared on PET-CT. The elevated tumor markers normalized and have continued to decrease. Abemaciclib combined with endocrine therapy was significantly effective as first-line treatment for premenopausal women with metastatic breast cancer.