Citations

Significance Millions of people affected by epilepsy may undergo surgical resection of the epileptic tissues to stop seizures if such epileptic foci can be accurately delineated. High-frequency oscillations (HFOs), existing in electroencephalography, are highly correlated with epileptic brain, which is promising for guiding successful neurosurgery. However, it is unclear whether and how pathological HFOs can be differentiated to localize the epileptogenic tissues given the presence of various nonepileptic high-frequency activities. Here, we show morphological and source imaging evidence that pathological HFOs can be identified by the concurrence of epileptiform spikes. We describe a framework to delineate the underlying epileptogenicity using this biomarker. Our work may offer translational tools to improve treatments by noninvasively demarking pathological activities and hence epileptic foci.

Abstract Introduction:The huge workload on doctors especially residents, who are the main healthcare providers in public hospitals, in addition to the vanishing incomes and lack of personal safety during the decade-long Syrian crisis, led to further hurdles for the focus on research. Postgraduate students in the medical and paramedical fields must conduct original research projects as part of their graduation requirements. However, that does not reflect on the research publications coming from Syria.Methods:A nation-wide cross-sectional study targeting medical, dental, and pharmacy postgraduate students who are at the phase of planning for their required projects. The questionnaire aimed to capture their attitudes towards research, perceived barriers, and previous research experiences.Results:The sample consisted of 429 residents representing about 21.5% of the target population. Nearly all the participants had positive opinion towards the important role of medical research and the significance of their participation. Agreement was also clear regarding perceived barriers including the lack of adequate training, and research facility. Seventy-one percent of the participants were not involved in any research before the time of their master theses, less than 13% of them had submitted an article for publication, and less than 5% had submitted more than one paper. Poor internet connectivity and poor reading and writing English skills were decisive negative factors in previous research experiences. Active mentors’ support and self-paced education on research skills had a significant positive impact on students’ research contributions with odds ratios of 2.24 [1.34-3.74] (P=0.003) and 2.28 [1.47-3.52] (P<0.001) respectively.Conclusion:The attitudes of postgraduate students towards research were quite positive but hindered by several obstacles. Further integration of research practical training in the curriculums, allowing long-distance mentoring, enhancing collaboration between peers, as well as narrowing the distance between students and mentors may significantly boost research productivity in Syria despite the conflicts.

High-grade transformation (HGT) or dedifferentiation has been described in a variety of salivary gland carcinomas, including acinic cell carcinoma, secretory carcinoma, adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, polymorphous adenocarcinoma, low-grade mucoepidermoid carcinoma, and hyalinizing clear cell carcinoma. High-grade (HG) transformed tumors are composed of a conventional low-grade component characterized by specific microscopic and immunohistochemical features for the given entity, intermingled with or juxtaposed to areas of HG morphology. This is usually either poorly differentiated adenocarcinoma, carcinoma not otherwise specified, or undifferentiated carcinoma, in which the original line of differentiation is lost. The HG component is composed of solid nests of anaplastic cells with large vesicular pleomorphic nuclei, prominent nucleoli, and abundant cytoplasm. Frequent mitoses and extensive necrosis may be present. The Ki-67 labeling index is consistently higher in the HG component. The molecular genetic mechanisms responsible for HGT of salivary gland carcinomas are largely unknown, though p53 inactivation and human epidermal growth factor receptor 2 overexpression and/or gene amplification have been demonstrated in the HG component in a few examples, the frequency varies for each histologic type. Salivary gland carcinomas with HGT are more aggressive than conventional carcinomas, with a higher local recurrence rate and a poorer prognosis. They have a high propensity for cervical lymph node metastasis suggesting a need for a wider resection and neck dissection. HGT of salivary gland carcinoma can occur either at initial presentation or less commonly at the time of recurrence, sometimes following postoperative radiotherapy. The potential for HGT in almost any type of salivary gland carcinoma warrants a thorough sampling of all salivary gland malignancies to prevent oversight of a HG component.

Purpose To assess the effectiveness of a nonopioid pain regimen in controlling postoperative pain as compared with a traditional opioid pain control following primary meniscectomy or meniscal repair. Methods Ninety‐nine patients undergoing primary meniscectomy or meniscal repair were assessed for participation. A prospective randomized control trial was performed in accordance with the Consolidated Standards of Reporting Trials 2010 statement. The 2 arms of the study included a multimodal nonopioid analgesic protocol and a standard opioid regimen with a primary outcome of postoperative pain level (visual analog scale) for the first 10 days postoperatively. Secondary outcomes included patient‐reported outcomes, complications, and patient satisfaction. Randomization was achieved using a random‐number generator. Patients were not blinded. Data collection was done by a blinded observer. Results Eleven patients did not meet the inclusion criteria, and 27 declined participation. A total of 61 patients were analyzed with 30 randomized to the opioid regimen and 31 randomized to the nonopioid regimen. Patients receiving the nonopioid regimen demonstrated noninferior visual analog scale scores compared with patients who received opioid pain medication ( P > .05). No significant differences were found in preoperative (opioid: 58.9 ± 7.0; nonopioid: 58.2 ± 5.5, P = .724) or postoperative (opioid: 59.8 ± 6.5; nonopioid: 54.9 ± 7.1, P = .064) Patient‐Reported Outcomes Measurement and Information System Pain Interference Short Form scores. No difference was found in recorded side effects between both groups at any given time point: constipation, nausea, diarrhea, upset stomach, and drowsiness ( P > .05). Conclusions This study found that a multimodal nonopioid pain protocol provided equivalent pain control and patient outcomes following primary meniscus surgery while having an equivalent side effect profile. All patients reported satisfaction with their pain management without requiring emergency opioid analgesia. Level of Evidence Level I, prospective randomized controlled trial.

Purpose To investigate the career longevity, game utilization, and performance of National Football League (NFL) athletes after glenohumeral instability events treated operatively versus nonoperatively. Methods Using public resources, we identified NFL players who sustained a shoulder instability event from September 2000 to February 2019. Players with prior shoulder instability, without NFL experience before injury, or who did not return to play (RTP) after injury were excluded. Demographic information, utilization (games and seasons), and season approximate value (SAV) statistics were recorded 1 year prior to injury and 3 years after RTP. Statistical analysis compared utilization and the SAV after RTP for athletes managed operatively versus nonoperatively. Results We identified 97 NFL players who sustained their first instability event while playing in the NFL, 91 of whom returned to play (93.8%). Quarterbacks were significantly more likely to undergo immediate surgical management compared with players in other positions ( P = .023). The final analysis included 58 players managed operatively and 33 managed nonoperatively by the end of the index season. Players treated operatively played in significantly more seasons after RTP during their remaining careers (4.1 ± 2.7 seasons vs 2.8 ± 2.5 seasons, P = .015). There were no differences in games played or started, offensive or defensive snap count percentage, or performance (SAV) before and after injury when compared between cohorts ( P > .05). After surgical stabilization, time to RTP (36.62 ± 10.32 weeks vs 5.43 ± 12.33 weeks, P < .05) and time interval before recurrent instability (105.7 ± 100.1 weeks vs 24.7 ± 40.6 weeks, P < .001) were significantly longer than with nonoperative treatment. Additionally, the operative cohort experienced less recurrent instability (27% vs 50%, P = .035). Conclusions Athletes who RTP in the NFL after a shoulder instability injury do so with a similar workload and performance irrespective of surgical or nonsurgical management. Whereas nonoperative treatment is associated with faster RTP, operative management is associated with fewer recurrent instability events, greater time between recurrent instability events, and greater career longevity. Level of Evidence Level III, retrospective case‐control study.

The incidence of hepatocellular carcinoma (HCC) is growing in the United States, especially among the elderly. Older patients are increasingly receiving transplants as a result of HCC, but the impact of advancing age on long‐term posttransplant outcomes is not clear. To study this, we used data from the US Multicenter HCC Transplant Consortium of 4980 patients. We divided the patients into 4 groups by age at transplantation: 18 to 64 years (n = 4001), 65 to 69 years (n = 683), 70 to 74 years (n = 252), and ≥75 years (n = 44). There were no differences in HCC tumor stage, type of bridging locoregional therapy, or explant residual tumor between the groups. Older age was confirmed to be an independent and significant predictor of overall survival even after adjusting for demographic, etiologic, and cancer‐related factors on multivariable analysis. A dose‐response effect of age on survival was observed, with every 5‐year increase in age older than 50 years resulting in an absolute increase of 8.3% in the mortality rate. Competing risk analysis revealed that older patients experienced higher rates of non–HCC‐related mortality (P = 0.004), and not HCC‐related death (P = 0.24). To delineate the precise cause of death, we further analyzed a single‐center cohort of patients who received a transplant as a result of HCC (n = 302). Patients older than 65 years had a higher incidence of de novo cancer (18.1% versus 7.6%; P = 0.006) after transplantation and higher overall cancer‐related mortality (14.3% versus 6.6%; P = 0.03). Even carefully selected elderly patients with HCC have significantly worse posttransplant survival rates, which are mostly driven by non–HCC‐related causes. Minimizing immunosuppression and closer surveillance for de novo cancers can potentially improve the outcomes in elderly patients who received a transplant as a result of HCC.

On March 11, 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic, and the reality of the situation has finally caught up to the widespread reach of the disease. The presentation of the disease is highly variable, ranging from asymptomatic carriers to critical COVID-19. The availability of angiotensin-converting enzyme 2 (ACE2) receptors may reportedly increase the susceptibility and/or disease progression of COVID-19. Comorbidities and risk factors have also been noted to increase COVID-19 susceptibility. In this paper, we hereby review the evidence pertaining to ACE2’s relationship to common comorbidities, risk factors, and therapies associated with the susceptibility and severity of COVID-19. We also highlight gaps of knowledge that require further investigation. The primary comorbidities of respiratory disease, cardiovascular disease, renal disease, diabetes, obesity, and hypertension had strong evidence. The secondary risk factors of age, sex, and race/genetics had limited-to-moderate evidence. The tertiary factors of ACE inhibitors and angiotensin II receptor blockers had limited-to-moderate evidence. Ibuprofen and thiazolidinediones had limited evidence.

Abstract Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers, such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity, two key risk factors in multiple myeloma disease prevalence, suggesting that BMAds may influence and be influenced by myeloma cells in the marrow. Here, we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAds play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from patients with multiple myeloma revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different preclinical murine models of multiple myeloma and in vitro using myeloma cell-adipocyte cocultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. In vivo, senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAds, in turn, provided resistance to dexamethasone-induced cell-cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug-resistant clone. Our findings reveal that bidirectional interactions between BMAds and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the BMAd or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma. Significance: This study changes the foundational understanding of how cancer cells hijack the bone marrow microenvironment and demonstrates that tumor cells induce senescence and metabolic changes in adipocytes, potentially driving new therapeutic directions.

Abstract Background: Atezolizumab (atezo) and bevacizumab (bev) combination therapy has demonstrated robust clinical activity in patients with unresectable HCC who have not received prior systemic therapy (Lee et al., APPLE 2019; Cheng et al., ESMO Asia 2019). In this exploratory analysis, we aimed to identify tumor-based molecular biomarkers that may be associated with clinical response or resistance to atezo + bev. We also investigated how VEGF blockade with bev could potentiate PD-L1 checkpoint inhibition with atezo in pts with advanced HCC. Methods: Archival tumor tissues or fresh biopsies taken prior to treatment were collected from HCC pts enrolled in the Phase 1b trial GO30140 (NCT02715531). Arm A (n = 104) was a single-arm evaluation of atezo + bev; Arm F (n = 119) was a randomized arm comparing atezo + bev with atezo. Whole-exome sequencing was carried out on these tumor tissues to determine tumor mutation burden (TMB). Gene expression in tumors was profiled by RNAseq analysis. The association between biomarker expression and clinical response (responders [R] vs. non-responders [NR]) or PFS was assessed by t-tests or Cox regression models, respectively. All p-values are descriptive. Results: In Arm A, 90/104 pts were biomarker evaluable. TMB was not associated with response to atezo + bev or PFS. In contrast, analysis of baseline tumor gene expression showed that pre-existing immunity appeared to be associated with clinical response and longer PFS, which included high expression of CD274 (PD-L1) (R vs. NR, p &lt; 2.1 × 10−5; PFS: HR = 0.42 [0.25-0.72]), and T effector signature (GZMB, PRF1, CXCL9) (R vs. NR, p &lt; 0.0004; PFS: HR = 0.46 [0.27-0.78]). Gene expression related to Notch pathway activation (i.e. high expression of HES1) appeared to be associated with lack of response to atezo + bev (p &lt; 0.039) and shorter PFS (HR = 2.1 [1.3-3.6]). In Arm F, 91/119 pts were biomarker evaluable. High expression of VEGF receptor 2 (VEGFR2; HR = 0.36 [0.16-0.81]), Treg (HR = 0.35 [0.15-0.82]), myeloid inflammation (HR = 0.43 [0.19-0.95]), and TREM1/MDSC signatures (HR = 0.43 [0.19-0.94]) was associated with longer PFS in patients treated with atezo + bev than in those treated with atezo alone. Analysis of 12 serial biopsy pairs confirmed reduced levels of VEGFR2 and Treg signatures after atezo + bev treatment. Conclusion: We identified candidate biomarkers for predicting response to atezo + bev in HCC. Furthermore, the findings in Arm F are consistent with previous preclinical studies supporting a multi-faceted role of VEGF/VEGFR signaling in promoting immune suppression in addition to angiogenesis. Overall, the data presented here further support the mechanistic hypotheses on how anti-VEGF may combine with immune checkpoint blockade to increase its clinical benefit. As these results are exploratory, future study is needed to confirm these findings in a larger population. Citation Format: Andrew X. Zhu, Yinghui Guan, Alexander R. Abbas, Hartmut Koeppen, Shan Lu, Chih-Hung Hsu, Kyung-Hun Lee, Michael S. Lee, Aiwu Ruth He, Amit Mahipal, Beiying Ding, Jessica Spahn, Wendy Verret, Baek-Yeol Ryoo, Yulei Wang. Genomic correlates of clinical benefits from atezolizumab combined with bevacizumab vs. atezolizumab alone in patients with advanced hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT044.