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1.
Anticancer Res ; 42(4): 2017-2022, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35347023

RESUMO

BACKGROUND/AIM: To assess response rates and survival in patients with recurrent platinum-sensitive epithelial ovarian cancer (EOC) who received PARP inhibitor (PARP-i) maintenance and who subsequently underwent salvage chemotherapy for disease progression after PARPi. PATIENTS AND METHODS: This retrospective investigation analyzed 103 patients who were treated in five Italian Gynecologic centers. The PARPi used was olaparib in 46 patients, niraparib in 55, and rucaparib in 2. The interval time between the last cycle of pre- PARPi platinum-based chemotherapy and the diagnosis of progression during PARPi maintenance was defined as platinum-free interval (PFI). RESULTS: Of the 28 patients with PFI <6 months, 23 received chemotherapy (non-platinum single agent, 20; trabectedin + pegylated liposomal doxorubicin (PLD), 3). Forty-two of the 43 patients with PFI 6-12 months underwent chemotherapy (platinum-based chemotherapy,11; trabectedin + PLD, 10; non platinum-single agent, 21). Thirty-one of the 32 patients with PFI >12 months received chemotherapy (platinum-based chemotherapy, 23; trabectedin + PLD, 3; non platinum - single agent, 5). An objective response was found in 13.0%, 26.2% and 41.9 % of the patients with PFI <6 months, 6-12 months, and >12 months (p= 0.03), respectively, and the corresponding median survivals after PARPi were 8.9 months, 17.5 months and 24.1 months (p= 0.002), respectively. CONCLUSION: Before the PARPi era, some randomized trials on platinum rechallenge in patients with recurrent EOC after more than 6 months from the last platinum cycle have shown response rates ranging from 47.2% to 66%. Response rates to chemotherapy for progression after PARPi appear to be lower than those expected according to PFI.


Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/etiologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Estudos Retrospectivos
2.
BMC Cancer ; 22(1): 349, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361149

RESUMO

BACKGROUND: The prognosis of patients with relapsed Ewing sarcoma is poor. In this study, we aimed to pooled-analyze the efficacy and safety of the combination of irinotecan and temozolomide in treating patients with relapsed Ewing sarcoma. METHODS: PubMed, Cochrane CENTRAL, Web of Science, and EMBASE were systematically searched on September 27, 2021. The primary outcomes were rates of objective response and disease control, and the secondary outcomes were toxicities. RESULTS: Six retrospective studies with 184 patients were enrolled in the analysis. The median age ranged from 14 to 21. The integrated rates were 44% (95% confidence interval [CI] 31-58) for objective response and 66% (55-77) for disease control. Grade 3-4 neutropenia, thrombocytopenia, and diarrhea occurred in 8% (3-16), 7% (3-11), and 8% (5-10) of chemotherapeutic cycles, respectively. 18% (7-32) and 6% (2-11) of patients suffered grade 3-4 neutropenia and thrombocytopenia after irinotecan plus temozolomide treatment. CONCLUSION: Irinotecan plus temozolomide combination chemotherapy showed antitumor activity and an acceptable safety profile in patients with relapsed Ewing sarcoma. More future prospective studies are needed to confirm the retrospective results.


Assuntos
Neutropenia , Sarcoma de Ewing , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina , Dacarbazina/efeitos adversos , Humanos , Irinotecano/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Sarcoma de Ewing/tratamento farmacológico , Temozolomida/uso terapêutico
3.
Head Neck ; 44(9): 2030-2039, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35915863

RESUMO

BACKGROUND: Optimal treatment strategies for patients with stage IVa-b hypopharyngeal squamous cell carcinoma (HSCC) remain controversial. This study aimed to examine the high-risk factors of postoperative tumor recurrence after surgical resection of HSCC and devise individualized postoperative adjuvant treatment (POAT). METHODS: Overall, 218 patients with stage IVa-b HSCC who received surgery as initial treatment and with negative surgical margins were evaluated. Independent risk factors of recurrence were identified, and survival outcomes were compared according to recurrence risk and POAT use. RESULTS: POAT significantly improved recurrence-free survival (RFS) and overall survival (OS) only in the high-risk patients (p = 0.003 and 0.018, respectively). Compared with postoperative radiotherapy alone, postoperative chemoradiotherapy (pCRT) achieved significantly better RFS (p = 0.035) and OS (p = 0.048). CONCLUSIONS: POATs are recommended for high-risk patients with stage Iva-b HSCC, with pCRT achieving superior outcomes. Regular re-examination after tumor resection is sufficient for low-risk patients.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Hipofaríngeas , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Hipofaríngeas/patologia , Melanoma , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Medição de Risco , Neoplasias Cutâneas , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia
4.
Eur Rev Med Pharmacol Sci ; 26(14): 5008-5013, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35916797

RESUMO

BACKGROUND: Glioblastoma (GBM) is a highly lethal disease despite integrated treatment comprising radiotherapy plus concomitant and adjuvant temozolomide, with a median overall survival of less than 15 months. For recurrent glioblastoma, there is yet no standard therapy, considering that Bevacizumab have failed to improve overall survival (OS) while regorafenib had a little benefit over standard chemotherapy. In addition, the disease control rate is almost exclusively stability, with a poor objective response rate. CASE REPORT: Here we present a case of rapid response to regorafenib in early glioblastoma progression at the end of adjuvant radiotherapy: after a single cycle of regorafenib the patient observed an impressive improvement in clinical condition, disappearance of headaches and a clear reduction of neoplastic tissue in MRI. A brief review about new radiological patterns in Magnetic Resonance Imaging (MRI) related to the introduction in clinical practice of antiangiogenic drugs and tyrosine kinase inhibitors has also been carried out. CONCLUSIONS: Regorafenib was certainly a first turning point in the second-line treatment of GBM, showing longer response rates and mostly disease stability than bevacizumab. A switch-maintenance strategy with tyrosine kinase inhibitors may represent a valid second-line therapeutic option.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/diagnóstico por imagem , Glioblastoma/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Compostos de Fenilureia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas
5.
Khirurgiia (Mosk) ; (8): 25-30, 2022.
Artigo em Russo | MEDLINE | ID: mdl-35920219

RESUMO

OBJECTIVE: To evaluate postoperative outcomes in patients with chest wall metastases. MATERIAL AND METHODS: We analyzed 40 patients who underwent surgery for chest wall metastatic lesions. Fourteen (35%) patients had sternal lesion, 26 (65%) ones - rib metastases. We used implants for chest wall defect closure in 15 (37.5%) patients. Chest wall repair with autologous tissues was performed in 19 (47.5%) patients. RESULTS: Median survival was 17 months. Most patients (n=30, 75%) showed improvement in the quality of life according to Karnofsky and EGOG scale after surgery. Continued tumor growth occurred in 4 (10%) patients within 8-16 months after surgery. There were 2 patients who suffered from tumor recurrence accompanied by other metastatic foci (progression). Complications were diagnosed in 5 (12.5%) patients. Tactical errors were identified in 4 (10%) patients and they were associated with progression of cancer in the form of new metastatic foci within 6 months after surgery. CONCLUSION: Active surgical approach for bone metastases in patients with favorable cancer-related prognosis can improve quality of life and survival at least in case of solitary lesions. New program for treatment strategy selection based on prognosis of life expectancy and algorithms of surgical treatment will reduce the risk of erroneous management and increase its effectiveness.


Assuntos
Neoplasias Ósseas , Parede Torácica , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/patologia , Neoplasias Ósseas/cirurgia , Humanos , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Qualidade de Vida , Parede Torácica/patologia , Parede Torácica/cirurgia
6.
Nat Commun ; 13(1): 4578, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931688

RESUMO

Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, including epithelial ovarian cancer. Patients often experience several response-relapse events, until tumors become resistant and life expectancy drops to 12-15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, leaving patients with limited options. Serine biosynthesis has been linked to cancer growth and poor prognosis in various cancer types, however its role in platinum-resistant ovarian cancer is not known. Here, we show that a subgroup of resistant tumors decreases phosphoglycerate dehydrogenase (PHGDH) expression at relapse after platinum-based chemotherapy. Mechanistically, we observe that this phenomenon is accompanied by a specific oxidized nicotinamide adenine dinucleotide (NAD+) regenerating phenotype, which helps tumor cells in sustaining Poly (ADP-ribose) polymerase (PARP) activity under platinum treatment. Our findings reveal metabolic vulnerabilities with clinical implications for a subset of platinum resistant ovarian cancers.


Assuntos
Neoplasias Ovarianas , Platina , Carcinoma Epitelial do Ovário/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Platina/farmacologia , Platina/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/farmacologia , Serina/farmacologia
7.
Cell Death Dis ; 13(8): 678, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931701

RESUMO

Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy with limited treatment options for recurrent or metastatic disease. Due to chemotherapy resistance and lack of targeted therapeutic approaches, current treatment options for the localized disease are limited to surgery and radiation, which fails to prevent locoregional recurrences and distant metastases in over 50% of patients. Approximately 20% of patients with ACC carry NOTCH-activating mutations that are associated with a distinct phenotype, aggressive disease, and poor prognosis. Given the role of NOTCH signaling in regulating tumor cell behavior, NOTCH inhibitors represent an attractive potential therapeutic strategy for this subset of ACC. AL101 (osugacestat) is a potent γ-secretase inhibitor that prevents activation of all four NOTCH receptors. While this investigational new drug has demonstrated antineoplastic activity in several preclinical cancer models and in patients with advanced solid malignancies, we are the first to study the therapeutic benefit of AL101 in ACC. Here, we describe the antitumor activity of AL101 using ACC cell lines, organoids, and patient-derived xenograft models. Specifically, we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway, providing a strong rationale for evaluation of AL101 in clinical trials for patients with NOTCH-driven relapsed/refractory ACC.


Assuntos
Carcinoma Adenoide Cístico , Neoplasias das Glândulas Salivares , Secretases da Proteína Precursora do Amiloide/metabolismo , Carcinoma Adenoide Cístico/tratamento farmacológico , Carcinoma Adenoide Cístico/genética , Inibidores Enzimáticos/farmacologia , Humanos , Recidiva Local de Neoplasia , Receptores Notch/metabolismo , Neoplasias das Glândulas Salivares/genética , Transdução de Sinais
8.
J Immunol Res ; 2022: 4472509, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935578

RESUMO

Ovarian cancer (OC) causes more deaths than any other cancer of the female reproductive system due to its late presentation and malignant nature. Although significant progress has been made in the diagnosis and treatment of OC over the last decade, chemotherapeutic drug resistance and cancer recurrence remain serious challenges in OC management. In the field of cancer therapy, traditional Chinese herbal medicines and their active compounds have been widely reported to have favorable therapeutic effects on cancer. Recent studies have also revealed the protective effect of puerarin in cancer, but the exact role and underlying mechanism of puerarin in OC remain unclear. Here, we established in vivo and in vitro OC models to evaluate the anticancer effect of puerarin. It was found that puerarin significantly inhibited OC cell viability and proliferation and induced cell apoptosis. In OC model mice, puerarin treatment suppressed tumor formation and modulated the gut microbiome. In addition, the expression of tumor suppressor genes was activated by puerarin in vitro and in vivo. These findings add to the existing knowledge on the usefulness of herbal active ingredients for the prevention and treatment of OC and provide a new perspective regarding the therapeutic potential of puerarin in cancer.


Assuntos
Microbioma Gastrointestinal , Neoplasias Ovarianas , Animais , Carcinoma Epitelial do Ovário , Feminino , Genes Supressores de Tumor , Humanos , Isoflavonas , Camundongos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico
9.
Biomater Adv ; 137: 212831, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35929264

RESUMO

Adjuvant systemic chemotherapy with gemcitabine (GEM) is recognized as the standard of care to improve the prognosis of patients with resected pancreatic cancer (PC); however, it is greatly limited by poor absorption of chemotherapy agents. Moreover, surgical site infection and Gammaproteobacteria-induced GEM resistance further decrease the chemotherapy efficacy and increase the risk of recurrence and even mortality. Here, we develop an implantable anti-bacterial and anti-cancer fibrous membrane (AAFM) to inhibit PC recurrence in a well-coordinated manner. Our AAFM can be readily prepared via simple co-electrospinning of GEM and poly-L-lactic acid (PLLA) and subsequent tannic acid (TA)-mediated in-situ generation of silver nanoparticles (AgNPs). The resultant membrane presents highly porous fibrous morphology and appropriate mechanical performance. Most importantly, we find the surface-deposited TA/AgNP complexes can exert multiple therapeutic effects: (1) they can act as a fence to extend GEM diffusion route, achieving a sustained drug release; (2) they can fight the pathogenic microorganisms in the local microenvironment and prevent infectious complications and alleviate Gammaproteobacteria-induced chemotherapy resistance; (3) they can combat residual cancer cells to synchronously strengthen the effectiveness of GEM-based chemotherapy. Altogether, our AAFM provides a proof-of-concept demonstration of the integrated anti-cancer and anti-bacterial strategy for enhanced therapeutic efficacy and will inspire the design of other high-performance implants for prevention of tumor relapse.


Assuntos
Nanopartículas Metálicas , Neoplasias Pancreáticas , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Prata/farmacologia , Microambiente Tumoral
10.
BMC Surg ; 22(1): 304, 2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35933336

RESUMO

BACKGROUND: Pelvic exenteration is a radical surgery performed in selected patients with locally advanced or recurrent pelvic malignancy. It involves radical en bloc resection of the adjacent anatomical structures affected by the tumor. The authors sought to evaluate the clinical application of a depithelized gracilis adipofascial flap for pelvic floor reconstruction after pelvic exenteration. METHODS: A total of 31 patients who underwent pelvic floor reconstruction with a gracilis adipofascial flap after pelvic exenterationat Peking University Third Hospital from 2014 to 2022 were enrolled in the study. The postoperative follow-up durations varied from 4 to 12 months. RESULTS: The survival rate of the flap was 96.77% with partial flap necrosis in one case. The total incidence of postoperative complications associated with the flap was 25.81%, with an incidence of 6.45% in the donor site and 19.35% in the recipient site. All complications were early complications, including postoperative infection and flap necrosis. All patients recovered after treatments, including anti-infectives, dressing change, debridement, and local flap repair. Long-term follow-up showed good outcomes without flap-related complications. CONCLUSIONS: A depithelized gracilis adipofascial flap can be applied for pelvic floor reconstruction after pelvic exenteration. The flap is an ideal and reliable choice for pelvic floor reconstruction with few complications, an elevated survival rate, sufficient volume, and mild effects on the function of the donor site.


Assuntos
Exenteração Pélvica , Procedimentos Cirúrgicos Reconstrutivos , Humanos , Necrose/etiologia , Recidiva Local de Neoplasia/cirurgia , Diafragma da Pelve/patologia , Diafragma da Pelve/cirurgia , Complicações Pós-Operatórias/cirurgia , Procedimentos Cirúrgicos Reconstrutivos/efeitos adversos , Estudos Retrospectivos
11.
Med Trop Sante Int ; 2(2)2022 Jun 30.
Artigo em Francês | MEDLINE | ID: mdl-35919250

RESUMO

Objective: To report on a case of rare giant anterior cervical lipoma. Patients and methods: This was a 60-year-old male patient received in March 2020 for an anterior cervical swelling in progressive evolution since 20 years. The condition was negatively impacting the patient's quality of life with a feeling of cervical heaviness, discomfort, head movement limitations, with no sign of compression. Despite this significant discomfort, the patient first consulted several traditional practitioners with different traditional treatments without success, the mass having been taken for a goiter. It is in the face of the failure of traditherapeuts that the patient finally decided to consult in our care structure. Results: Physical examination found a large left paramedian formation which appeared soft, mobile vis-a-vis the two plans, and sensitive; it measured 13 cm on its longer axis, and surrounding skin showed scarifications, witness to previous traditional treatments. Cervical CT eliminated goiter and made it possible to diagnose a giant cervical lipoma. A cervicotomy was performed under general anesthesia with a total one-block excision of an encapsulated mass. The evolution was favorable with a good healing. The histological examination of the mass identified a well-differentiated lipoma. There was no relapse up until 24 months later. Conclusion: The giant anterior cervical lipoma is rare. The differential diagnosis is mainly posed with a large goiter or liposarcoma. CT or MRI make it possible to confirm the diagnosis. Its treatment is exclusively surgical and the examination of the operative piece by the pathologist confirms the diagnosis. An extended post-operative monitoring is recommended given the risks of relapse and of malignant degeneration.


Assuntos
Lipoma , Burkina Faso , Diagnóstico Diferencial , Bócio , Humanos , Lipoma/diagnóstico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Qualidade de Vida
12.
Inn Med (Heidelb) ; 63(7): 717-723, 2022 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-35925268

RESUMO

Treatment concepts for patients with localized and locally advanced non-small cell lung cancer (NSCLC) are based on local treatment, surgery and/or radiotherapy, with curative intent. An adjuvant systemic treatment is added after primary resection of an operable NSCLC primarily to reduce the systemic risk of relapse. Locally advanced stages with mediastinal lymph node involvement carry a substantial risk of local and distant recurrence and require multimodal treatment strategies in an interdisciplinary approach. Recently, immunotherapy with programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) checkpoint inhibitors is increasingly being integrated into adjuvant, neoadjuvant or perioperative treatment concepts.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Imunoterapia , Neoplasias Pulmonares/terapia , Terapia Neoadjuvante , Recidiva Local de Neoplasia
13.
Urologie ; 61(8): 844-849, 2022 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-35925288

RESUMO

BACKGROUND: Chronopharmacology takes into account, among other things, the circadian rhythm, a recurring, daily rhythm of biological functions that is significantly influenced by the day-night rhythm. Daily rhythm, diseases, and therapies influence each other: the circadian rhythm, among other factors, could influence the effect of pharmacological and nonpharmacological therapies, especially in urological oncology. AIM: This article focuses on the question of the optimal time for therapeutic interventions and considers relevant basics of chronobiological principles depending on possible biomarkers that could be targets of a future therapeutic approach. RESULTS: With chronomodulated chemotherapy, cancer therapies are not only more tolerable, but also more effective. Effects and side effects of an active substance can change according to the circadian rhythm. Due to the introduction of particularly targeted, oral tumor therapies, a daily application would be organizationally possible, but further clinical studies are necessary for this. The internal clock could play an unexpected role, especially in hormone-dependent prostate cancer: the amount of the circadian factor Cry1 not only seems to increase in the advanced stage, but is also closely associated with a poorer prognosis. Epidemiological studies also show a connection between hormone-dependent tumors and the disruption of the rhythmic release of melatonin. Melatonin appears to be able to improve therapy as an adjunct to cancer therapy in some urological tumor entities.


Assuntos
Melatonina , Ritmo Circadiano , Humanos , Masculino , Melatonina/farmacologia , Recidiva Local de Neoplasia
14.
JAMA Netw Open ; 5(8): e2225438, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35925605

RESUMO

Importance: Risk of relapse may be increased in the postpartum period of neuromyelitis optica spectrum disorder (NMOSD). Information regarding factors associated with pregnancy-related attacks is still lacking. Objectives: To identify factors associated with pregnancy-related NMOSD attacks, investigate the integrated annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score in each phase of pregnancy, and summarize pregnancy outcomes and complications in patients with NMOSD. Data Sources: An electronic search was performed in the MEDLINE, PubMed in-process and non-MEDLINE, EMBASE, Web of Science, and Cochrane databases using the OvidSP search platform, updated through December 30, 2021. Study Selection: All published and unpublished studies in English were considered, covering all patients with NMOSD with an informative pregnancy. Data Extraction and Synthesis: Two independent reviewers extracted the published data with a standardized procedure following MOOSE and PRISMA guidelines. The end points were calculated with the DerSimonian and Laird inverse variance (for random effects) method. Main Outcomes and Measures: The primary outcome was the rate of pregnancies with pregnancy-related NMOSD attacks, measured by risk ratios (RRs). The mean differences (MDs) in ARR and EDSS scores between each phase of pregnancy, pregnancy outcomes, and complications were defined as the secondary outcomes. Results: A total of 15 studies were analyzed, including 443 patients with NMOSD with 639 informative pregnancies. Patients receiving immunosuppressive treatment during pregnancy (RR, 0.43; 95% CI, 0.32-0.57; P < .001) and with older age at conception (RR, 0.67; 95% CI, 0.47-0.95; P = .02) had lower rates of pregnancy with pregnancy-related attacks. The increase in the ARR was highest in the first trimester after delivery compared with before pregnancy (MD, 1.28; 95% CI, 0.94-1.62; P < .001). The EDSS scores increased significantly both during pregnancy (MD, 0.44; 95% CI, 0.20-0.69; P < .001) and in the postpartum period (MD, 0.88; 95% CI, 0.51-1.26; P < .001) compared with before pregnancy. Conclusions and Relevance: This systematic review and meta-analysis found that receiving immunosuppressive treatment during pregnancy and older age at conception were associated with reduced risk of pregnancy-related NMOSD attacks, which mostly occurred in the first trimester of the postpartum period, although more high-quality prospective studies are needed.


Assuntos
Neuromielite Óptica , Feminino , Humanos , Imunossupressores/efeitos adversos , Recidiva Local de Neoplasia/induzido quimicamente , Neuromielite Óptica/induzido quimicamente , Neuromielite Óptica/epidemiologia , Neuromielite Óptica/terapia , Período Pós-Parto , Gravidez , Resultado da Gravidez/epidemiologia
15.
PLoS One ; 17(8): e0271584, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35921335

RESUMO

Ovarian cancer (OC) is a lethal gynecological malignancy with a five-year survival rate of only 46%. Development of resistance to platinum-based chemotherapy is a common cause of high mortality rates among OC patients. Tumor and transcriptomic heterogeneity are drivers of platinum resistance in OC. Platinum-based chemotherapy enriches for ovarian cancer stem cells (OCSCs) that are chemoresistant and contribute to disease recurrence and relapse. Studies examining the effect of different treatments on subpopulations of HGSOC cell lines are limited. Having previously demonstrated that combined treatment with an enhancer of zeste homolog 2 inhibitor (EZH2i) and a RAC1 GTPase inhibitor (RAC1i) inhibited survival of OCSCs, we investigated EZH2i and RAC1i combination effects on HGSOC heterogeneity using single cell RNA sequencing. We demonstrated that RAC1i reduced expression of stemness and early secretory marker genes, increased expression of an intermediate secretory marker gene and induced inflammatory gene expression. Importantly, RAC1i alone and in combination with EZH2i significantly reduced oxidative phosphorylation and upregulated Sirtuin signaling pathways. Altogether, we demonstrated that combining a RAC1i with an EZH2i promoted differentiation of subpopulations of HGSOC cells, supporting the future development of epigenetic drug combinations as therapeutic approaches in OC.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário/genética , Linhagem Celular , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/genética , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Feminino , Humanos , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Platina/uso terapêutico , Análise de Célula Única , Transcriptoma
16.
Nat Commun ; 13(1): 4517, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35922426

RESUMO

Deciphering Multiple Myeloma evolution in the whole bone marrow is key to inform curative strategies. Here, we perform spatial-longitudinal whole-exome sequencing, including 140 samples collected from 24 Multiple Myeloma patients during up to 14 years. Applying imaging-guided sampling we observe three evolutionary patterns, including relapse driven by a single-cell expansion, competing/co-existing sub-clones, and unique sub-clones at distinct locations. While we do not find the unique relapse sub-clone in the baseline focal lesion(s), we show a close phylogenetic relationship between baseline focal lesions and relapse disease, highlighting focal lesions as hotspots of tumor evolution. In patients with ≥3 focal lesions on positron-emission-tomography at diagnosis, relapse is driven by multiple distinct sub-clones, whereas in other patients, a single-cell expansion is typically seen (p < 0.01). Notably, we observe resistant sub-clones that can be hidden over years, suggesting that a prerequisite for curative therapies would be to overcome not only tumor heterogeneity but also dormancy.


Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Filogenia , Tomografia por Emissão de Pósitrons , Sequenciamento Completo do Exoma
18.
JAMA Netw Open ; 5(8): e2225485, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35947386

RESUMO

Importance: Adjuvant endocrine therapy (AET) reduces breast cancer recurrence, but symptom burden is a key barrier to adherence. Black women have lower AET adherence and worse health outcomes than White women. Objective: To investigate the association between symptom burden and AET adherence differences by race. Design, Setting, and Participants: A retrospective cohort study using electronic health records with patient-reported data from a large cancer center in the US. Patients included Black and White women initiating AET therapy for early-stage breast cancer from August 2007 to December 2015 who were followed for 1 year from AET initiation. Sixty symptoms classified into 7 physical and 2 psychological symptom clusters were evaluated. For each cluster, the number of symptoms with moderate severity at baseline, and symptoms with 3-point or greater increases during AET were counted. Adherence was measured as the proportion of days covered by AET during the first-year follow-up. Multivariable regressions for patients' adherence adjusting for race, symptom measures, sociodemographic characteristics, and clinical characteristics were conducted. Kitagawa-Blinder-Oaxaca decomposition was used to quantify racial differences in adherence explained by symptoms and patient characteristics. Analyses were conducted from July 2021 to January 2022. Exposures: Physical and psychological symptoms at baseline and changes during AET. Results: Among 559 patients (168 [30.1%] Black and 391 [69.9%] White; mean [SD] age 65.5 [12.1] years), Black women received diagnoses younger (mean [SD] age at diagnosis, 58.7 [13.7] vs 68.5 [10.0] years old) than White women, with more advanced stages (30 Black participants [17.9%] vs 31 White participants [7.9%] had stage III disease at diagnosis), and lived in areas with fewer adults attaining high school education (mean [SD], 78.8% [7.8%] vs 84.0% [9.3%]). AET adherence in the first year was 78.8% for Black and 82.3% for White women. Black women reported higher severity in most symptom clusters than White women. Neuropsychological, vasomotor, musculoskeletal, cardiorespiratory, distress, and despair symptoms at baseline and increases during the follow-up were associated with 1.2 to 2.6 percentage points decreases in adherence, which corresponds to 4 to 9 missed days receiving AET in the first year. After adjusting for psychological symptoms, being Black was associated with 6.5 percentage points higher adherence than being White. Conclusions and Relevance: In this cohort study, severe symptoms were associated with lower AET adherence. Black women had lower adherence rates that were explained by their higher symptom burden and baseline characteristics. These findings suggest that better symptom management with a focus on psychological symptoms could improve AET adherence and reduce racial disparities in cancer outcomes.


Assuntos
Neoplasias da Mama , Adulto , Idoso , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Criança , Estudos de Coortes , Feminino , Humanos , Adesão à Medicação/psicologia , Recidiva Local de Neoplasia/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Fatores Raciais , Estudos Retrospectivos , Síndrome , beta-Aminoetil Isotioureia/uso terapêutico
19.
N Engl J Med ; 387(6): 506-513, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35947709

RESUMO

BACKGROUND: The benefits of removing small (≤6 mm), asymptomatic kidney stones endoscopically is unknown. Current guidelines leave such decisions to the urologist and the patient. A prospective study involving older, nonendoscopic technology and some retrospective studies favor observation. However, published data indicate that about half of small renal stones left in place at the time that larger stones were removed caused other symptomatic events within 5 years after surgery. METHODS: We conducted a multicenter, randomized, controlled trial in which, during the endoscopic removal of ureteral or contralateral kidney stones, remaining small, asymptomatic stones were removed in 38 patients (treatment group) and were not removed in 35 patients (control group). The primary outcome was relapse as measured by future emergency department visits, surgeries, or growth of secondary stones. RESULTS: After a mean follow-up of 4.2 years, the treatment group had a longer time to relapse than the control group (P<0.001 by log-rank test). The restricted mean (±SE) time to relapse was 75% longer in the treatment group than in the control group (1631.6±72.8 days vs. 934.2±121.8 days). The risk of relapse was 82% lower in the treatment group than the control group (hazard ratio, 0.18; 95% confidence interval, 0.07 to 0.44), with 16% of patients in the treatment group having a relapse as compared with 63% of those in the control group. Treatment added a median of 25.6 minutes (interquartile range, 18.5 to 35.2) to the surgery time. Five patients in the treatment group and four in the control group had emergency department visits within 2 weeks after surgery. Eight patients in the treatment group and 10 in the control group reported passing kidney stones. CONCLUSIONS: The removal of small, asymptomatic kidney stones during surgery to remove ureteral or contralateral kidney stones resulted in a lower incidence of relapse than nonremoval and in a similar number of emergency department visits related to the surgery. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Veterans Affairs Puget Sound Health Care System; ClinicalTrials.gov number, NCT02210650.).


Assuntos
Cálculos Renais , Recidiva Local de Neoplasia , Doença Crônica , Humanos , Incidência , Cálculos Renais/epidemiologia , Cálculos Renais/cirurgia , Recidiva Local de Neoplasia/complicações , Estudos Prospectivos , Estudos Retrospectivos
20.
Nat Commun ; 13(1): 4587, 2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35933466

RESUMO

The tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays a crucial role in shaping their progression. Many desmoplastic tumours including breast cancer involve the significant accumulation of type I collagen. However, recently it has become clear that the precise distribution and organisation of matrix molecules such as collagen I is equally as important in the tumour as their abundance. Cancer-associated fibroblasts (CAFs) coexist within breast cancer tissues and play both pro- and anti-tumourigenic roles through remodelling the ECM. Here, using temporal proteomic profiling of decellularized tumours, we interrogate the evolving matrisome during breast cancer progression. We identify 4 key matrisomal clusters, and pinpoint collagen type XII as a critical component that regulates collagen type I organisation. Through combining our proteomics with single-cell transcriptomics, and genetic manipulation models, we show how CAF-secreted collagen XII alters collagen I organisation to create a pro-invasive microenvironment supporting metastatic dissemination. Finally, we show in patient cohorts that collagen XII may represent an indicator of breast cancer patients at high risk of metastatic relapse.


Assuntos
Neoplasias da Mama , Colágeno Tipo XII/metabolismo , Metástase Neoplásica , Microambiente Tumoral , Neoplasias da Mama/patologia , Colágeno , Colágeno Tipo I , Matriz Extracelular/patologia , Feminino , Humanos , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Proteômica
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