Performance of a multigene genomic classifier and clinical parameters in predicting malignancy in a Southeast Asian cohort of patients with cytologically indeterminate thyroid nodules.

BACKGROUND: Most thyroid nodules are benign. It is important to determine the likelihood of malignancy in such nodules to avoid unnecessary surgery. The primary objective of this study was to characterize the genetic landscape and the performance of a multigene genomic classifier in fine-needle aspiration (FNA) biopsies of cytologically indeterminate thyroid nodules in a Southeast Asian cohort. The secondary objective was to assess the predictive contribution of clinical characteristics to thyroid malignancy. METHODS: This prospective, multicenter, blinded study included 132 patients with 134 nodules. Molecular testing (MT) with ThyroSeq v3 was performed on clinical or ex-vivo FNA samples. Centralized pathology review also was performed. RESULTS: Of 134 nodules, consisting of 61% Bethesda category III, 20% category IV, and 19% category V cytology, and 56% were histologically malignant. ThyroSeq yielded negative results in 37.3% of all FNA samples and in 42% of Bethesda category III-IV cytology nodules. Most positive samples had RAS-like (41.7%), followed by BRAF-like (22.6%), and high-risk (17.9%) alterations. Compared with North American patients, the authors observed a higher proportion of RAS-like mutations, specifically NRAS, in Bethesda categories III and IV and more BRAF-like mutations in Bethesda category III. The test had sensitivity, specificity, negative predictive value, and positive predictive value of 89.6%, 73.7%, 84.0%, and 82.1%, respectively. The risk of malignancy was predicted by positive MT and high-suspicion ultrasound characteristics according to American Thyroid Association criteria. CONCLUSIONS: Even in the current Southeast Asian cohort with nodules that had a high pretest cancer probability, MT could lead to potential avoidance of diagnostic surgery in 42% of patients with Bethesda category III-IV nodules. MT positivity was a stronger predictor of malignancy than clinical parameters.

Assessor- and participant-blinded, randomized controlled trial of dense cranial electroacupuncture stimulation plus body acupuncture for neuropsychiatric sequelae of stroke.

AIM: Acupuncture has benefits in the rehabilitation of neuropsychiatric sequelae of stroke. This study was aimed to evaluate the effectiveness of dense cranial electroacupuncture stimulation plus body acupuncture (DCEAS+BA) in treating poststroke depression (PSD), functional disability, and cognitive deterioration. METHODS: In this assessor- and participant-blinded, randomized controlled trial, 91 stroke patients who initially had PSD were randomly assigned to either DCEAS+BA (n = 45) or minimum acupuncture stimulation as controls (n = 46) for three sessions per week over 8 consecutive weeks. The primary outcome was baseline-to-end-point change in score of the 17-item Hamilton Depression Rating Scale. Secondary outcomes included the Montgomery-Åsberg Depression Rating Scale for depressive symptoms, the Barthel Index for functional disability, and the Montreal Cognitive Assessment for cognitive function. RESULTS: DCEAS+BA-treated patients showed strikingly greater end-point reduction than MAS-treated patients in scores of the three symptom domains. The clinical response rate, defined as an at least 50% baseline-to-end-point reduction in 17-item Hamilton Depression Rating Scale score, was markedly higher in the DCEAS+BA-treated group than that of controls (40.0% vs 17.4%, P = 0.031). Incidence of adverse events was not different in the two groups. Subgroup analysis revealed that DCEAS+BA with electrical stimulation on forehead acupoints was more apparent in reducing Barthel-Index-measured disability than that without electrical stimulation. CONCLUSION: DCEAS+BA, particularly with electrical stimulation on forehead acupoints, reduces PSD, functional disability, and cognitive deterioration of stroke patients. It can serve as an effective rehabilitation therapy for neuropsychiatric sequelae of stroke.

Characterization of infections and hypogammaglobulinemia treated with the combination of pertuzumab and trastuzumab.

PURPOSE: We update a patient series that reported a high incidence of infection with Gram-positive cocci in women treated with the combination of pertuzumab and trastuzumab and further characterize this clinical problem. PATIENTS: Treating physicians and advanced practice partners identified women who developed infections while on treatment with pertuzumab and trastuzumab alone or in combination with chemotherapy and enrolled them onto this registry trial. RESULTS: Between March, 2014 and May, 2017, 48 patients with HER2-positive breast cancers were reported to have 59 individual infections. The median age was 48 years. Twenty-four patients received neoadjuvant therapy, 17 were treated for metastatic disease, and 7 were treated in the adjuvant setting. Pertuzumab and trastuzumab were combined with carboplatin and docetaxel in 24 (49%) patients, docetaxel in 10 (21%), nab-paclitaxel in 12 (24%), and without other agents in 2 (4%). Granulocyte growth factors were administered in 24 (49%) patients and no patients were documented to be neutropenic. Folliculitis developed in 25 (52%) patients and was counted as a single infection. Abscesses developed at a number of sites in 24 (49%) patients, including a septic knee requiring total knee replacement. Paronychia occurred in 7 (15%) patients, and 5 (10%) developed cellulitis. When cultures were obtained, Gram-positive cocci were consistently identified. Hypogammaglobulinemia was documented in 14 (36%) of the 33 patients tested. CONCLUSIONS: Our data continue to support an increased risk of infections with Gram-positive cocci as a potentially serious adverse event in women treated with pertuzumab and trastuzumab.

The Effect of Epidermal Growth Factor Receptor Mutation on Intracranial Progression-Free Survival of Non-Small Cell Lung Cancer Patients with Brain Metastasis Underwent Gamma Knife Radiosurgery

Background@#The aim of this study was to survey prognostic factors, particularly those focusing on epidermal growth factor receptor (EGFR) mutations, of patients with non-small cell lung cancer (NSCLC) after Gamma Knife Radiosurgery (GKRS) for metastatic brain tumors. @*Methods@#We retrospectively reviewed the medical records of 98 patients with NSCLC who underwent GKRS for brain metastases from August 2010 to July 2017. The primary endpoint was progression-free survival (PFS) of the intracranial disease. We analyzed variables such as age, sex, Karnofsky Performance Status, recursive partitioning analysis (RPA) class, smoking status, primary cancer pathology, EGFR mutations, and time to brain metastases as prognostic factors. @*Results@#The median overall survival (OS) of the patients was 16 months [95% confidence interval (CI), 13-21 months]. Median systemic PFS and intracranial PFS were 9 months (95% CI, 8-11 months) and 11 months (95% CI, 7-14 months), respectively. Kaplan-Meier survival analysis revealed that the patients with EGFR mutations had longer intracranial PFS than those without EGFR mutation (median intracranial PFS: 19 vs. 10 months with p=0.01) while they had no benefits in OS and systemic PFS. Furthermore, the patients harboring adenocarcinoma had longer OS ( p<0.01) and intracranial PFS ( p<0.01) and the patients with lower RPA class had longer OS ( p=0.02) and intracranial PFS ( p=0.03). @*Conclusion@#EGFR mutations, primary cancer pathology, and RPA class may be proposed as prognostic factors for intracranial PFS in NSCLC patients after GKRS for brain metastasis in this study.

Analysis of PAX8 immunohistochemistry in lung cancers: a meta-analysis

Background@#In this meta-analysis, we aimed to evaluate the PAX8 immunohistochemical expressions in primary lung cancers and metastatic cancers to the lung. @*Methods@#We identified and reviewed relevant articles from the PubMed databases. Ultimately, 18 articles were included in this meta-analysis. PAX8 expression rates were analyzed and compared between primary and metastatic lung cancers. @*Results@#The PAX8 expression rate in primary lung cancers was 0.042 (95% confidence interval [CI], 0.025 to 0.071). PAX8 expression rates of small cell (0.129; 95% CI, 0.022 to 0.496) and non-small cell carcinomas of the lung (0.037; 95% CI, 0.022 to 0.061) were significantly different (p=.049 in a meta-regression test). However, the PAX8 expression rates of adenocarcinoma (0.013; 95% CI, 0.006 to 0.031) and squamous cell carcinoma (0.040; 95% CI, 0.016 to 0.097) were not significantly different. PAX8 expression rates of metastatic carcinomas to the lung varied, ranging from 1.8% to 94.9%. Metastatic carcinomas from the lung to other organs had a PAX8 expression rate of 6.3%. The PAX8 expression rates of metastatic carcinomas from the female genital organs, kidneys, and thyroid gland to the lung were higher than those of other metastatic carcinomas. @*Conclusions@#Primary lung cancers had a low PAX8 expression rate regardless of tumor subtype. However, the PAX8 expression rates of metastatic carcinomas from the female genital organs, kidneys, and thyroid were significantly higher than those of primary lung cancers.

Disappearance of a Distal Shunt Catheter: A Case Report of an Unusual Cause of Shunt Malfunction / 대한신경손상학회지

Shunt malfunction is a common complication in patients who undergo ventriculoperitoneal shunt (VPS) placement for the treatment of hydrocephalus. A plethora of reports regarding shunt malfunctions due to distal catheter migration have been demonstrated in the literature. However, to our knowledge, there have been no reports thus far of shunt malfunctions caused by the complete disappearance of a distal catheter. A 70-year-old man was admitted to our hospital for progressive gait disturbance beginning approximately 5 months ago. He received a VPS for posthemorrhagic hydrocephalus and was doing well over the course of 18 months of follow-up. Since no increase in the size of the ventricle was observed on brain computed tomography taken at the outpatient clinic, we tried to readjust the pressure setting of his programmable shunt valve to relieve his symptoms. Without any progression, we discovered later by chance that the distal shunt catheter was missing. Shunt revision surgery was performed. At the 2-year follow-up, a slight improvement in gait was observed. Although it is very rare, the distal catheter can disappear without any noticeable symptoms. If shunt malfunction is suspected, it is important to check whether the entire shunt system is structurally intact.

Anterior Spinal Artery Syndrome Occurring after One Level Segmental Artery Ligation during Spinal Surgery / 대한신경손상학회지

In treating the ventral pathology of spine, ligating the segmental vessels is sometimes necessary. This may cause spinal cord ischemia, and concerns of neurologic injury have been presented. However, spinal cord ischemic injury after sacrificing segmental vessels during spine surgery is very rare. Reports of this have been scarce in the literature and most of these complications occur after multi-level segmental vessel ligation. Here we report a case of a patient with postoperative anterior spinal artery syndrome, which occurred after ligating one level segmental vessels during spinal surgery for a T8 vertebral pathologic fracture. Despite its rarity, the risk of spinal cord ischemic injury after segmental vessel ligation is certainly present. Surgeons must keep in mind such risk, and surgery should be planned under a careful risk-benefit consideration.

Factors predicting clinically significant functional gain and discharge to home in stroke in-patients after rehabilitation - A retrospective cohort study.

OBJECTIVE: This study explored factors which predict stroke survivors who could achieve "clinically significant functional gain" and return home when being discharged from a local hospital after in-patient stroke rehabilitation programme. METHODS: This study included 562 inpatients with stroke who were residing at community dwellings before onset of stroke, and transferred to a convalescent hospital for rehabilitation from four acute hospitals over one year. The main outcome variables of prediction were (a) achieving "clinically significant functional gain" as measured by (a1) achievement of "minimal clinically important difference" (MCID) of improvement in Functional Independence Measure Motor Measure (FIM-MM)", (a2) one or more level(s) of improvement in function group according to the patients' FIM-MM, and (b) discharge to home. Sixteen predictor variables were identified and studied firstly with univariate binary logistic regression and those significant variables were then put into multivariate binary logistic regression. RESULTS: Based on multivariate regression, the significant predictors for "clinically significant functional gain" were: younger age <75 years old, higher Glasgow Coma Scale score at admission, with haemorrhagic stroke, intermediate FIM-MM function group. Those significant predictors for "discharge to home" were: living with family/caregivers before stroke, higher FIM score at admission, and one or more level(s) of improvement in FIM-MM function group. CONCLUSIONS: This study identified findings consistent with overseas studies in additional to some new interesting findings. Early prediction of stroke discharge outcomes helps rehabilitation professionals and occupational therapists to focus on the use of appropriate intervention strategies and pre-discharge preparation.

Mutation and immune profiling of metaplastic breast cancer: Correlation with survival.

The goal of this study is to characterize the genomic and immune profiles of metaplastic breast cancer (MpBC) and identify the association with survival through an analysis of archived tumor tissue. A next-generation sequencing-based mutational assay (Onco-48) was performed for 21 MpBC patients. Clinicopathologic characteristics were captured, including relapse free survival (RFS) and overall survival (OS). Immunohistochemistry (IHC) for CD3, CD4, CD8, and programmed death-ligand 1 (PD-L1) was also performed. Recurrence free survival (RFS) at 5 years was 57% (95% CI 0.34-0.75) and overall survival (OS) at 5 years was 66% (95% CI 0.41-0.82). The most commonly altered genes were TP53 (68.4%, 13/19), PIK3CA (42.1%, 8/19), and PTEN (15.8%, 3/19. For patients with PIK3CA mutations, RFS and OS were significantly worse than for those without (HR 5.6, 95% CI 1.33-23.1 and HR 8.0, 95% CI 1.53-41.7, respectively). Cox regression estimated that PD-L1 expression was associated with worse RFS and OS (HR 1.08, 95% CI 1.01-1.16 and HR 1.05, 95% CI 1.00-1.11, respectively, for an absolute increase in PD-L1 expression of 1%). In conclusion, PIK3CA mutation and PD-L1 expression confer poor prognosis in this cohort of patients with MpBC.

Collaborating to Achieve the Optimal Family Medicine Workforce.

When the Family Medicine for America's Health (FMAHealth) Workforce Education and Development Tactic Team (WEDTT) began its work in December 2014, one of its charges from the FMAHealth Board was to increase family physician production to achieve the diverse primary care workforce the United States needs. The WEDTT created a multilevel interfunctional team to work on this priority initiative that included a focus on student, resident, and early-career physician involvement and leadership development. One major outcome was the adoption of a shared aim, known as 25 x 2030. Through a collaboration of the WEDTT and the eight leading family medicine sponsoring organizations, the 25 x 2030 aim is to increase the percentage of US allopathic and osteopathic medical students choosing family medicine from 12% to 25% by the year 2030. The WEDTT developed a package of change ideas based on its theory of what will drive the achievement of 25 x 2030, which led to specific projects completed by the WEDTT and key collaborators. The WEDTT offered recommendations for the future based on its 3-year effort, including policy efforts to improve the social accountability of US medical schools, strategy centered around younger generations' desires rather than past experiences, active involvement by students and residents, engagement of early-career physicians as role models, focus on simultaneously building and diversifying the family medicine workforce, and security of the scope future family physicians want to practice. The 25 x 2030 initiative, carried forward by the family medicine organizations, will use collective impact to adopt a truly collaborative approach toward achieving this much needed goal for family medicine.

Addressing Family Medicine's Capacity to Improve Health Equity Through Collaboration, Accountability and Coalition-Building.

Achieving health equity requires an evaluation of social, economic, environmental, and other factors that impede optimal health for all. Family medicine has long valued an ecological perspective of health, partnering with families and communities. However, both the quantity and degree of continued health disparities requires that family medicine intentionally work toward improvement in health equity. In recognition of this, Family Medicine for America's Health (FMAHealth) formed a Health Equity Tactic Team (HETT). The team's charge was to address primary care's capacity to improve health equity by developing action-oriented approaches accessible to all family physicians. The HETT has produced a number of projects. These include the Starfield II Summit, the focus of which was "Primary Care's Role in Achieving Health Equity." Multidisciplinary thought leaders shared their work around health equity, and actionable interventions were developed. These formed the basis of subsequent work by the HETT. This includes the Health Equity Toolkit, designed for a broad interdisciplinary audience of learners to learn to improve care systems, reduce disparities, and improve patient outcomes. The HETT is also building a business case for health equity. This has focused efforts on demonstrating to the private sector an economic argument for health equity. The HETT has formed a close partnership with the American Academy of Family Physicians' (AAFP's) Center for Diversity and Health Equity (CDHE), collaborating on numerous efforts to increase awareness of health equity. The team has also focused on engaging leadership in all eight US national family medicine organizations to participate in its activities and to ensure that health equity remains a top priority in its leadership. Looking ahead, family medicine will be required to continuously engage with government and nongovernment agencies, academic centers, and the private sector to create partnerships to systematically tackle health inequities.

Expression and purification of a new lectin from mussel Mytilus trossulus.

The gene of mtl from the mussel Mytilus trossulus was cloned into pET-40b(+) expression vector. After expression in E. coli using designed MX-medium an instable soluble form of MTL was obtained. The developed isolation method of the recombinant protein in "semi-denatured" conditions allowed obtaining an active soluble form of the homogenous lectin from the mussel M. trossulus (r-MTL). Both of the lectins had similar antigenic and spatial structures.

Response to Comment on “Prognostic Role of Claudin-1 Immunohistochemistry in Malignant Solid Tumors: A Meta-Analysis”

No abstract available.

Diffuse Large B-Cell Lymphoma Arising within Ileal Neobladder: An Expanding Spectrum of Diffuse Large B-Cell Lymphoma Associated with Chronic Inflammation / Journal of the Korean Cancer Association, 대한암학회지

Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI), specifically arising in ileal neobladder, is a rare neoplasm. We present an unusual case of Epstein–Barr virus (EBV)–positive DLBCL-CI arising within neobladder with detailed clinical, histological, and immunophenotypical features in an immunocompetent patient. An 88-year-old male was admitted for gross hematuria. He had undergone radical cystectomy and ileal neobladder 17 years ago for invasive bladder cancer. Computed tomography showed enhancing lesions on dome and posterior wall of neobladder with mucosal thickening and multiple enlarged retroperitoneal lymphadenopathies. Transurethralresection of neobladder lesion revealed the diffuse infiltration of large lymphoid cells which were positive for CD20, CD30, and multiple myeloma oncogen-1 with EBV-encoded small RNAs co-localizing, and diagnosis of EBV-positive DLBCL-CI was made. After multi-agent chemotherapy, the lesion disappeared. We suggest that clinicians should consider the possibility of DLBCL-CI in patients presented with hematuria during follow-up after bladder reconstruction.

Discordance of Epidermal Growth Factor Receptor Mutation between Brain Metastasis and Primary Non-Small Cell Lung Cancer

BACKGROUND: The aim of this study was to compare epidermal growth factor receptor (EGFR) mutations between non-small cell lung cancer (NSCLC) and corresponding brain metastases (BMs) in Korea society. METHODS: From 2011 to 2016, a total of 74 patients underwent surgical resection of a metastatic brain tumor from NSCLC. Among them, we performed retrospective analysis for 46 patients who underwent EGFR sequencing of primary NSCLC tissues. RESULTS: Among these 46 cases, 18 (39.1%) cases showed EGFR mutation in primary lung cancer. Detected mutation sites were exon 19 (8 cases), exon 21 (6 cases), exon 18 (1 cases), and multiple mutations (3 cases). In 18 cases of BM, EGFR mutation studies were done. Among them, 8 (25.6%) cases showed mutation on exon 19 (5 cases) or exon 21 (3 cases). To compare EGFR mutation status between primary lung cancer and BM, 18 paired tissues from both NSCLC and matched BM were collected. Four (22.5%) patients were discordant for the status of EGFR between primary and metastatic sites. CONCLUSION: EGFR mutations were significantly discordant between primary tumors and corresponding metastases in a significant portion of NSCLC. In treatment of BM of EGFR mutant metastatic NSCLC, due to possibility of discordance, pathologic confirming through brain biopsy is recommended.

Prognostic Role of Claudin-1 Immunohistochemistry in Malignant Solid Tumors: A Meta-Analysis

BACKGROUND: Although the correlation between low claudin-1 expression and worse prognosis has been reported, details on the prognostic implications of claudin-1 expression in various malignant tumors remain unclear. The present study aimed to elucidate the prognostic roles of claudin- 1 immunohistochemistry (IHC) in various malignant tumors through a meta-analysis. METHODS: The study included 2,792 patients from 22 eligible studies for assessment of the correlation between claudin-1 expression and survival rate in various malignant tumors. A subgroup analysis based on the specific tumor and evaluation criteria of claudin-1 IHC was conducted. RESULTS: Low claudin-1 expression was significantly correlated with worse overall survival (OS) (hazard ratio [HR], 1.851; 95% confidence interval [CI], 1.506 to 2.274) and disease-free survival (DFS) (HR, 2.028; 95% CI, 1.313 to 3.134) compared to high claudin-1 expression. Breast, colorectal, esophageal, gallbladder, head and neck, and lung cancers, but not cervical, liver or stomach cancers, were significantly correlated with worse OS. Breast, colorectal, esophageal, and thyroid cancers with low claudin-1 expression were associated with poorer DFS. In the lower cut-off subgroup (< 25.0%) with respect to claudin-1 IHC, low claudin-1 expression was significantly correlated with worse OS and DFS. CONCLUSIONS: Taken together, low claudin-1 IHC expression is significantly correlated with worse survival in various malignant tumors. More detailed criteria for claudin-1 IHC expression in various malignant tumors are needed for application in daily practice.

Effective osimertinib treatment in a patient with discordant T790 M mutation detection between liquid biopsy and tissue biopsy.

BACKGROUND: We report the successful treatment of the patient with osimertinib 80 mg/day following disease progression and a discordance in the detection of a mechanism of resistance epithelial growth factor receptor (EGFR) T790 M between liquid biopsy and tissue biopsy methods. CASE PRESENTATION: A 57-year-old Hispanic male patient initially diagnosed with an EGFR 19 deletion positive lung adenocarcinoma and clinically responded to initial erlotinib treatment. The patient subsequently progressed on erlotinib 150 mg/day and repeat biopsies both tissue and liquid were sent for next-generation sequencing (NGS). A T790 M EGFR mutation was detected in the blood sample using a liquid biopsy technique, but the tissue biopsy failed to show a T790 M mutation in a newly biopsied tissue sample. He was then successfully treated with osimertinib 80 mg/day, has clinically and radiologically responded, and remains on osimertinib treatment after 10 months. CONCLUSIONS: Second-line osimertinib treatment, when administered at 80 mg/day, is both well tolerated and efficacious in a patient with previously erlotinib treated lung adenocarcinoma and a T790 M mutation detected by liquid biopsy.

A single institution experience with palbociclib toxicity requiring dose modifications.

PURPOSE: Since the widespread implementation of adding palbociclib to endocrine therapy in clinical practice, myelosuppression is becoming increasingly recognized as a toxicity that may lead to dose modification. We aimed to characterize toxicities observed with palbociclib resulting in dose modifications and prescriber preferences in modifying palbociclib dosage in response to treatment-related toxicities outside the context of a clinical trial. METHODS: We conducted a single institution, retrospective study of treatment-related adverse events (AEs) resulting in modifications in dose and schedule and the methods by which dose modifications occurred in patients with advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer receiving palbociclib and endocrine therapy. RESULTS: From 2/2015 to 10/2016, 100 patients were identified for inclusion in this study. Treatment with palbociclib and endocrine therapy resulted in dose modifications in 38.0% of patients due to AEs with 18.4% requiring subsequent dose changes. Most palbociclib dose modifications occurred during the first 2 cycles. Grade 3-4 neutropenia accounted for 54.8% events of palbociclib dose modification. Most providers (65.8%) dose reduced palbociclib from 125 mg to 100 mg as their preferred method of dose modification, while others dose reduced from 125 mg to 75 mg (10.5%) and altered the schedule to 125 mg every other day (7.9%). A comparable rate of palbociclib dose modifications and subsequent dose changes were identified in an age ≥ 65 subgroup. In this group, dose adjustments were most commonly from grade 3-4 neutropenia, occurred mainly during cycle 1, and were most frequently addressed by dose reduction from 125 to 100 mg. CONCLUSIONS: Neutropenia remains the predominant cause for palbociclib dose modification and most modifications occur within the first two cycles. Older age (≥ 65) does not affect palbociclib tolerance. Our findings provide context outside of a clinical trial that inform ongoing studies evaluating the safety and feasibility of palbociclib-based therapies.