Neoadjuvant T-DM1 for HER2-positive breast cancer used as a bridging strategy during COVID-19 pandemic: lessons learned-a case series.

Background: Coronavirus disease 19 (COVID-19) has played a pivotal role in changing medical care around the world. During the pandemic, the operating rooms (ORs) were closed to elective surgery. Since breast cancer surgery is not regarded as an emergent procedure, there was an adoption of treatment regimen modification due to delays in treatment. Therefore, a decision was made to bridge early-stage HER2-positive breast cancer patients with neoadjuvant treatment to postpone surgery. Consequently, to reduce the frequency of dosing and the number of visits, as well as avoid steroid premedication, these patients were treated with ado-trastuzumab emtansine (T-DM1) every three weeks as opposed to weekly taxol and herceptin (TH). Case Description: Five patients with early-stage HER2-positive cancer were treated with neoadjuvant T-DM1 3.6 mg/kg IV every three weeks. Three of the five patients developed cancer progression identified by their physical exam and/or imaging. T-DM1 was discontinued, and all three patients underwent immediate surgery. The remaining two patients, 4 and 5, had a complete and partial pathological response, respectively. All five patients received adjuvant therapy after surgery, and currently, none of these patients show evidence of disease on follow-up. Conclusions: Our findings underscore the obstacles and treatment challenges encountered during the COVID-19 pandemic while preventing the spread of the virus and cancer progression. Furthermore, the use of T-DM1 for neoadjuvant treatment remains controversial, particularly when T-DM1 is used as a bridge to surgery during critical times. Perhaps better patient selection or a different drug regimen could have resulted in a better outcome in our study.

Clinical profile and treatment outcomes of idiopathic intracranial hypertension: a multicenter study from Korea.

BACKGROUND: Currently, there is a relative lack of detailed reports regarding clinical presentation and outcome of idiopathic intracranial hypertension in Asians. This study aims to describe the clinical features and treatment outcomes of Korean patients with idiopathic intracranial hypertension. METHODS: We prospectively recruited patients with idiopathic intracranial hypertension from one hospital and retrospectively analyzed the medical records of 11 hospitals in Korea. We collected data regarding preceding medical conditions or suspected medication exposure, headache phenotypes, other associated symptoms, detailed neuroimaging findings, treatments, and outcomes after 1-2 and 3-6 months of treatment. RESULTS: Fifty-nine (83.1% women) patients were included. The mean body mass index was 29.11 (standard deviation, 5.87) kg/m2; only 27 patients (45.8%) had a body mass index of ≥ 30 kg/m2. Fifty-one (86.4%) patients experienced headaches, patterns of which included chronic migraine (15/51 [29.4%]), episodic migraine (8/51 [15.7%]), probable migraine (4/51 [7.8%]), chronic tension-type headache (3/51 [5.9%]), episodic tension-type headache (2/51 [3.9%]), probable tension-type headache (2/51 [3.9%]), and unclassified (17/51 [33.3%]). Medication overuse headache was diagnosed in 4/51 (7.8%) patients. After 3-6 months of treatment, the intracranial pressure normalized in 8/32 (25.0%), improved in 17/32 (53.1%), no changed in 7/32 (21.9%), and worsened in none. Over the same period, headaches remitted or significantly improved by more than 50% in 24/39 patients (61.5%), improved less than 50% in 9/39 (23.1%), and persisted or worsened in 6/39 (15.4%) patients. CONCLUSION: Our findings suggest that the features of Asian patients with idiopathic intracranial hypertension may be atypical (i.e., less likely obese, less female predominance). A wide spectrum of headache phenotypes was observed. Medical treatment resulted in overall favorable short-term outcomes; however, the headaches did not improve in a small proportion of patients.

Oculomotor fatigability with decrements of saccade and smooth pursuit for diagnosis of myasthenia gravis.

BACKGROUND AND OBJECTIVES: As the efficacy of current diagnostic methods for myasthenia gravis (MG) remains suboptimal, there is ongoing interest in developing more effective diagnostic models. As oculomotor fatigability is one of the most common and diagnostic symptoms in MG, we aimed to investigate whether quantitative saccadic and smooth-pursuit fatigability analyses with video-oculography (VOG) are useful for diagnosis of MG. METHODS: A convenience cohort of 46 MG patients was recruited prospectively, including 35 with ocular and 11 with generalized MG (mean age, 50.9 ± 14.5 years; 17 females); 24 healthy controls (HCs) (mean age, 50.6 ± 16.3 years; 13 females) also were enrolled. Seventy-five repetitive saccades and smooth pursuits were recorded in ranges of 20° (horizontal plane) and 15° (vertical plane) using a three-dimensional VOG system. Based on the oculomotor range of the second saccade and smooth pursuit and the mean ranges of the last five of each, the estimated decrements (%) reflecting oculomotor fatigability were calculated. RESULTS: The baseline oculomotor ranges did not show significant difference between the MG and HCs groups. However, following repetitive saccades and pursuits, the oculomotor ranges were decreased substantially during the last five cycles compared to baseline in the MG group. No such decrements were observed in the HC group (p < 0.01, Mann-Whitney U test). Receiver operating characteristic (ROC) analysis revealed that repetitive vertical saccades yielded the best differentiation between the MG and HC groups, with a sensitivity of 78.3% and specificity of 95.8% when using a decrement with an amplitude of 6.4% as the cutoff. CONCLUSION: This study presents an objective and reproducible method for measuring decrements of oculomotor ranges after repetitive saccadic and pursuit movements. Quantification of oculomotor fatigability using VOG could be a sensitive and specific diagnostic tool for MG and allows easy, cost-effective, accurate, and non-invasive measurements. CLASSIFICATION OF EVIDENCE: This study provides class III evidence that VOG-based quantification of saccadic and pursuit fatigability accurately identifies patients with MG.

Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer: The Phase 2 TBCRC041 Randomized Clinical Trial.

Importance: Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i-resistant MBC is unknown. Objective: To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC. Design, Setting, and Participants: This phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)-negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (<10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022. Interventions: Alisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2). Main Outcomes and Measures: Improvement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%. Results: All 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]). Conclusions and Relevance: This randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i-resistant MBC. The overall safety profile was tolerable. Trial Registration: ClinicalTrials.gov Identifier: NCT02860000.

The Differential Effects of Acute Right- vs. Left-Sided Vestibular Deafferentation on Spatial Cognition in Unilateral Labyrinthectomized Mice.

This study aimed to investigate the disparity in locomotor and spatial memory deficits caused by left- or right-sided unilateral vestibular deafferentation (UVD) using a mouse model of unilateral labyrinthectomy (UL) and to examine the effects of galvanic vestibular stimulation (GVS) on the deficits over 14 days. Five experimental groups were established: the left-sided and right-sided UL (Lt.-UL and Rt.-UL) groups, left-sided and right-sided UL with bipolar GVS with the cathode on the lesion side (Lt.-GVS and Rt.-GVS) groups, and a control group with sham surgery. We assessed the locomotor and cognitive-behavioral functions using the open field (OF), Y maze, and Morris water maze (MWM) tests before (baseline) and 3, 7, and 14 days after surgical UL in each group. On postoperative day (POD) 3, locomotion and spatial working memory were more impaired in the Lt.-UL group compared with the Rt.-UL group (p < 0.01, Tamhane test). On POD 7, there was a substantial difference between the groups; the locomotion and spatial navigation of the Lt.-UL group recovered significantly more slowly compared with those of the Rt.-UL group. Although the differences in the short-term spatial cognition and motor coordination were resolved by POD 14, the long-term spatial navigation deficits assessed by the MWM were significantly worse in the Lt.-UL group compared with the Rt.-UL group. GVS intervention accelerated the vestibular compensation in both the Lt.-GVS and Rt.-GVS groups in terms of improvement of locomotion and spatial cognition. The current data imply that right- and left-sided UVD impair spatial cognition and locomotion differently and result in different compensatory patterns. Sequential bipolar GVS when the cathode (stimulating) was assigned to the lesion side accelerated recovery for UVD-induced spatial cognition, which may have implications for managing the patients with spatial cognitive impairment, especially that induced by unilateral peripheral vestibular damage on the dominant side.

Perspectives on PARP inhibitors as pharmacotherapeutic strategies for breast cancer.

Introduction Approximately 10% of all breast cancer cases occur in individuals who have germline pathogenic variants of the BRCA 1, BRCA 2, and other genes associated with impaired DNA damage repair that is associated with an increased risk of breast, ovarian, and other cancers. Inhibitors of poly-ADP ribose polymerase (PARP) induce synthetic lethality in cancer cells harboring such pathogenic variants.Area covered In this review, the authors review the mechanisms of action, antitumor activity, and adverse events associated with PARP inhibitors for the treatment of advanced breast cancer. The authors then summarize the area and provide their expert perspectives on the area.Expert opinion Two PARP inhibitors are approved in metastatic breast cancer, including olaparib and talozaparib. Both agents were approved based on phase III trials demonstrating that they were associated with improved progression-free survival compared with treatment of physician's choice in patients receiving second-third line therapy for locally advanced, inoperable, or metastatic breast cancer in patients with germline pathogenic BRCA 1 or BRCA2 variants.

Acquired Ocular Motor Nerve Palsy in Neurology Clinics: A Prospective Multicenter Study.

BACKGROUND AND PURPOSE: This study aimed to determine the patterns and etiologies of acquired ocular motor nerve palsy (OMNP) diagnosed in neurology clinics. We also investigated the clinical features that may predict the causes other than microvascular ischemia in isolated OMNP. METHODS: We performed a prospective multicenter study that had recruited 298 patients with acquired OMNP from the neurology clinics of referral-based 9 university hospitals in Korea. We finally selected 235 patients with isolated OMNP and divided them into older (age ≥50 years, n=188) and younger (age <50 years, n=47) groups. We investigated the underlying etiologies of acquired OMNP. We also estimated the frequency of microvascular ischemia and other causes in isolated OMNP, and sought to determine the clinical features that can predict the causes other than microvascular ischemia. RESULTS: Abducens nerve palsy was the most common (40%) of the acquired OMNPs, followed by oculomotor nerve palsy (27%), trochlear nerve palsy (23%), and multiple OMNPs (10%). The etiologies included microvascular ischemia (47%), inflammatory (21%), stroke (5%), trauma (5%), neoplasm (3%), and others (2%), with the cause not being determined in 13% of the patients. Microvascular ischemia was the most common cause (83%) in patients aged ≥50 years with isolated OMNP, followed by inflammation (6%), stroke (6%), neoplasm (3%), and aneurysm (1%). Microvascular ischemia was more common in the older than the younger group (83% vs. 49%, p<0.001). The intensity of headache was the only risk factor for causes other than microvascular ischemia in isolated OMNP. CONCLUSIONS: Vascular and inflammatory disorders are the most common causes of acquired OMNP diagnosed in neurology clinics. Microvascular ischemia was the predominant cause of isolated OMNP. Severe headache indicates causes other than microvascular ischemia in isolated OMNP.

Update on opsoclonus-myoclonus syndrome in adults.

Opsoclonus-myoclonus syndrome in adults is a rare and heterogeneous disorder with the clinical features of opsoclonus, myoclonus, ataxia, and behavioral and sleep disturbances. The pathophysiology is thought to be immunological on the basis of paraneoplastic or infectious etiologies. Immunomodulatory therapies should be performed although the response may be incomplete. A number of autoantibodies have been identified against a variety of antigens, but no diagnostic immunological marker has yet been identified. This review focuses on underlying mechanisms of opsoclonus-myoclonus syndrome, including findings that have been identified recently, and provides an update on the clinical features and treatments of this condition.

Opsoclonus-myoclonus syndrome following long-term use of cyclosporine.

BACKGROUND: Cyclosporine A (CsA) is a widely used immunosuppressive agent that may provoke unexpected neurologic complications. The mechanism is unclear and variable intervals have been reported between CsA administration and onset of the related side effects. Here, we describe a case of delayed-onset CsA neurotoxicity presenting as opsoclonus-myoclonus syndrome (OMS). CASE DETAILS: A 37-year-old woman with a two-week period of opsoclonus and upper extremity myoclonus was admitted to our hospital. The patient had been taking CsA for 17 years after receiving a kidney transplant. Further evaluation did not reveal any other abnormalities. Seven days after switching from CsA to tacrolimus, in the absence of additional immune-modulating therapy, her neurologic symptoms improved considerably. CONCLUSION: This is the case of delayed, long-term complications of CsA presenting as OMS. Symptoms resolved by substituting CsA with another immunomodulating drug. The etiology of the neurologic complications may involve paradoxically-enhanced delayed-type hypersensitivity.

Iron-doped ZnO as a support for Pt-based catalysts to improve activity and stability: enhancement of metal-support interaction by the doping effect.

In heterogeneous catalysis, the role of the interface between a metal and a metal oxide in deciding catalytic performance has remained a long-standing question. Out of many molecular-scale factors that affect the properties of metal-oxide interfaces, doping or impurities in the oxides can result in excess charge carriers or oxygen vacancies on the oxides, which lead to a change in catalytic activity. For a model system with a tunable dopant, we employed Pt nanoparticles with Fe doping. We synthesized a series of Fe-doped ZnO with different Fe loadings (i.e., 0, 1, and 4%) using the co-precipitation method, and then deposited Pt nanoparticles onto these supports. The Pt-based catalysts were employed to investigate the effect of the dopant to promote the catalytic performance for the CO oxidation reaction. The 4% Fe loading sample showed the highest catalytic activity among the catalysts, with a turnover frequency of 5.37 s-1 at 126 °C. The dopant was found to enhance the interaction between the Pt nanoparticles and the catalyst support, including the prevention of metal sintering, which resulted in an improvement of catalytic activity.

A multicenter prospective observational study on the safety and efficacy of tacrolimus in patients with myasthenia gravis.

INTRODUCTION: Several clinical studies using tacrolimus revealed reasonable therapeutic mechanisms and efficacy in patients with myasthenia gravis (MG). However, long-period studies in a large number of patients with MG are limited; therefore, the aim of this study was to investigate the therapeutic efficacies and safety of tacrolimus in patients with MG during a 12-month follow-up period. METHODS: Tacrolimus was administered to 150 patients with MG who were recruited based on the inclusion criteria. Fifteen medical centers in Korea participated in this study. The efficacy of tacrolimus was assessed using MG composite scales (MGCS) and the prednisolone-sparing effect. And the adverse drug reactions (ADRs) of tacrolimus were monitored in each patient from the beginning of tacrolimus treatment to the end of the follow-up period. RESULTS: After starting tacrolimus, the 32 patients were affected by ADRs, and consequentially 134 patients of the enrolled patients were followed up for 12months. They showed that the mean prednisolone dosage significantly decreased (6.1±7.6mg/day), compared to that in the baseline (11.3±9.5mg/day), and MGCS significantly improved after 12months of tacrolimus treatment, compared to that at the baseline. CONCLUSIONS: Our study showed that tacrolimus would be an effective immunosuppressant as an initial therapeutic agent in patients with MG; in addition, it showed tolerable safety profiles during the 12-month follow-up evaluation.

Longitudinal multi-modal neuroimaging in opsoclonus-myoclonus syndrome.

To investigate structural, metabolic, and functional connectivity changes in visual and oculomotor structures in a patient with paraneoplastic opsoclonus-myoclonus syndrome, serial resting-state functional and structural MRI, and FDG-PET data were collected during the acute stage and later on when the opsoclonus had resolved. In the acute stage, an FDG-PET scan demonstrated a substantially increased metabolism in structures around the deep cerebellar nuclei [e.g., fastigial nucleus (FN)] and a relatively reduced metabolism in the bilateral occipital lobes which normalized over 12 months. Functional connectivity increased initially between the seeds of the oculomotor and visual systems, including the primary and motion-sensitive visual cortex, frontal eye fields, superior colliculus, and cerebellar oculomotor vermis (OMV), and then decreased in the chronic stage as the symptoms resolved. The functional connectivity between the OMV and FN showed a positive correlation during the acute stage, which decreased later on. We provide a descriptive presentation of the changes of abnormal functional connectivity throughout visuo-oculomotor brain areas during opsoclonus and suggest directions for further research on the pathogenesis of opsoclonus.

Breast Cancer-Associated Fibroblasts: Where We Are and Where We Need to Go.

Cancers are heterogeneous tissues comprised of multiple components, including tumor cells and microenvironment cells. The tumor microenvironment has a critical role in tumor progression. The tumor microenvironment is comprised of various cell types, including fibroblasts, macrophages and immune cells, as well as extracellular matrix and various cytokines and growth factors. Fibroblasts are the predominant cell type in the tumor microenvironment. However, neither the derivation of tissue-specific cancer-associated fibroblasts nor markers of tissue-specific cancer-associated fibroblasts are well defined. Despite these uncertainties it is increasingly apparent that cancer-associated fibroblasts have a crucial role in tumor progression. In breast cancer, there is evolving evidence showing that breast cancer-associated fibroblasts are actively involved in breast cancer initiation, proliferation, invasion and metastasis. Breast cancer-associated fibroblasts also play a critical role in metabolic reprogramming of the tumor microenvironment and therapy resistance. This review summarizes the current understanding of breast cancer-associated fibroblasts.

Pilot study to determine whether transient receptor potential melastatin type 8 (TRPM8) antibodies are detected in scleroderma.

OBJECTIVES: A key mediator in cold-sensation is the protein transient receptor potential melastatin 8 (TRPM8), which is expressed on sensory nerves and cutaneous blood vessels. These receptors are activated by cold temperatures and play a key role in body thermoregulation. Cold sensitivity and Raynaud's phenomenon are frequent clinical features in scleroderma, and are thought to be secondary to a local defect in cutaneous thermoregulation. We investigated whether autoantibodies targeting TRPM8 were present in the sera of patients with scleroderma as evidence for a possible mechanism for an acquired immune mediated defect in thermoregulation. METHODS: Sera from 50 well-characterised scleroderma patients with Raynaud's phenomenon were studied. TRPM8 autoantibodies were assayed as follows: 1. immunoprecipitation with 35S-methionine-labelled TRPM8 generated by in vitro transcription and translation, 2. immunoblotting lysates made from cells transiently transfected with TRPM8 cDNA, 3. Immunoprecipitation of TRPM8 transfected lysates with detection by blotting and 4. flow cytometry. RESULTS: Fifty scleroderma patients with Raynaud's phenomenon (41 female, 39 Caucasian, 23 with limited scleroderma, and 20 with history of cancer) were studied. Four different methods to assay for TRPM8 antibodies were set up, optimised and validated using commercial antibodies. All 50 scleroderma patients' sera were assayed using each of the above methods, and all were negative for TRPM8 autoantibodies. CONCLUSIONS: Antibodies against TRPM8 are not found in scleroderma patient sera, suggesting that the abnormal cold sensitivity and associated abnormal vascular reactivity in scleroderma patients is not the result of an immune process targeting TRPM8.

Global microRNA expression is essential for murine mast cell development in vivo.

MicroRNAs (miRNAs) are small, noncoding RNAs that have been shown to play a critical role in normal physiology and disease, such as hematopoietic development and cancer. However, their role in mast-cell function and development is poorly understood. The major objective of this study was to determine how global miRNA expression affects mast-cell physiology. The RNase III endonuclease, Dicer, is required for the processing of pre-miRNAs into mature miRNAs. To investigate the effect of global miRNA depletion on mast cells in vivo, we generated a mast-cell-specific knock out of Dicer in mice. Transgenic mice (Mcpt5-Cre) that express Cre selectively in connective tissue mast cells were crossed with mice carrying the floxed conditional Dicer allele (Dicer fl/fl). Mcpt5-Cre × Dicer fl/fl mice with homozygous Dicer gene deletion in mast cells were found to have a profound mast-cell deficiency with near complete loss of peritoneal, gastrointestinal, and skin mast cells. We examined the in vivo functional consequence of mast-cell-specific Dicer deletion using an immunoglobulin-E-dependent passive systemic anaphylaxis murine model. Immunoglobulin-E-sensitized wild type Mcpt5-Cre × Dicer +/+ and heterozygous Mcpt5-Cre × Dicer fl/+ mice show marked hypothermia with antigen; however, homozygous Mcpt5-Cre × Dicer fl/fl mice were completely unresponsive to antigen challenge. These studies suggest a critical role for Dicer and miRNA expression for establishment of tissue compartments of functional mast cells in vivo.

Regulation of nasal airway homeostasis and inflammation in mice by SHP-1 and Th2/Th1 signaling pathways.

Allergic rhinitis is a chronic inflammatory disease orchestrated by Th2 lymphocytes. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 is known to be a negative regulator in the IL-4α/STAT-6 signaling pathway of the lung. However, the role of SHP-1 enzyme and its functional relationship with Th2 and Th1 cytokines are not known in the nasal airway. In this study, we aimed to study the nasal inflammation as a result of SHP-1 deficiency in viable motheaten (mev) mice and to investigate the molecular mechanisms involved. Cytology, histology, and expression of cytokines and chemokines were analyzed to define the nature of the nasal inflammation. Targeted gene depletion of Th1 (IFN-γ) and Th2 (IL-4 and IL-13) cytokines was used to identify the critical pathways involved. Matrix metalloproteinases (MMPs) were studied to demonstrate the clearance mechanism of recruited inflammatory cells into the nasal airway. We showed here that mev mice had a spontaneous allergic rhinitis-like inflammation with eosinophilia, mucus metaplasia, up-regulation of Th2 cytokines (IL-4 and IL-13), chemokines (eotaxin), and MMPs. All of these inflammatory mediators were clearly counter-regulated by Th2 and Th1 cytokines. Deletion of IFN-γ gene induced a strong Th2-skewed inflammation with transepithelial migration of the inflammatory cells. These findings suggest that SHP-1 enzyme and Th2/Th1 paradigm may play a critical role in the maintenance of nasal immune homeostasis and in the regulation of allergic rhinitis.

The balance of cell surface and soluble type III TGF-ß receptor regulates BMP signaling in normal and cancerous mammary epithelial cells.

Bone morphogenetic proteins (BMPs) are members of the TGF-ß superfamily that are over-expressed in breast cancer, with context dependent effects on breast cancer pathogenesis. The type III TGF-ß receptor (TßRIII) mediates BMP signaling. While TßRIII expression is lost during breast cancer progression, the role of TßRIII in regulating BMP signaling in normal mammary epithelium and breast cancer cells has not been examined. Restoring TßRIII expression in a 4T1 murine syngeneic model of breast cancer suppressed Smad1/5/8 phosphorylation and inhibited the expression of the BMP transcriptional targets, Id1 and Smad6, in vivo. Similarly, restoring TßRIII expression in human breast cancer cell lines or treatment with sTßRIII inhibited BMP-induced Smad1/5/8 phosphorylation and BMP-stimulated migration and invasion. In normal mammary epithelial cells, shRNA-mediated silencing of TßRIII, TßRIII over-expression, or treatment with sTßRIII inhibited BMP-mediated phosphorylation of Smad1/5/8 and BMP induced migration. Inhibition of TßRIII shedding through treatment with TAPI-2 or expression of a non-shedding TßRIII mutant rescued TßRIII mediated inhibition of BMP induced Smad1/5/8 phosphorylation and BMP induced migration and/or invasion in both in normal mammary epithelial cells and breast cancer cells. Conversely, expression of a TßRIII mutant, which exhibited increased shedding, significantly reduced BMP-mediated Smad1/5/8 phosphorylation, migration, and invasion. These data demonstrate that TßRIII regulates BMP-mediated signaling and biological effects, primarily through the ligand sequestration effects of sTßRIII in normal and cancerous mammary epithelial cells and suggest that the ratio of membrane bound versus sTßRIII plays an important role in mediating these effects.

Implication of lymph node metastasis detected on 18F-FDG PET/CT for surgical planning in patients with peripheral intrahepatic cholangiocarcinoma.

OBJECTIVES: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma. ICC can be divided into 2 types according to their location: peripheral and hilar types. Intense F-FDG uptake on PET was reported in peripheral ICC. However, the usefulness of PET/CT in detecting tumors and predicting prognosis in peripheral ICC has not been fully evaluated. In this study, we evaluated the clinical role of F-FDG PET/CT to predict the recurrence after the curative resection in patients with surgically indicated peripheral ICC. METHODS: Eighteen patients with ICC underwent preoperative CT and F-FDG PET/CT scans. SUVmax of tumor, tumor to normal liver SUV ratio (TNR), lymph node status evaluated by F-FDG PET/CT, tumor and lymph node size measured by CT, vascular invasion confirmed by pathology, and satellite nodules found on CT were compared between 1-year recurrence group and recurrence-free group by chi-square test. RESULTS: Of total 23 measurable lymph nodes, 4 nodes were positive and other 19 nodes were negative or equivocal on CT. Among those 23 nodes, 9 nodes were positive and other 14 nodes were negative on F-FDG PET/CT. The sensitivity and specificity of CT were 20.0% and 86.4%, and those of F-FDG PET/CT were 80.0% and 92.3%. In the comparison between 1-year recurrent and nonrecurrent groups, lymph node metastasis detected on F-FDG PET/CT had statistically positive correlation with the 1-year recurrence after surgical resection (P = 0.02). Other factors showed no statistically significant difference between the groups. CONCLUSION: We found that lymph node metastasis detected on F-FDG PET/CT correlated positively with 1-year recurrence after surgical resection in patients with peripheral ICC.