RESUMO
Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent TOP as part of Advanced Medical Care B with approval from the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were carried out in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those 30 transcripts, 6 had treatment implications and 4 had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647).
Assuntos
Genômica , Neoplasias , Humanos , Japão , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de PrecisãoRESUMO
BACKGROUND: Precision medicine with gene panel testing based on next-generation sequencing for patients with cancer is being used increasingly in clinical practice. HER2, which encodes the human epidermal growth factor receptor 2 (HER2), is a potentially important driver gene. However, therapeutic strategies aimed at mutations in the HER2 extracellular domain have not been clarified. We therefore investigated the effect of EGFR co-targeted therapy with HER2 on patient-derived cancer models with the HER2 extracellular domain mutation E401G, based on our previous findings that this mutation has an epidermal growth factor receptor (EGFR)-mediated activation mechanism. METHODS: We generated a xenograft (PDX) and a cancer tissue-originated spheroid (CTOS) from a patient's cancer containing an amplified HER2 E401G mutation. With these platforms, we compared the efficacy of afatinib, a tyrosine kinase inhibitor having anti-HER2 and anti-EGFR activity, with two other therapeutic options: lapatinib, which has similar properties but weaker EGFR inhibition, and trastuzumab plus pertuzumab, for which evidence exists of treatment efficacy against cancers with wild-type HER2 amplification. Similar experiments were also performed with H2170, a cell line with wild-type HER2 amplification, to contrast the characteristics of these drug's efficacies against HER2 E401G. RESULTS: We confirmed that PDX and CTOS retained morphological and immunohistochemical characteristics and HER2 gene profiles of the original tumor. In both PDX and CTOS, afatinib reduced tumor size more than lapatinib or trastuzumab plus pertuzumab. In addition, afatinib treatment resulted in a statistically significant reduction in HER2 copy number at the end of treatment. On the other hand, in H2170 xenografts with wild-type HER2 amplification, trastuzumab plus pertuzumab was most effective. CONCLUSIONS: Afatinib, a dual inhibitor of HER2 and EGFR, showed a promising effect on cancers with amplified HER2 E401G, which have an EGFR-mediated activation mechanism. Analysis of the activation mechanisms of mutations and development of therapeutic strategies based on those mechanisms are critical in precision medicine for cancer patients.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Afatinib , Lapatinib , Antineoplásicos/uso terapêutico , Receptor ErbB-2/metabolismo , Trastuzumab , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Mutação , Linhagem Celular Tumoral , Receptores ErbB/genéticaRESUMO
BACKGROUND: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. LAY SUMMARY: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.
Assuntos
Antineoplásicos , Neuroblastoma , Adulto , Antineoplásicos/efeitos adversos , Criança , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Ftalazinas/efeitos adversos , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Poli(ADP-Ribose) PolimerasesRESUMO
We here present a 33-year-old woman who was referred to our hospital with a complaint of back pain and was found to have elevated IgG and hypercalcemia, as well as osteolytic lesions of pelvis and spines. 18F-FDG-PET/CT scan revealed numerous uptakes in the bones. An examination of the bone marrow revealed increased plasma cells (10.2%). Despite clinical similarities to multiple myeloma, any evidence of plasma cell clonal proliferation, including serum M-protein and light chain restriction, was not found. A reexamination of the bone marrow with a biopsy revealed the proliferation of abnormal cells with chromogranin A and synaptophysin expression but no expression of hematopoietic and epithelial cell markers. Based on these results together with extra-adrenal lesions, a diagnosis of malignant paraganglioma was made. Malignant paraganglioma is known to frequently cause bone metastasis and skeletal related events, whose clinical manifestations are similar to those of multiple myeloma. Since patients with osteolytic lesions, hypercalcemia, and hypergammaglobulinemia are likely to be referred to hematologists, malignant paraganglioma should be considered as a differential diagnosis.
Assuntos
Hipercalcemia , Mieloma Múltiplo , Paraganglioma , Feminino , Humanos , Adulto , Mieloma Múltiplo/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Fluordesoxiglucose F18/metabolismo , Paraganglioma/diagnósticoRESUMO
Cowden syndrome is a rare autosomal dominant disorder characterized by multiple hamartomas in various tissues, including the skin, mucous membranes, and gastrointestinal tract. Germline mutations of the PTEN tumor suppressor gene are responsible for Cowden syndrome. Cowden syndrome is associated with an increased risk of breast, thyroid, renal and uterine cancers; however, ovarian cancer rarely develops in women with Cowden syndrome, although somatic PTEN mutation often occurs in some types of ovarian carcinomas. Herein we report the first case of ovarian carcinosarcoma that developed in a woman with Cowden syndrome. A 55-year-old woman with a history of breast cancer, thyroid goiter, and palatal papillomatosis presented with pelvic distention. CT scan revealed a pelvic tumor suggesting ovarian cancer. She underwent a total abdominal hysterectomy, a bilateral salpingo-oophorectomy, and an omentectomy, but the surgical cytoreduction was suboptima( l >2 cm residual disease). Pathological examination showed a mixed tumor composed of high-grade carcinoma and heterologous sarcoma. Immunohistochemically, tumor cells were positive for p53. She was diagnosed with stage â ¢C ovarian carcinosarcoma. Genetic testing detected a PTEN variant, confirming the diagnosis of Cowden syndrome. She received paclitaxel/ carboplatin chemotherapy. However, no response was observed and she died of disease 2 months postoperatively.
Assuntos
Carcinossarcoma , Síndrome do Hamartoma Múltiplo , Neoplasias Ovarianas , Carcinossarcoma/complicações , Carcinossarcoma/cirurgia , Feminino , Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/cirurgia , Humanos , Histerectomia , Pessoa de Meia-Idade , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgiaRESUMO
We report on a woman with aggressive estrogen receptor-positive, KRAS-mutated ovarian cancer who achieved a remarkable response to combination therapy with the MEK inhibitor (trametinib) and the aromatase inhibitor (letrozole), even though the disease had failed to respond to a combination of a PI3K inhibitor and different MEK inhibitor, as well as to trametinib and the estrogen modulator, tamoxifen, and to letrozole by itself. The mechanism of action for exceptional response was elucidated by in vitro experiments that demonstrated that the fact that tamoxifen can have an agonistic effect in addition to antagonist activity, whereas letrozole results only in estrogen depletion was crucial to the response achieved when letrozole was combined with an MEK inhibitor. Our current observations indicate that subtle variations in mechanisms of action of outwardly similar regimens may have a major impact on outcome and that such translational knowledge is critical for optimizing a precision medicine strategy. KEY POINTS: This report describes the remarkable response of a patient with KRAS-mutated, estrogen receptor-positive low-grade serous ovarian cancer treated with trametinib (MEK inhibitor) and letrozole (aromatase inhibitor), despite prior progression on similar agents including tamoxifen (estrogen modulator). In vitro investigation revealed that tamoxifen can have agonistic in addition to antagonistic effects, which could be the reason for the patient not responding to the combination of trametinib and tamoxifen. The current observations suggest that drugs with different mechanisms of action targeting the same receptor may have markedly different anticancer activity when used in combinations.
Assuntos
Neoplasias Ovarianas , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Feminino , Humanos , Nitrilas , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Triazóis/farmacologia , Triazóis/uso terapêuticoRESUMO
BACKGROUND: The clinical utility of plasma cell-free DNA in precision cancer medicine has not been established. A pilot study was conducted to investigate the clinical utility of comprehensive genomic profiling by liquid biopsy in a Japanese population. METHODS: In this PROFILE study, 102 patients with advanced solid tumors who showed progression with standard systemic therapy underwent liquid biopsy between August 2017 and February 2020. Liquid biopsy was performed using Guardant360. RESULTS: Of the 102 patients, 56 were women, and the median age was 65 years. Regarding the types of cancer, 31 were hepatobiliary and pancreatic cancer, 17 were gastrointestinal cancer, and 13 were breast cancer. Frequently altered genes were TP53 (53.9%, 46/102), KRAS (25.5%, 26/102), PIK3CA (19.6%, 20/102), and EGFR (17.6%, 18/102). At least one genetic aberration was detected in 92 patients (90.2%). Actionable mutation was discovered in 88 patients (86.3%), and 67 patients (65.7%) were clinical trial candidates. Of the 102 patients, 22 (21.6%) were able to receive biomarker-matched therapy. Their best responses were as follows: 1 complete response, 3 partial responses, 7 stable diseases, and 11 progressive diseases. Additionally, the treated patients were divided on the basis of matching scores (≥ 50% vs. < 50%). The patients were divided into high and low groups. The high group had a higher disease control rate (DCR) of 75% compared with 20% in the low group (P = 0.010). CONCLUSIONS: The results indicate that liquid biopsy is useful for identifying actionable mutations associated with the clinical response of selected patients.
Assuntos
Ácidos Nucleicos Livres , Neoplasias , Idoso , Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Japão , Masculino , Mutação , Neoplasias/genética , Projetos PilotoRESUMO
BACKGROUND: To promote precision oncology in clinical practice, the Japanese Society of Medical Oncology, the Japanese Society of Clinical Oncology, and the Japanese Cancer Association, jointly published "Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment" in 2017. Since new information on cancer genomic medicine has emerged since the 1st edition of the guidance was released, including reimbursement for NGS-based multiplex gene panel tests in 2019, the guidance revision was made. METHODS: A working group was organized with 33 researchers from cancer genomic medicine designated core hospitals and other academic institutions. For an impartial evaluation of the draft version, eight committee members from each society conducted an external evaluation. Public comments were also made on the draft. The finalized Japanese version was published on the websites of the three societies in March 2020. RESULTS: The revised edition consists of two parts: an explanation of the cancer genomic profiling test (General Discussion) and clinical questions (CQs) that are of concern in clinical practice. Particularly, patient selection should be based on the expectation that the patient's post-test general condition and organ function will be able to tolerate drug therapy, and the optimal timing of test should be considered in consideration of subsequent treatment plans, not limited to treatment lines. CONCLUSION: We expect that the revised version will be used by healthcare professionals and will also need to be continually reviewed in line with future developments in cancer genome medicine.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias , Humanos , Oncologia , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Seleção de Pacientes , Medicina de PrecisãoRESUMO
The year 2019 was considered to be the first year of cancer genome medicine in Japan, with three gene-panel tests using next-generation sequencing (NGS) techniques being introduced into clinical practice. Among the three tests, the Oncomine CDx Target test was approved under the category of regular molecular testing for lung cancer, which meant that this test could be used to select patients for molecularly targeted drugs. Conversely, the other two tests, NCC OncoPanel and FoundationOne CDx, were assigned to be used under the National Cancer Genome Medicine Network, and implementation was restricted to patients for whom standard treatment was completed or expected to be completed. These NGS tests can detect a series of genetic alterations in individual tumors, which further promotes the development of therapeutic agents and elucidates molecular pathways. The NGS tests require appropriate tissue size and tumor cell content, which can be accessed only by pathologists. In this report, we review the current reimbursement schema in our national healthcare policy and the requirements of the specimens for NGS testing based on the recently published 'Guidance of Gene-panel Testing Using Next-Generation Sequencers for Lung Cancer', by the Japanese Society of Lung Cancer.
Assuntos
Testes Genéticos , Neoplasias Pulmonares , Patologia Molecular/métodos , DNA de Neoplasias , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , MutaçãoRESUMO
BACKGROUND: FoundationOne CDx is a cancer genome profiling test that has already been approved by the FDA, but its clinical utility in Japanese patients is unknown. In this study, we examined the clinical utility of FoundationOne CDx. METHODS: 46 samples from 43 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne CDx between September 2018-January 2019. RESULTS: The median age of 43 patients was 63 years(ranged 18 to 82 years), and among them 24 were males and 19 females. Major cancer types were hepato-biliary and pancreatic(8 cases)and other digestive organs(8 cases). All 27 cases in which genome cancer board had been completed by January 17, 2019 were analyzable, and the number of detected gene mutations(except VUS)was an average of 4.3(ranged 0 to 14)per case. Of the 27 cases, one or more mutations were found in 26 cases(96%), and in all such 26 cases actionable mutations with candidates for therapeutic agents were found. In 4(15%)of them, the treatment corresponding to the gene mutation was performed. Among the cases in which target disease matched and clinical trials of the drug were being conducted in Japan, only one case participated in the trial. The most common reason for not participating in the trial was disease deterioration and PS reduction (33%). CONCLUSIONS: The FoundationOne CDx test showed that it can detect gene mutations in various cancer types in Japanese patients.
Assuntos
Neoplasias , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mutação , Adulto JovemRESUMO
BACKGROUND: Patients with rare tumors may lack approved treatments and clinical trial access. Although each rare tumor is uncommon, cumulatively they account for approximately 25% of cancers. We recently initiated a Rare Tumor Clinic that emphasized a precision medicine strategy. MATERIALS AND METHODS: We investigated the first 40 patients presenting at the Rare Tumor Clinic. Next-generation sequencing (NGS) of tissue and plasma-derived, circulating-tumor DNA (ctDNA), and protein markers were assessed. RESULTS: Median age was 58 years (range, 31-78 years); 70% (28/40) were women; median number of previous systemic therapies was 2 (range 0-7). The most common diagnoses were sarcoma (n = 7) for solid tumors and Erdheim-Chester disease (n = 5) for hematologic malignancies. Twenty distinct diagnoses were seen. Examples of ultrarare tumors included ameloblastoma, yolk sac liver tumor, ampullary cancer, and Castleman's disease. Altogether, 32 of 33 patients (97%) with tissue NGS and 15 of 33 (45%) with ctDNA sequencing harbored ≥1 alteration. Overall, 92.5% of patients (37/40) had ≥1 actionable target based on either genomic (n = 32) or protein (n = 27) markers. In total, 52.5% (21/40) received matched therapy; 52.4% (11/21) achieved stable disease (SD) ≥6 months (n = 3), partial remission (PR; n = 6), or complete remission (CR; n = 2). Matched therapy resulted in significantly longer progression-free survival compared with last prior unmatched therapy (hazard ratio 0.26, 95% confidence interval 0.10-0.71, p = .008). CONCLUSION: Identifying genomic and protein markers in patients with rare/ultrarare tumors was feasible. When therapies were matched, >50% of patients attained SD ≥6 months, PR, or CR. Further precision medicine clinical investigations focusing on rare and ultrarare tumors are urgently needed. IMPLICATIONS FOR PRACTICE: Although rare tumors are infrequent by definition, when all subtypes of rare cancers are combined, they account for approximately 25% of adult malignancies. However, patients with rare tumors may lack approved treatments and clinical trial access. This paper describes an institutional a Rare Tumor Clinic focused on a precision medicine strategy. Performing genomics and protein analyses was feasible amongst patients with rare cancers. Over 50% of patients attained SD ≥6 months, PR, or CR when they received matched therapy (genomically targeted and/or immunotherapy). Further studies investigating the efficacy of the precision therapy approach among rare tumors are warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Biomarcadores Tumorais , Terapia Combinada , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias/patologia , Medicina de Precisão , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood-derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC. MATERIALS AND METHODS: We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild-type allele fraction was calculated. RESULTS: All patients (100%) had somatic alterations (median = 3 alterations/patient [range, 1-8]); median mutant allele fraction, 0.29% (range, 0.1%-37.77%). Mutations were identified in several genes: TP53 (57% of patients), CTNNB1 (29%), PTEN (7%), CDKN2A (7%), ARID1A (7%), and MET (7%); amplifications, in CDK6 (14%), EGFR (14%), MYC (14%), BRAF (7%), RAF1 (7%), FGFR1 (7%), CCNE1 (7%), PIK3CA (7%), and ERBB2/HER2 (7%). Eleven patients (79%) had ≥1 theoretically actionable alteration. No two patients had identical genomic portfolios, suggesting the need for customized treatment. A patient with a CDKN2A-inactivating and a CTNNB1-activating mutation received matched treatment: palbociclib (CDK4/6 inhibitor) and celecoxib (COX-2/Wnt inhibitor); des-gamma-carboxy prothrombin level decreased by 84% at 2 months (1,410 to 242 ng/mL [normal: ≤7.4 ng/mL]; alpha fetoprotein [AFP] low at baseline). A patient with a PTEN-inactivating and a MET-activating mutation (an effect suggested by in silico molecular dynamic simulations) received sirolimus (mechanistic target of rapamycin inhibitor) and cabozantinib (MET inhibitor); AFP declined by 63% (8,320 to 3,045 ng/mL [normal: 0-15 ng/mL]). CONCLUSION: ctDNA derived from noninvasive blood tests can provide exploitable genomic profiles in patients with HCC. IMPLICATIONS FOR PRACTICE: This study reports that blood-derived circulating tumor DNA can provide therapeutically exploitable genomic profiles in hepatocellular cancer, a malignancy that is known to be difficult to biopsy.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is a leading cause of cancer-related death worldwide. It is highly refractory to most systemic therapies. Recently, significant progress has been made in uncovering genomic alterations in HCC, including potentially targetable aberrations. The most common molecular anomalies in this malignancy are mutations in the TERT promoter, TP53, CTNNB1, AXIN1, ARID1A, CDKN2A and CCND1 genes. PTEN loss at the protein level is also frequent. Genomic portfolios stratify by risk factors as follows: (i) CTNNB1 with alcoholic cirrhosis; and (ii) TP53 with hepatitis B virus-induced cirrhosis. Activating mutations in CTNNB1 and inactivating mutations in AXIN1 both activate WNT signaling. Alterations in this pathway, as well as in TP53 and the cell cycle machinery, and in the PI3K/Akt/mTor axis (the latter activated in the presence of PTEN loss), as well as aberrant angiogenesis and epigenetic anomalies, appear to be major events in HCC. Many of these abnormalities may be pharmacologically tractable. Immunotherapy with checkpoint inhibitors is also emerging as an important treatment option. Indeed, 82% of patients express PD-L1 (immunohistochemistry) and response rates to anti-PD-1 treatment are about 19%, and include about 5% complete remissions as well as durable benefit in some patients. Biomarker-matched trials are still limited in this disease, and many of the genomic alterations in HCC remain challenging to target. Future studies may require combination regimens that include both immunotherapies and molecularly matched targeted treatments.
Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Animais , Biomarcadores Tumorais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Regulação Neoplásica da Expressão Gênica , Variação Genética , Genômica/métodos , Humanos , Imunoterapia/métodos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Transdução de SinaisAssuntos
Coriocarcinoma/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Adulto , Coriocarcinoma/patologia , Coriocarcinoma/cirurgia , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios XRESUMO
Metastatic basal cell carcinoma may be treated with hedgehog pathway inhibitors, including vismodegib and sonidegib. However, patients can demonstrate resistance to these agents. We describe a man with metastatic basal cell carcinoma who did not respond well to vismodegib and sonidegib. Next generation sequencing of his metastatic liver tumor demonstrated a high tumor mutational burden (103 mutations per megabase) and the genomic amplification of PD-L1, both of which are features that predict response to anti-PD1/PD-L1 immunotherapy. Treatment with nivolumab, an anti-PD1 checkpoint inhibitor, resulted in near complete remission. Yet, he developed new primary cutaneous basal cell carcinomas while receiving immunotherapy and while his metastatic disease showed an ongoing response. His new superficial skin cancer had a lower tumor mutational burden (45 mutations per megabase) than the metastatic disease. Since immunotherapy response rates are higher in patients with more genomically complex tumors, our observations suggest that, in contrast with the premise of earlier treatment is better, which holds true for targeted and cytotoxic therapies, immunotherapy may be better suited to more advanced disease.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/tratamento farmacológico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biópsia , Carcinoma Basocelular/genética , Resistencia a Medicamentos Antineoplásicos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Nivolumabe , Retratamento , Pele/patologia , Neoplasias Cutâneas/genética , Resultado do TratamentoRESUMO
Antiangiogenesis therapy has become a vital part of the armamentarium against cancer. Hypertension is a dose-limiting toxicity for VEGF inhibitors. Thus, there is a pressing need to address the associated adverse events so these agents can be better used. The hypertension may be mediated by reduced NO bioavailability resulting from VEGF inhibition. We proposed that the hypertension may be prevented by coadministration with endostatin (ES), an endogenous angiogenesis inhibitor with antitumor effects shown to increase endothelial NO production in vitro. We determined that Fc-conjugated ES promoted NO production in endothelial and smooth muscle cells. ES also lowered blood pressure in normotensive mice and prevented hypertension induced by anti-VEGF antibodies. This effect was associated with higher circulating nitrate levels and was absent in eNOS-knockout mice, implicating a NO-mediated mechanism. Retrospective study of patients treated with ES in a clinical trial revealed a small but significant reduction in blood pressure, suggesting that the findings may translate to the clinic. Coadministration of ES with VEGF inhibitors may offer a unique strategy to prevent drug-related hypertension and enhance antiangiogenic tumor suppression.
Assuntos
Pressão Sanguínea/fisiologia , Endostatinas/metabolismo , Hipertensão/metabolismo , Hipertensão/prevenção & controle , Óxido Nítrico/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Animais , Anticorpos/química , Ensaios Clínicos Fase II como Assunto , Feminino , Coração/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/prevenção & controleRESUMO
The heart is formed from cardiogenic progenitors expressing the transcription factors Nkx2-5 and Isl1 (refs 1 and 2). These multipotent progenitors give rise to cardiomyocyte, smooth muscle and endothelial cells, the major lineages of the mature heart. Here we identify a novel cardiogenic precursor marked by expression of the transcription factor Wt1 and located within the epicardium-an epithelial sheet overlying the heart. During normal murine heart development, a subset of these Wt1(+) precursors differentiated into fully functional cardiomyocytes. Wt1(+) proepicardial cells arose from progenitors that express Nkx2-5 and Isl1, suggesting that they share a developmental origin with multipotent Nkx2-5(+) and Isl1(+) progenitors. These results identify Wt1(+) epicardial cells as previously unrecognized cardiomyocyte progenitors, and lay the foundation for future efforts to harness the cardiogenic potential of these progenitors for cardiac regeneration and repair.
Assuntos
Linhagem da Célula , Coração/embriologia , Miócitos Cardíacos/citologia , Pericárdio/citologia , Células-Tronco/citologia , Animais , Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Miócitos Cardíacos/metabolismo , Pericárdio/embriologia , Pericárdio/metabolismo , Células-Tronco/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas WT1/genética , Proteínas WT1/metabolismoRESUMO
BACKGROUND: The simplified Pulmonary Embolism Severity Index (sPESI) has limitations when evaluating acute pulmonary embolism (PE) in patients with concurrent malignancy. Despite its utility in predicting outcomes among cancer patients, the role of the Eastern Cooperative Oncology Group Performance Status (ECOG PS) in acute PE remains underexplored. This study aims to assess the prognostic significance of ECOG PS ≥ 3 on short- and long-term mortality in acute PE with malignancy, correlating it with the sPESI. METHODS AND RESULTS: We retrospectively analyzed 44 hemodynamically stable acute PE patients with unresectable or metastatic malignancies ineligible for curative treatment at Kameda Medical Center, a tertiary medical facility in Japan, from April 1, 2019, to March 2, 2023. Of these patients, 16 (36.4%) had ECOG PS ≥ 3. No 30-day mortality occurred in patients with ECOG PS ≤ 2, compared to 18.8% in those with ECOG PS ≥ 3 (p = 0.04). Groups were similar in the sPESI scores, hospital-onset PE proportion, and initial treatments. Post PE diagnosis, 92.9% of ECOG PS ≤ 2 patients and 50% of ECOG PS ≥ 3 patients received chemotherapy (p = 0.002). Cox regression analysis revealed ECOG PS ≥ 3 was independently associated with increased overall survival hazard (adjusted HR = 4.0; P = 0.002). CONCLUSIONS: ECOG PS ≥ 3 suggests a poorer short-term prognosis and independently predicts a worse long-term prognosis in hemodynamically stable acute PE patients with advanced malignancies.
RESUMO
The serine-threonine protein kinase B-RAF (BRAF) fusions are rarely observed in non-small cell lung cancer (NSCLC) accounting for less than 1%, and therapeutic evidence for molecular-targeted drugs is lacking, unlike for BRAF V600E mutation by RAF and MEK inhibitors. A 75-year-old female patient with no smoking history and mild renal dysfunction developed recurrent lung adenocarcinoma and was initially treated with pembrolizumab immunotherapy followed by chemotherapy using docetaxel showing a certain efficacy but the disease finally progressed. Comprehensive genome profiling showed a novel SLC44A1-BRAF fusion and the tumor progression was controlled with the MEK inhibitor trametinib. Because of the rarity of NSCLC with BRAF fusion, the description of this case would be helpful for the treatment strategy for such tumors.