Ixazomib, Oral Metronomic Cyclophosphamide, and Dexamethasone for First-Line Treatment of Multiple Myeloma: A Phase II Brown University Oncology Group Study.

BACKGROUND: Newly diagnosed multiple myeloma patients have many available treatment options. While lenalidomide, bortezomib, and dexamethasone (RVD) is the preferred initial treatment for many patients, several other agents may provide similar efficacy with less toxicity and improved ease of administration. METHODS: We evaluated the safety and efficacy of the all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. RESULTS: The study was stopped prior to planned enrollment due to slow recruitment, with 12 patients available for final analysis. The overall response rate was 58.3% with 2 patients achieving a very good partial response (16.7%) and 5 patients achieving a partial response (41.7%). Median progression-free survival was 16 months, and median overall survival was 43 months. There were no episodes of grade 3 or greater peripheral neuropathy. Grade 3 or greater dermatologic toxicity was experienced in 50% of patients. CONCLUSION: Although limited enrollment prevented full efficacy evaluation, our data do not support further study of metronomic cyclophosphamide in combination with ixazomib and dexamethasone in the treatment of newly diagnosed multiple myeloma. The activity of this regimen in the relapsed/refractory setting requires further study (ClinicalTrials.gov Identifier: NCT02412228).

Evaluation of Gas 6 as a Prognostic Marker in Papillary Renal Cell Carcinoma.

INTRODUCTION: Growth arrest-specific protein 6 (Gas 6) is a ligand that plays a role in proliferation and migration of cells. For several tumor entities, high levels of Gas 6 are associated with poorer survival. We examined the prognostic role of Gas 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), which is still unclear. METHODS: The patients' sample collection is a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Gas 6 was determined by immunohistochemistry. RESULTS: In total, Gas 6 staining was evaluable in 180 of 240 type 1 and 110 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed no significant difference in 5-year overall survival for all pRCC nor either subtype. Also, Gas+ and Gas- groups did not significantly differ in any tumor or patient characteristics. CONCLUSION: Gas 6 was not found to be an independent prognostic marker in pRCC. Future studies are warranted to determine if Gas 6 plays a role as prognostic marker or therapeutic target in pRCC.

Seroconversion and outcomes after initial and booster COVID-19 vaccination in adults with hematologic malignancies.

BACKGROUND: Patients with hematologic malignancies have impaired humoral immunity secondary to their malignancy and its treatment, placing them at risk of severe coronavirus disease-19 (COVID-19) infection and reduced response to vaccination. METHODS: The authors retrospectively analyzed serologic responses to initial and booster COVID-19 vaccination in 378 patients with hematologic malignancy and subsequently tracked COVID-19-related outcomes. RESULTS: Seroconversion occurred in 181 patients (48%) after initial vaccination; patients who had active malignancy or those who were recently treated with a B-cell-depleting monoclonal antibody had the lowest rates of seroconversion. For initial nonresponders to vaccination, seroconversion after a booster dose occurred in 48 of 85 patients (56%). The seroconversion rate after the booster was similar for patients on (53%) and off (58%) active therapy (p = .82). Thirty-three patients (8.8%) developed a COVID-19 infection, and there were three COVID-19-related deaths (0.8%). Although no significant association was observed between postvaccination seroconversion and the incidence of COVID-19 infection, no patient with seroconversion died from COVID-19, and no patient who received tixagevimab/cilgavimab (N = 25) was diagnosed with a COVID-19 infection. CONCLUSIONS: Booster vaccinations can promote seroconversion in a significant proportion of patients who are seronegative after the initial vaccination course regardless of the specific vaccine or on/off treatment status at the time of revaccination. Although postvaccination seroconversion may not be associated with a decrease in any (including asymptomatic) COVID-19 infection, the authors' experience suggested that effective vaccination (including a booster), supplemented by passive immunization using tixagevimab/cilgavimab in case of lack of seroconversion, effectively eliminated the risk of COVID-19 death in the otherwise high-risk population. LAY SUMMARY: Patients with hematologic malignancy, especially lymphoma, have an impaired response to coronavirus disease 2019 (COVID-19) vaccination. In this single-institution review, less than one half of the patients studied made detectable antibodies. For those who did not make detectable antibodies after initial vaccination, over one half (65%) were able to produce antibodies after booster vaccination. By the end of February 2022, 33 of the original 378 patients had a documented COVID-19 infection. The only deaths from COVID-19 were in those who had undetectable antibodies, and no patient who received prophylactic antibody therapy developed a COVID-19 infection.

Simultaneous FAPI PET/MRI Targeting the Fibroblast-Activation Protein for Breast Cancer.

Background Integrated PET/MRI is a promising modality for breast assessment. The most frequently used tracer, fluorine 18 (18F) fluorodeoxyglucose (FDG), is applied for whole-body staging in advanced breast cancer but has limited accuracy in evaluating primary breast lesions. The fibroblast-activation protein (FAP) is abundantly expressed in invasive breast cancer. FAP-directed PET tracers have recently become available, but results in primary breast tumors remain lacking. Purpose To evaluate the use of FAP inhibitor (FAPI) breast PET/MRI in assessing breast lesions and of FAPI whole-body scanning for lymph node (LN) and distant staging using the ligand gallium 68 (68Ga)-FAPI-46. Materials and Methods In women with histologically confirmed invasive breast cancer, all primary 68Ga-FAPI-46 breast and whole-body PET/MRI and PET/CT examinations conducted at the authors' center between October 2019 and December 2020 were retrospectively analyzed. MRI lesion characteristics and standardized uptake values (SUVs) were quantified with dedicated software. Mann-Whitney U tests were used to compare tumor SUVs across different tumor types. The Pearson correlation coefficient was calculated between SUV and measures of MRI morphologic characteristics. Results Nineteen women (mean age, 49 years ± 9 [standard deviation]) were evaluated-18 to complement initial staging and one for restaging after therapy for distant metastases. Strong tracer accumulation was observed in all 18 untreated primary breast malignancies (mean maximum SUV [SUVmax] = 13.9 [range, 7.9-29.9]; median lesion diameter = 26 mm [range, 9-155 mm]), resulting in clear tumor delineation across different gradings, receptors, and histologic types. All preoperatively verified LN metastases in 13 women showed strong tracer accumulation (mean SUVmax= 12.2 [range, 3.3-22.4]; mean diameter = 21 mm [range, 14-35 mm]). Tracer uptake established or supported extra-axillary LN involvement in seven women and affected therapy decisions in three women. Conclusion This retrospective analysis indicates use of 68Ga fibroblast-activation protein inhibitor tracers for breast cancer diagnosis and staging. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Mankoff and Sellmyer in this issue.

Characterization of Extracranial Giant Cell Arteritis with Intracranial Involvement and its Rapidly Progressive Subtype.

OBJECTIVE: The objective of this study was to characterize patients with extracranial giant cell arteritis with intracranial involvement. METHODS: In a multicenter retrospective study, we included 31 patients with systemic giant cell arteritis (GCA) with intracranial involvement. Clinical characteristics, pattern of arterial involvement, and cytokine profiles were assessed. Patients with GCA without intracranial involvement (n = 17), and with intracranial atherosclerosis (n = 25) served as controls. RESULTS: Erythrocyte sedimentation rate (ESR) was elevated in 18 patients (69.2%) with and in 16 patients (100%) without intracranial involvement (p = 0.02). Headache was complained by 15 patients (50.0%) with and 13 patients (76.5%) without intracranial involvement (p = 0.03). Posterior circulation arteries were affected in 26 patients (83.9%), anterior circulation arteries in 17 patients (54.8%), and both territories in 12 patients (38.7%). Patients with GCA had vertebral artery stenosis proximal and, in contrast, patients with atherosclerosis distal to the origin of posterior inferior cerebellar artery (PICA). Among patients with GCA with intracranial involvement, 11 patients (37.9%) had a rapid progressive disease course characterized by short-term recurrent ischemic events. The median modified Rankin Scale (mRS) at follow-up in these patients was 4 (interquartile range [IQR] = 2.0-6.0) and 4 patients (36.4%) died. Vessel wall expression of IL-6 and IL-17 was significantly increased in patients with rapid progressive course. INTERPRETATION: Typical characteristics of GCA, headache, and an elevated ESR, are frequently absent in patients with intracranial involvement. However, differentiation of intracranial GCA from atherosclerosis can be facilitated by the typical pattern of vertebral artery stenosis. About one-third of patients with intracranial GCA had a rapid progressive course with poor outcome. IL-17 and IL-6 may represent potential future treatment targets. ANN NEUROL 2021;90:118-129.

The Prognostic Impact of PD-L2 in Papillary Renal-Cell Carcinoma.

INTRODUCTION: Programmed death-1 ligand (PD-L1) has been often studied in different types of renal-cell carcinoma (RCC). For example, in clear-cell renal carcinoma it is well established that programmed death-1 receptor and PD-L1 are important prognostic markers. In contrast, the role of programmed death-2 ligand (PD-L2) as prognostic marker remains unclear. The aim of this study was to evaluate if PD-L2 expression could play a role as a prognostic marker for papillary RCC (pRCC). METHODS: The patients' sample collection was a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of PD-L2 was determined by immunohistochemistry. In total, PD-L2 staining was evaluable in 185 of 240 type 1 and 99 of 128 type 2 pRCC cases. RESULTS: PD-L2 staining was positive in 67 (36.2%) of type 1 and in 31 (31.3%) of type 2 pRCC specimens. The prevalence of PD-L2+ cells was significantly higher in high-grade type 1 tumors (p = 0.019) and in type 2 patients with metastasis (p = 0.002). Kaplan-Meier analysis disclosed significant differences in 5-year overall survival (OS) for patients with PD-L2- compared to PD-L2+ in pRCC type 1 of 88.4% compared to 73.6% (p = 0.039) and type 2 of 78.8% compared to 39.1% % (p < 0.001). However, multivariate analysis did not identify the presence of PD-L2+ cells neither in type 1 nor type 2 pRCC as an independent predictor of poor OS. DISCUSSION/CONCLUSION: PD-L2 expression did not qualify as an independent prognostic marker in pRCC. Future studies will have to determine whether anti-PD-L2-targeted treatment may play a role in pRCC and expression can potentially serve as a predictive marker for these therapeutic approaches.

Outcomes of lenalidomide- or bortezomib-based regimens in older patients with plasma cell myeloma.

The "triplet" regimen of lenalidomide, bortezomib, and dexamethasone (RVD) showed survival advantage over lenalidomide-dexamethasone (RD) in clinical trials, but older patients with myeloma often receive doublet regimens (RD or bortezomib-dexamethasone, VD), or VD plus cyclophosphamide (VCD). We compared these first-line regimens using real-world data from Medicare beneficiaries receiving therapy between 2007 and 2015. In each comparative analysis, we balanced confounding characteristics using a propensity score. Outcomes included overall (OS) and event-free survival (EFS, reporting hazard ratios [HR] with 95% confidence intervals [CI]), adverse events, and costs. We identified 6076 patients with median age 76 and median OS of 2.6 years. In the comparison of RVD vs RD/VD doublets, RVD showed significantly better OS (HR = 0.83; 95% CI, 0.72-0.95) and EFS (HR = 0.68; 95% CI, 0.61-0.76). So, RVD was associated with more frequent hospitalizations, anemia, and neuropathy, but no increase in thromboembolism or secondary cancers. Costs were higher with RVD. In the comparison of RD vs VD, RD demonstrated better EFS (HR = 0.74; 95% CI, 0.68-0.81) and marginally better OS (HR = 0.91; 95% CI, 0.83-0.99). And, RD resulted in significantly more thromboembolic events, less neuropathy, and no significant difference in hospitalizations, transfusions, or secondary cancers. In the comparison of VCD vs VD, we observed no significant difference in any outcome. Superior survival favors RVD over doublet regimens, but even in 2015 RVD was applied for only about 25% of Medicare beneficiaries with myeloma. For patients not eligible for RVD due to toxicity, VCD offers no survival benefit over VD. Lenalidomide-dexamethasone may be the preferred line doublet considering its advantage over VD.

Postnatal Brain Growth Patterns in Pontocerebellar Hypoplasia.

BACKGROUND: Pontocerebellar hypoplasia (PCH) is a rare group of disorders mainly affecting the cerebellum and pons. Supratentorial structures are variably involved. We assessed brain growth patterns in patients with the most frequent forms of PCH, namely PCH1B (OMIM#614678) and PCH2A (OMIM#277470), since in these types of PCH, pre- and postnatal neurodegeneration is established by neuropathological profiling. To assess the influence of the different pathomechanisms on postnatal growth patterns, we included CASK-associated microcephaly and PCH (MICPCH, OMIM#300749) patients in our analyses, as MICPH mimics PCH on magnetic resonance imaging (MRI) but represents a developmental disorder including abnormal neuronal migration. METHODS: A total of 66 patients were included: 9 patients with PCH1B, 18 patients with PCH2A, 6 patients with MICPCH, and 33 age- and gender-matched hospital-based controls. Segmentation of the vermis and cerebellum was performed manually, as were measurements of the thickness of the head of the caudate nucleus, the width of the anterior horn, and lateral ventricle size. RESULTS: The cerebellum was severely hypoplastic at birth in all patients, and postnatal growth was nearly absent. In patients with PCH1B/2A, we found relative sparing of the vermis compared with the cerebellar hemispheres. In addition, PCH1B and PCH2A cases demonstrated thinning of the head of the caudate nucleus, an associated increase in anterior horn width, and an increase in lateral ventricle size. None of these features were seen in the MICPCH group. CONCLUSIONS: Our findings confirm the progressive nature including caudate nucleus atrophy in PCH1B and PCH2A. In MICPCH, the relative sparing of supratentorial structures confirms its different pathomechanism.

A multicenter retrospective study of 223 patients with t(14;16) in multiple myeloma.

The t(14;16) translocation, found in 3%-5% of newly diagnosed (ND) multiple myeloma (MM), has been associated with adverse outcomes. However, the studies establishing the characteristics of t(14;16) included solely small cohorts. The goal of the current international, multicenter (n = 25 centers), retrospective study was to describe the characteristics and outcomes of t(14;16) patients in a large, real-world cohort (n = 223). A substantial fraction of patients had renal impairment (24%) and hemoglobin <10 g/dL (56%) on initial presentation. Combined therapy of both immunomodulatory drug and proteasome inhibitor (PI) in the first line was used in 35% of patients. Autologous stem cell transplantation was performed in 42% of patients. With a median follow up of 4.1 years (95% CI 3.7-18.7), the median progression-free survival (PFS) and overall survival (OS) from first line therapy were 2.1 years (95% CI 1.5-2.4) and 4.1 years (95% CI 3.3-5.5), respectively. Worse OS was predicted by age > 60 years (HR = 1.65, 95% CI [1.05-2.58]), as well as revised International Scoring System (R-ISS) 3 (vs R-ISS 2; HR = 2.59, 95% CI [1.59-4.24]). In conclusion, based on the largest reported cohort of t(14;16) patients, quarter of this subset of MM patients initially presents with renal failure, while older age and the R-ISS 3 predict poor survival.

Outcomes of secondary solid tumor malignancies among patients with myeloma: A population-based study.

BACKGROUND: Therapeutic advances have extended survival for patients with myeloma, who may develop secondary cancers. METHODS: Using the population-based Surveillance, Epidemiology, and End Results registry (2004-2015), the authors examined the characteristics, overall and cause-specific survival, and cumulative incidence function of cancer-related death among patients with myeloma with secondary cancers of the breast, prostate, lung, colon/rectum, or bladder or melanoma. Each patient was matched based on age, sex, race, and year of diagnosis to 50 controls from a general population who were diagnosed with the index cancer. RESULTS: Patients with myeloma with breast, prostate, or lung cancer were more commonly diagnosed at an early stage, whereas the stage distribution did not differ significantly among patients with melanoma, colorectal cancer, or bladder cancer. For all studied cancers except those of the lung, overall mortality was significantly higher among patients with myeloma compared with controls (hazard ratios, 1.84-2.81). However, the cumulative incidence function of cancer-related death did not differ (subhazard ratios, 0.84-0.99) and was surpassed by myeloma-related deaths (23% to 35% at 5 years). In patients with lung cancer, cancer-related mortality was uniquely lower among patients with myeloma (subhazard ratio, 0.59; 95% confidence interval, 0.52-0.68), even after adjustment for stage of disease. There was no significant difference noted with regard to noncancer deaths for any studied solid tumor. Use of surgery (evaluated in patients with nonmetastatic tumors, and in addition matched by disease stage) did not differ between cases and controls, except for fewer prostatectomies being noted among patients with myeloma (odds ratio, 0.56; 95% confidence interval, 0.42-0.74). CONCLUSIONS: The results of the current study support curative treatment approaches to secondary cancers among patients with myeloma while highlighting the need for ongoing active myeloma management.

Correlation between SFRP1 expression and clinicopathological parameters in patients with triple-negative breast cancer.

Aim: Breast cancer is a heterogeneous disease with distinct molecular and clinical behavior demanding reliable biomarkers, especially in triple-negative breast cancer (TNBC). This study seeks to improve the understanding of SFRP1 as a potential biomarker in breast cancer focusing on TNBC. Materials & methods: SFRP1 expression was investigated via immunohistochemistry with two anti-SFRP1-antibodies on tissue-microarrays of 376 invasive breast cancers. Results: Statistical analysis revealed a highly significant association between TNBC (n = 36) and SFRP1 expression (p < 0.001). SFRP1 expression was significantly associated with younger age, higher tumor stage, size and grade. Conclusion: SFRP1 expression is strongly correlated with TNBC on protein level. Associations with age and tumor grade support the role of SFRP1 as a biomarker for chemotherapy response in TNBC.

Multispectral optoacoustic tomography of the human breast: characterisation of healthy tissue and malignant lesions using a hybrid ultrasound-optoacoustic approach.

BACKGROUND AND AIM: Multispectral optoacoustic tomography (MSOT) represents a new in vivo imaging technique with high resolution (~250 µm) and tissue penetration (>1 cm) using the photoacoustic effect. While ultrasound contains anatomical information for lesion detection, MSOT provides functional information based on intrinsic tissue chromophores. We aimed to evaluate the feasibility of combined ultrasound/MSOT imaging of breast cancer in patients compared to healthy volunteers. METHODS: Imaging was performed using a handheld MSOT system for clinical use in healthy volunteers (n = 6) and representative patients with histologically confirmed invasive breast carcinoma (n = 5) and ductal carcinoma in situ (DCIS, n = 2). MSOT values for haemoglobin and oxygen saturation were assessed at 0.5, 1.0 and 1.5 cm depth and selected wavelengths between 700 and 850 nm. RESULTS: Reproducible signals were obtained in all wavelengths with consistent MSOT signals in superficial tissue in breasts of healthy individuals. In contrast, we found increased signals for haemoglobin in invasive carcinoma, suggesting a higher perfusion of the tumour and tumour environment. For DCIS, MSOT values showed only little variation compared to healthy tissue. CONCLUSIONS: This preliminary MSOT breast imaging study provided stable, reproducible data on tissue composition and physiological properties, potentially enabling differentiation of solid malignant and healthy tissue. KEY POINTS: • A handheld MSOT probe enables real-time molecular imaging of the breast. • MSOT of healthy controls provides a reproducible reference for pathology identification. • MSOT parameters allows for differentiation of invasive carcinoma and healthy tissue.

Successful treatment of oral Crohn's disease by anti-TNF-alpha dose escalation - a case report.

BACKGROUND: Crohn's Disease (CD) is typically characterized by abdominal symptoms, however, besides gastrointestinal symptoms, CD patients may suffer from extraintestinal manifestations which are far less common and medical treatment can be challenging. CASE PRESENTATION: We report about a 34-year-old Crohn's Disease (CD) patient in clinical remission under adalimumab therapy who presented in the clinic for Cranio-Maxillo Surgery due to severe pain in the mandibular area. Ulcerative lesions of the buccal-side mucosa of the right mandible were detected. To rule out malignancy, a biopsy was obtained and revealed ulcerative stomatitis with noncaseating granulomas consistent with oral CD. Shortening the adalimumab administration interval to weekly injections resulted in a complete healing of the oral CD lesions without residual inflammation. CONCLUSION: The case presented here demonstrates that gastroenterologists should evaluate and consider oral CD lesions as a possible marker of disease activity in patients despite having quiescent intestinal CD.

The next generation of therapy for multiple myeloma: a review of ongoing clinical trials utilizing ClinicalTrials.gov.

The therapeutic armamentarium for multiple myeloma has grown significantly over the past decade. We characterized ongoing multiple myeloma clinical trials utilizing ClinicalTrials.gov . A search of ClinicalTrials.gov on 21 April 2017 returned 239 therapeutic interventional trials in multiple myeloma. A majority (84.1%) of trials are early-phase (I/II). Immunotherapies are significantly more likely to be studied in Phase I trials than Phase II trials (p = 0.0049). Primary sponsor (academic, cooperative group, industry) is significantly associated with phase of trial (p = 0.0334). Quality of life assessment is included as a secondary objective in only 10.1% of trials. Areas of need are continued advancement of immunotherapies, late-phase studies utilizing a triplet control group, and an objective focus on quality of life.

A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: Expanding the phenotype of ITPR1-related spinocerebellar ataxia's.

We report a de novo missense mutation (c.7649T>A) in the inositol, 1,4,5 triphosphate receptor type 1 (ITPR1) gene in a patient with severe pontocerebellar hypoplasia. The mutation results in an amino acid substitution of a highly conserved isoleucine by asparagine (p. I2550N) in the transmembrane domain. Mutations and deletions of the ITPR1 gene are associated with several types of autosomal dominant spinocerebellar ataxia, varying in age of onset and severity. Patients have signs of cerebellar ataxia and at most, a mild cerebellar atrophy on MRI. In contrast, the patient we report here has profound cerebellar and pontine hypoplasia. Our finding therefore further expands the spectrum of ITPR1-related ataxias. © 2016 Wiley Periodicals, Inc.

tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia.

Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.

Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood.

INTRODUCTION: We describe the natural history of patients with a Zellweger spectrum disorder (ZSD) surviving into adulthood. METHODS: Retrospective cohort study in patients with a genetically confirmed ZSD. RESULTS: All patients (n = 19; aged 16-35 years) had a follow-up period of 1-24.4 years (mean 16 years). Seven patients had a progressive disease course, while 12 remained clinically stable during follow-up. Disease progression usually manifests in adolescence as a gait disorder, caused by central and/or peripheral nervous system involvement. Nine were capable of living a partly independent life with supported employment. Systematic MRI review revealed T2 hyperintense white matter abnormalities in the hilus of the dentate nucleus and/or peridentate region in nine out of 16 patients. Biochemical analyses in blood showed abnormal peroxisomal biomarkers in all patients in infancy and childhood, whereas in adolescence/adulthood we observed normalization of some metabolites. CONCLUSIONS: The patients described here represent a distinct subgroup within the ZSDs who survive into adulthood. Most remain stable over many years. Disease progression may occur and is mainly due to cerebral and cerebellar white matter abnormalities, and peripheral neuropathy.

Detection of SMARCB1 loss in ascites cells in the diagnosis of an abdominal rhabdoid tumor.

We report on how MLPA and Sequencing of SMARCB1/INI1/SNF5 might be applied for initial diagnosis of rhabdoid tumor patients. These techniques were successfully used to detect loss of SMARCB1 in tumor cells of the ascites in a 3-month-old patient in which tumor biopsy could not initially be made due to life threatening intraabdominal bleedings.

Mutation update: the spectra of nebulin variants and associated myopathies.

A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (∼7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype-phenotype correlations in NEB-associated disease.

Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling.

BACKGROUND: Triple negative breast cancer (TNBC) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of overexpression or amplification of HER2. Despite an increased probability of response to chemotherapy, many patients resistant to current chemotherapy regimens suffer from a worse prognosis compared to other breast cancer subtypes. However, molecular determinants of response to chemotherapy specific to TNBC remain largely unknown. Thus, there is a high demand for biomarkers potentially stratifying triple negative breast cancer patients for neoadjuvant chemotherapies or alternative therapies. METHODS: In order to identify genes correlating with both the triple negative breast cancer subtype as well as response to neoadjuvant chemotherapy we employed publicly available gene expression profiles of patients, which had received neoadjuvant chemotherapy. Analysis of tissue microarrays as well as breast cancer cell lines revealed correlation to the triple negative breast cancer subtype. Subsequently, effects of siRNA-mediated knockdown on response to standard chemotherapeutic agents as well as radiation therapy were analyzed. Additionally, we evaluated the molecular mechanisms by which SFRP1 alters the carcinogenic properties of breast cancer cells. RESULTS: SFRP1 was identified as being significantly overexpressed in TNBC compared to other breast cancer subtypes. Additionally, SFRP1 expression is significantly correlated with an increased probability of positive response to neoadjuvant chemotherapy. Knockdown of SFRP1 in triple negative breast cancer cells renders the cells more resistant to standard chemotherapy. Moreover, tumorigenic properties of the cells are modified by knockdown, as shown by both migration or invasion capacity as well reduced apoptotic events. Surprisingly, we found that these effects do not rely on Wnt signaling. Furthermore, we show that pro-apoptotic as well as migratory pathways are differentially regulated after SFRP1 knockdown. CONCLUSION: We could firstly show that SFRP1 strongly correlates with the triple negative breast cancer subtype and secondly, that SFRP1 might be used as a marker stratifying patients to positively respond to neoadjuvant chemotherapy. The mechanisms by which tumor suppressor SFRP1 influences carcinogenic properties of cancer cells do not rely on Wnt signaling, thereby demonstrating the complexity of tumor associated signaling pathways.