Comparison of Two Blood-Based Genotyping Tests to Investigate the KRAS G12C Mutation in Patients with Non-Small-Cell Lung Cancer at Failure of First-Line Treatments

Although molecular profiling at diagnosis has traditionally relied on direct sampling of neoplastic tissue, cancer clonal evolution represents a critical obstacle to use primary tissue biopsies to guide clinical decision-making at the time of progressive disease. Liquid biopsies might offer enormous advantages over tissue biopsies, tracking in real-time temporal-based tumor dynamics following each line of treatment. Here, we compared two liquid biopsy assays, specifically real-time polymerase chain reaction and next-generation sequencing, to track the KRAS G12C mutation at onset of progression from previous lines of therapy. The KRAS G12C mutation was acquired at the time of progressive disease in 24% of patients. Furthermore, all patients with KRAS G12C mutation-positive tissue became negative in ctDNA at progressive disease. The presence of other somatic mutations in all these samples confirmed the tumor origin of the circulating DNA. This pilot study suggests that in the assessment of the plasma KRAS G12C mutation as a druggable target, real-time PCR assay Idylla might be a suitable approach to better match patients to interventional biomarker-targeted therapies.

Clinical Outcomes in Patients Admitted with Malignancy Associated Hemophagocytic Lymphohistiocytosis (HLH)

Background: Hemophagocytic Lymphohistiocytosis (HLH) is an aggressive and life threatening clinical syndrome that involves the rapid and excessive activation of the immune systems. It is associated with many conditions including infections, rheumatologic and autoimmune conditions, and drug-induced especially from chemotherapy. However, HLH associated with malignancy has especially poor outcomes. In this study we aim to investigate the clinical predictors of outcomes in patients who were admitted with malignancy associated HLH. Methods: The National Inpatient Sample (NIS) was queried for all hospitalizations with a primary diagnosis of Hemophagocytic Lymphohistiocytosis from 2011 to 2017 using ICD-9-CM code 288.5 and ICD-10-CM code D 76.1. We looked at the most common malignancies associated with HLH. We also examined the most common comorbidities in this patient population. We analyzed the relation of different malignancies and co-morbidities with adverse outcomes, primarily the mortality rate. Data was analyzed using SPSS 27.0 Results: A total of 650 patients were identified during this studied time period who were admitted for malignancy associated with HLH. The mean age of this patient population was 52.41 years. Amongst these patients n=431 (66.7%) were males and the rest were females. By far the most common malignancy associated with HLH included Lymphomas, which were present in n=483 (74.3%) patients. Non-Hodgkin's Lymphoma was much more common and present in n=431 (66.3%) patients, while Hodgkin's Lymphoma was present in n=56 (8.6%) of the patients. The other common malignancies included various leukemias n= 129 (19.8%), including AML n=35 (5.4%), ALL n=20 (3.1%), and CML n= 35 (5.4%), and solid tumors n=36 (5.4%), including lung cancer n=9 (1.4%) ,Breast Cancer n=9 (1.4%), and GI cancers n=10 (1.5%). The most common comorbidities present in this HLH population included hypertension n=169 (26%), weight loss/malnutrition n=150 (23.5%), Kidney disease n=70 (10.8%), Diabetes n=97 (14.9%), heart failure n=55 (8.5%) liver disease n=72 (11.1%), rheumatologic disorders n=33 (5.1%) and obesity n=28 (4.3%). The main patient outcome assessed was inpatient mortality. The overall inpatient mortality was 24.6 % in this patient population. In those patients who died, the odds of having bone and soft tissue cancer was the highest (odd ratio of 2.24). The odds ratio for other malignancies included AML (OR=2.12), Hodgkin's Lymphoma (OR=1.21), Multiple Myeloma (OR=1.20), CLL (OR=0.89), NHL (OR=0.79), Breast cancer (OR=0.3). In those patient who died, the odds of having various comorbidities was the highest for liver disease (OR=2.7), alcohol abuse (OR=2.6), coagulopathy (OR=2.4), weight loss (OR=1.91), heart failure (OR=1.5), pulmonary disease (OR=1.31) and renal disease (OR=1.31). Conclusion: HLH is an aggressive clinical syndrome that is rarely associated with various malignancies. Analysis of the National Inpatient Sample (NIS) data from hospital admissions in the United States shows that it is more common in males (66.7%). Despite advances in medical treatments the mortality is around 24.6%. By far the most common malignancy reported in this patient population is Non-Hodgkin's lymphoma that is present in (66.3%) of this patient population. Worse mortality rates were associated with patients who had underlying bone and soft tissue cancer, AML, Multiple Myeloma, and Hodgkin's lymphoma. Comorbidities including liver disease, alcohol abuse, coagulopathy, heart failure, and renal disease were also associated with worse mortality rates. Disclosures Anwer: BMS / Celgene: Honoraria, Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Allogene Therapeutics: Research Funding.

The Clinical Significance Of Circulating Mir-21, Mir-142, Mir-143, And Mir-146a In Patients With Prostate Cancer

Prostate cancer (PCa) is the most common type of solid tissue cancer among men in western countries. To enlighten the underlying molecular mechanisms in the pathophysiology of PCa and to help the development of new diagnostics and treatment models, we planned to determine the levels of circulating miR-21, miR-142, miR-143, miR-146a, and RNU 44 levels as controls for the early diagnosis of PCa. The circulating miRNA levels in peripheral blood samples from 43 localized PCa patients, 12 metastatic PCa (MET) patients, and as a control group, 42 benign prostate hyperplasia (BPH) patients with a total of 97 volunteers were determined the by PCR method. No differences in the ΔCT values were found among the groups. In PCa and PCaMet groups the expression of miR21 and miR142 were higher compared to the BHP group. No other differences were observed among the other groups. miR21 expression in the PCa group was 6.29 folds upregulated whereas in the PCaMet group 10.84 folds upregulated. When the total expression of miR142 is evaluated, it showed a positive correlation with mir21 and mir 146 (both p<0.001). Also, the expression of miR146 shows a positive correlation with both miR21 and miR143 (both p<0.001). Expression of miRNAs was found to be an independent diagnostic factor in patients with Gleason score, PSA, and free PSA levels. In conclusion, our study showed that co-expression of miR-21, miR-142, miR-143, and miR-146a and the upregulation of miR-21 resulted in increased prostate carcinoma cell growth. In the PCaMet group, miR21 is the most upregulated of all miRNAs. These miRNA markers that are expressed in different levels may provide a novel diagnostic tool to help diagnose PCa with aggressive behavior.

Protein Arginine Methyltransferase (PRMT) Inhibitors—AMI-1 and SAH Are Effective in Attenuating Rhabdomyosarcoma Growth and Proliferation in Cell Cultures

Rhabdomyosarcoma (RMS) is a malignant soft tissue cancer that develops mostly in children and young adults. With regard to histopathology, four rhabdomyosarcoma types are distinguishable: embryonal, alveolar, pleomorphic and spindle/sclerosing. Currently, increased amounts of evidence indicate that not only gene mutations, but also epigenetic modifications may be involved in the development of RMS. Epigenomic changes regulate the chromatin architecture and affect the interaction between DNA strands, histones and chromatin binding proteins, thus, are able to control gene expression. The main aim of the study was to assess the role of protein arginine methyltransferases (PRMT) in the cellular biology of rhabdomyosarcoma. In the study we used two pan-inhibitors of PRMT, called AMI-1 and SAH, and evaluated their effects on proliferation and apoptosis of RMS cells. We observed that AMI-1 and SAH reduce the invasive phenotype of rhabdomyosarcoma cells by decreasing their proliferation rate, cell viability and ability to form cell colonies. In addition, microarray analysis revealed that these inhibitors attenuate the activity of the PI3K-Akt signaling pathway and affect expression of genes related to it.

Synovial Sarcoma of Ethmoidal Sinus

Background Synovial sarcoma is an aggressive soft tissue cancer of extremities mainly and rare in head and neck region, whereas rarest in ethmoidal sinus as only three cases have been reported till date. Case Reports We managed two cases of synovial sarcoma who presented with nasal obstruction, epistaxis, and swelling around the nasofacial region. Endoscopic nasal biopsy and immunohistochemistry markers confirmed synovial sarcoma in both the cases. While one case was managed by surgery and chemoradiation, the second patient received two cycles of ifosfamide-based chemotherapy and succumbed after 6 weeks of diagnosis. Conclusion Head and neck sarcomas are aggressive and carry a poor prognosis. Surgical resection with postoperative radiotherapy is the standard treatment. However, they have a high risk of recurrence and hence aggressive management and close follow-up is warranted for the optimal outcome.

Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation

Cell lines have been essential for major discoveries in cancer including Ewing sarcoma (EwS). EwS is a highly aggressive pediatric bone or soft-tissue cancer characterized by oncogenic EWSR1-ETS fusion transcription factors converting polymorphic GGAA-microsatellites (mSats) into neo-enhancers. However, further detailed mechanistic evaluation of gene regulation in EwS have been hindered by the limited number of well-characterized cell line models. Here, we present the Ewing Sarcoma Cell Line Atlas (ESCLA) comprising 18 EwS cell lines with inducible EWSR1-ETS knockdown that were profiled by whole-genome-sequencing, DNA methylation arrays, gene expression and splicing arrays, mass spectrometry-based proteomics, and ChIP-seq for EWSR1-ETS and histone marks. Systematic analysis of these multi-dimensional data illuminated hundreds of new potential EWSR1-ETS target genes, the nature of EWSR1-ETS-preferred GGAA-mSats, and potential indirect modes of EWSR1-ETS-mediated gene regulation. Moreover, we identified putative co-regulatory transcription factors and heterogeneously regulated EWSR1-ETS target genes that may have implications for the clinical heterogeneity of EwS. Collectively, our freely available ESCLA constitutes an extremely rich resource for EwS research and highlights the power of leveraging multidimensional and comprehensive datasets to unravel principles of heterogeneous gene regulation by dominant fusion oncogenes.

Malignant granular cell tumor of the arm – case report

Granular cell tumor (GCT) is a rare form of soft tissue cancer that is usually benign. Its malignant evolution is encountered in less than 2% of cases, having a more rapid and unfavorable evolution. Clinical presentation betraying malignant features could be increased tumor size, rapid growth, deep localization, and female gender. This paper presents the case of a 52-year-old patient with a hard, rapidly evolving tumor in the left arm. The diagnosis of granular cell tumor was made based on histopathological examination using the Fanburg and Smith criteria to differentiate the formation as malignant, but with certainty this was subsequently confirmed by the existence of a metastasis. Surgical excision was performed and the evolution was favorable. Evolution and treatment differ depending on the benign or malignant form, but surgical treatment with wide local excision is recommended. This may be followed by chemotherapy or radiotherapy, and follow-up of patients for the rest of their lives is mandatory.

Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives

Ewing sarcoma, a highly aggressive bone and soft-tissue cancer, is considered a prime example of the paradigms of a translocation-positive sarcoma: a genetically rather simple disease with a specific and neomorphic-potential therapeutic target, whose oncogenic role was irrefutably defined decades ago. This is a disease that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease. International collaborations have defined the current standard of care in prospective studies, delivering multiple cycles of systemic therapy combined with local treatment; both are associated with significant morbidity that may result in strong psychological and physical burden for survivors. Nevertheless, the combination of non-directed chemotherapeutics and ever-evolving local modalities nowadays achieve a realistic chance of cure for the majority of patients with Ewing sarcoma. In this review, we focus on the current standard of diagnosis and treatment while attempting to answer some of the most pressing questions in clinical practice. In addition, this review provides scientific answers to clinical phenomena and occasionally defines the resulting translational studies needed to overcome the hurdle of treatment-associated morbidities and, most importantly, non-survival.

A Case Report of a Malignant Peripheral Nerve Sheath Tumor of the Paravertebral Region

Introduction: Malignant peripheral nerve sheath tumor (MPNST) is a type of connective tissue cancer, which may also have genetic backgrounds. More than half of patients have neurofibromatosis. The treatment of this tumor is a combination of surgery, radiotherapy, and chemotherapy. As usual, the tumor may be present anywhere with several manifestations. Case Presentation: A 4-year old boy presented with sweating and pain in the right forearm that was diagnosed with MPNST developed in the paravertebral region after laboratory and radiographic evaluation. Conclusions: The patient was treated successfully and followed up for one year without any complications.

Controversias en cirugía: Erradicación del Helicobacter pylori ¿Terapia a todos o según indicaciones usuales?

La infección por Helicobacter pylori (H. pylori), es la infección bacteriana crónica más frecuente de la raza humana, afecta al 50 % de la población mundial y, por lo menos, al 80 % de la población colombiana. Esta bacteria es reconocida desde hace más de 15 años como un carcinógeno tipo I. De acuerdo con las indicaciones del Consenso de “Maastricht V” esta infección debe ser buscada y tratada en los pacientes con úlcera péptica activa, Linfoma MALT (por sus siglas en inglés, mucosa associated lymphoid tissue), cáncer gástrico temprano, púrpura que presenten síntomas dispépticos crónicos y usuarios crónicos de AINES. Debido al papel que tiene en la fisiopatología del cáncer gástrico, nace la iniciativa de realizar una búsqueda activa del H. pylori y erradicarlo en todas las personas, incluyendo aquellas asintomáticas en países con alta incidencia de esta neoplasia. Existen diversas publicaciones alrededor del mundo que así lo sugieren, mostrando resultados con impacto positivo en el curso y progresión de la enfermedad, sobre todo en las etapas más tempranas de la infección. Sin embargo, otros autores resaltan la creciente problemática de la resistencia bacteriana, y demuestran que el peso estadístico y los diferentes análisis de los estudios disponibles en la actualidad tienen poca validez para dar una recomendación extendida al paciente asintomático. Se cuestiona que tal vez, estamos utilizando las estrategias inadecuadas para manejar una situación de salud pública, ya que estamos enfocados en impactar a cada individuo con terapias antibióticas complejas, en vez de a la población en general con políticas de salud pública.