Molecular and oral manifestations of langerhans cell histiocytosis preceding acute myeloid leukemia.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a heterogeneous neoplastic disorder that is rarely seen in patients aged 60 years and older. It is reported that elderly patients with LCH have a higher chance of having malignancies. In the oral cavity, patients with LCH can present with mucosal ulcers and extensive osteolysis, making it difficult for clinicians to make a proper diagnosis. CASE PRESENTATION: We reported an 82-year-old Chinese woman with oral symptoms as the first presentation of LCH, and eventually developed acute myeloid leukemia (AML). She suffered diffuse ulcers involving the entire gingival mucosa and the left half hard palate, and had lost several teeth. Genomic DNA sequencing of the cells from LCH revealed multiple mutations in TET2, BRAF, SRSF2, NRAS, MAP2K4 and so on. The patient declined the BRAFV600E inhibitor (Vemurafenib). Although a dramatic improvement of the oral ulcers was achieved after symptomatic treatment, the patient developed acute myeloid leukemia (AML) and died. CONCLUSIONS: This report presented the diagnostic difficulties of LCH with oral manifestations and highlighted the importance of radiological assessments and laboratory tests. Moreover, many of the mutations detected in our LCH patient are frequently seen in AML, suggesting that AML and LCH cells in this patient share the same origin.

Partial remission with sintilimab monotherapy in a patient carrying a CD274 amplification in refractory diffuse large B­cell lymphoma: A case report.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with varying characteristics, in terms of genomic variation, cell morphology and clinical presentation. At present, only ~66% of patients are cured with initial treatment and those with refractory DLBCL exhibit a poor prognosis. Thus, further investigations into novel effective treatment options for DLBCL are required. The present study reports the case of a patient resistant to multiple therapies, including rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus enzastaurin (trial no. CTR20171560), GemOx plus lenalidomide and selinexor (trial no. ATG-010-DLBCL-001). The patient harbored a CD274 amplification, as identified via next-generation sequencing (NGS), and exhibited a high programmed death-ligand 1 Tumor Proportion Score of up to 95%. Consequently, the patient was treated with sintilimab monotherapy and the response lasted for 12 months of follow-up without major immune-related adverse events. This case highlights the role of NGS technology in selecting treatment options for refractory DLBCL. Furthermore, the results of the present study suggest that sintilimab may have potential in the treatment of patients with refractory DLBCL.

Rapid response to fifth-line brigatinib plus entrectinib in an ALK-rearranged lung adenocarcinoma with an acquired ETV6-NTRK3 fusion: a case report.

The management of non-small cell lung cancer (NSCLC), specifically targeting the anaplastic lymphoma kinase (ALK) with tyrosine kinase inhibitors (TKIs), is challenged by the emergence of therapeutic resistance. Resistance mechanisms to ALK TKIs can be broadly classified into ALK-dependent and ALK-independent pathways. Here, we present a case with lung adenocarcinoma (LUAD) harboring an ALK rearrangement. The patient had developed resistance to sequential ALK TKI therapies, with an acquired ETV6-NTRK3 (E4:N14) fusion as a potential mechanism of ALK-independent resistance to lorlatinib. Subsequently, the patient was treated with the combination of brigatinib plus entrectinib and demonstrated a positive response, achieving an 8-month progression-free survival. Our case provides a potential treatment option for LUAD patients with ALK rearrangements and highlights the utility of next-generation sequencing (NGS) in uncovering genetic alterations that can guide the selection of effective treatment strategies.

Case Report: Lung adenocarcinoma associated with germline ERCC2 frameshift mutation.

Family history is an established risk factor for lung cancer. Previous studies have found that germline genetic alterations, such as those in EGFR, BRCA1, BRCA2, CHEK2, CDKN2A, HER2, MET, NBN, PARK2, RET, TERT, TP53, and YAP1, are associated with an increased risk of developing lung cancer. The study reports the first of a lung adenocarcinoma proband with germline ERCC2 frameshift mutation c.1849dup (p. A617Gfs*32). Her family cancer history review demonstrated that her two healthy sisters, a brother with lung cancer, and three healthy cousins were positive for ERCC2 frameshift mutation, which might contribute to increased cancer risk. Our study highlights the necessity of performing comprehensive genomic profiling in discovering rare genetic alterations, early cancer screening, and monitoring for patients with family cancer history.

A Primary Lung and Breast Cancer Patient with Germline EGFR R776H Mutation: A Case Report and Literature Review.

For advanced non-small cell lung cancer (NSCLC) patients with common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or the exon 21 L858R mutation), tyrosine kinase inhibitors (TKIs) are the standard therapies. However, EGFR germline mutations are extremely rare in lung cancer, and the effective therapy is unclear. This study reports a patient with primary breast and lung cancer carried rare germline EGFR R776H and somatic L861Q mutation, who benefit from EGFR TKIs. Her family cancer history review demonstrated that her three out of four sisters with lung cancer were positive for EGFR R776H. Interestingly, only her healthy sister had type O blood, different from other sisters with type B blood. Our study provides a meaningful insight into the potential treatment option for patients with germline EGFR R776H and somatic L861Q mutation and highlights the importance of next-generation sequencing (NGS) in discovering rare genetic alterations to guide the prevention of genetic disease.

Comprehensive next-generation sequencing reveals low-grade fibromyxoid sarcoma of the vulva missed by morphological diagnosis: a case report.

Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft tissue tumor composed of bland spindled cells in a variably fibrous to myxoid stroma. Its occurrence in the vulva region is rare, and thus, it may not be always taken into account in the differential diagnosis. Here, we describe a 34-year-old woman presented with a right vulvar mass and underwent complete surgical excision. The final pathologic diagnosis revealed LGFMS of the vulva based on the morphological, immunophenotypic, and molecular genetic features. The patient has not experienced a local or metastatic recurrence after 9-month follow-up. Despite being rare, LGFMS of the vulva should be considered when making a diagnosis of vulvar lesions. We also report that the genetic testing by next-generation sequencing (NGS) represents a very useful tool for the differential diagnosis of LGFMS from its mimics. Moreover, we have reviewed the literature on LGFMS of the vulva and summarized the characteristics of the patients, providing assistance for the diagnosis of such patients. Most vulvovaginal LGFMS can be fully removed through surgery. However, ongoing monitoring over the long term is essential as local and/or distant spread can occur decades after the initial diagnosis.

Comprehensive next-generation sequencing reveals double primary colorectal carcinoma missed by diagnostic imaging: A case report.

BACKGROUND: Multiple primary colorectal carcinoma (MPCC) is a rare clinical disease, which is challenging to differentiate from metastatic disease using histopathological methods. Next-generation sequencing (NGS) has been employed to identify multiple primary cancers. CASE SUMMARY: This study a rare case of a 63-year-old male patient diagnosed with MPCC by targeted NGS, which was initially missed by radiological evaluation. The patient was found to have two tumors located on the surface of the colorectum which had distinct genomic alterations. Based on wild-type KRAS detected in the unresected tumor, the patient benefited from the epidermal growth factor receptor (EGFR) inhibitor cetuximab treatment, but developed novel mutations including KIF5B-RET fusion, which provides a possible resistance mechanism to anti-EGFR therapy. CONCLUSION: Our case highlights the necessity of using genetic testing for primary tumor diagnosis and the application of serial plasma circulating tumor DNA profiling for dynamic disease monitoring.

An Effective Hormonal Therapy for a Patient with Estrogen Receptor 1 (ESR1)-Amplified Metastatic Ovarian Cancer: A Case Report.

Hormonal therapy is an important treatment option for estrogen receptor (ER)-positive patients with advanced ovarian cancer. Although ER overexpression has been previously used as an indicator for hormonal therapy, the clinical outcomes of advanced ovarian cancer patients receiving hormonal therapy remain unsatisfactory. Additional biomarkers for screening patients are needed to improve its efficacy. In this study, we reported a metastatic ovarian cancer case with estrogen receptor 1 (ESR1) gene amplification and protein overexpression, which showed sustained partial response to hormonal therapy, including letrozole and tamoxifen, and displayed an overall survival of 47 months. The response to the therapy was evaluated by imageological examinations, cancer antigen-125 (CA-125) tests, and circulating tumor DNA (ctDNA) sequencing using capture-based hybrid next-generation sequencing. Our clinical data suggested that ESR1 amplification might be a potential predictor of response to hormonal therapy in ovarian cancer. The combination of tumor detection techniques including imaging, CA-125 and ctDNA would enable confirmation of tumor response with high confidence.

A refractory liver metastatic solid pseudopapillary neoplasm pancreas harbored CTNNB1 mutation showed good response to celecoxib: A case report.

Solid pseudopapillary neoplasm (SPN) of the pancreas is rare relatively low-grade malignant neoplasm and metastasis rarely. Surgical resection is the primary treatment option for primary and metastatic lesions of SPN, and chemotherapy is often ineffective in non-operable SPNs. SPNs are characterized by the presence of somatic CTNNB1 exon 3 mutations, leading to the activation of Wnt/ß-catenin/Cox-2 signal pathway. Here, we firstly report that a refractory liver metastatic pancreatic SPN patient after the failure of multi-line chemotherapies benefited from the Cox-2 selective inhibitor (Celecoxib) based on CTNNB1 D32V mutation detected by next-generation sequencing (NGS), achieving a more than 22-month progression-free survival without any adverse events. Our case provides a potential treatment option for liver metastatic SPN patients with CTNNB1 mutations and highlights the application of NGS for the better treatment decision making.

Uterine perivascular epithelioid tumors (PEComas) with lung metastasis showed good responses to mTOR and VEGFR inhibitors: A case report.

Perivascular epithelioid cell tumors (PEComas) are extremely rare mesenchymal neoplasms for which the uterus is the most common site. The prognosis of malignant PEComa is poor as it is characterized by resistance to classical chemotherapies. Both mTOR inhibitors and VEGFR inhibitors exhibited clinical utility in treating malignant PEComas, but the combination of these two regimens has rarely been reported. In the present case, a uterine PEComa patient developed lung and bone metastases after the failure of chemotherapies and derived benefit from the combination regimen of an mTOR inhibitor (everolimus) and a VEGFR inhibitor (apatinib), achieving a 15-month progression-free survival. Targeted NGS revealed TP53 and TSC2 mutations in the patient's primary uterine tumors and plasma ctDNA at disease progression. Plasma ctDNA clearance was consistent with a radiologic partial response determined by RECIST 1.1 and a reduction of neuron-specific enolase (NSE) and cancer antigen 125 (CA125) levels. Thus, we provided clinical evidence supporting the administration of combined therapy of mTOR and VEGFR inhibitors to metastatic uterine PEComa patients and highlighted the application of serial plasma ctDNA profiling for dynamic disease monitoring.

Tumor Heterogeneity and Drug Resistance Mutations Using ctDNA in Metastatic EGFR Mutation-Positive Lung Adenocarcinoma: A Case Report.

For advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, EGFR tyrosine kinase inhibitors (TKIs) have been approved as the standard therapy and shown clinical benefits. However, the emergence of drug resistance is inevitable. Tumor heterogeneity was often observed by imaging method to evaluate the progression of primary and metastatic lesions. Tissue biopsy was also unlikely to accurately capture the complete genomic landscape from a single tissue sample. Recently, genomic characterization of circulating tumor DNA (ctDNA) offer an opportunity to reveal the clonal dynamics throughout the course of a patient's illness and provide comprehensive genomic landscape of tumors to assess tumor heterogeneity. Here, we reported a lung adenocarcinoma (LADC) with EGFR mutations who was treated with sequential EGFR TKIs. The CT image of the patient's different lesions suggested that dynamic change of tumor heterogeneity had occurred. Targeted next-generation sequencing (NGS) analysis of ctDNA revealed dynamic changes of mutational profiles between the primary and metastatic tumors to discover tumor evolution to guide treatment decision-making.

NGS-Based ctDNA Profiling After the Resistance of Second-Line Osimertinib for Patient with EGFR-Mutated Pulmonary Adenocarcinoma.

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is effective in EGFR T790M positive non-small-cell lung cancer (NSCLC). Despite the efficacy of osimertinib, patients inevitably develop resistance and the mechanisms of osimertinib resistance are heterogeneous. Here, we report that a lung adenocarcinoma patient with EGFR L858R mutation who was treated with second-line osimertinib therapy acquired multiple resistance to osimertinib by the non-invasive circulating tumor DNA (ctDNA) genotyping. This case provides the possible mechanisms of osimertinib resistance that occur during the disease progression and supports the longitudinal monitoring of ctDNA for the detection of novel acquired resistance and tumor heterogeneity.

Efficient Everolimus Treatment for Metastatic Castration Resistant Prostate Cancer with AKT1 Mutation: A Case Report.

Metastatic castration resistant prostate cancer (mCRPC), the advanced stage of prostate cancer (PCa), develops resistance to first line androgen deprivation therapy (ADT). Aberrant androgen receptor (AR) and PI3K-Akt-mTOR signaling pathway are responsible for the development and progression of mCRPC. We herein describe a case of a 64-year-old male mCRPC patient with somatic AKT1 and AR mutations. The patient, who had been heavily pretreated by ADT and AR inhibitors, showed stable disease progression when he received everolimus, an mTOR inhibitor. The PSA level dropped drastically from 1493.0 ng/mL to 237.6 ng/mL, after 3 months of treatment. The overall survival (OS) was 43 months, of which the progression-free survival (PFS) with everolimus treatment was 7 months. The administration of mTOR inhibitor, everolimus, could achieve good clinical responses along with prolonging PFS for mCRPC patients harboring AKT1 mutations. Technology in precision medicine, such as targeted next-generation sequencing (NGS) of cancer-relevant genes, has promising function in personalized therapy.

Favorable Response to Olaparib in a Patient with Cancer of Unknown Primary Carrying a Germline BRCA1 R71K Mutation.

The treatment options for cancer of unknown primary (CUP) are challenging due to the lack of knowledge about the primary sites, often resulting in a poor prognosis. The emerging next-generation sequencing (NGS) technique has provided a reliable approach to facilitate tumor primary site prediction and targetable gene alteration identification for CUP patients. In this report, we described a 63-year-old female patient who experienced recurrent CUP. NGS-based genetic profiling results revealed a pathogenic germline BRCA1 R71K mutation. Accordingly, the patient received the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib treatment and demonstrated a favorable response to this treatment. Our case suggests that NGS holds great promise for providing improved diagnosis and treatment options to patients with CUP, warranting further clinical investigation.