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Biomedicine & Pharmacotherapy =... May 2022Lung cancer has some of the highest morbidity and mortality rates of all cancers, and an important risk factor for mortality in patients with lung cancer is tumor... (Review)
Review
Lung cancer has some of the highest morbidity and mortality rates of all cancers, and an important risk factor for mortality in patients with lung cancer is tumor metastasis. Even if a tumor is completely removed at an early stage of the disease, quite a number of patients still have the risk of recurrence. With the advent of molecular diagnostic and therapeutics, more and more studies have found that a poor prognosis may be related to lymph node micrometastasis. However, clinicians still find that predicting the prognosis and choosing the type of surgery and postoperative adjuvant chemotherapy are still challenging. Thus, this article reviews the current research status of lymph node micrometastasis in non-small cell lung cancer, envision to provide some updates and insights in this area.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Neoplasm Micrometastasis; Neoplasm Staging
PubMed: 35303567
DOI: 10.1016/j.biopha.2022.112817 -
JAMA Network Open Dec 2020Standard therapy for locally advanced rectal cancer includes concurrent chemoradiotherapy followed by surgery and adjuvant chemotherapy (CRT plus A). An alternative... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Standard therapy for locally advanced rectal cancer includes concurrent chemoradiotherapy followed by surgery and adjuvant chemotherapy (CRT plus A). An alternative strategy known as total neoadjuvant therapy (TNT) involves administration of CRT plus neoadjuvant chemotherapy before surgery with the goal of delivering uninterrupted systemic therapy to eradicate micrometastases. A comparison of these 2 approaches has not been systematically reviewed previously.
OBJECTIVE
To determine the differences in rates of pathologic complete response (PCR), disease-free and overall survival, sphincter-preserving surgery, and ileostomy between patients receiving TNT vs standard CRT plus A.
DATA SOURCES
MEDLINE (via PubMed) and Embase (via OVID) were searched from inception through July 1, 2020, for the following terms: anal/anorectal neoplasms OR anal/anorectal cancer AND total neoadjuvant treatment OR total neoadjuvant therapy. Only studies in English were included.
STUDY SELECTION
Randomized clinical trials or prospective/retrospective cohort studies comparing outcomes in patients with locally advanced rectal cancer who received TNT vs CRT plus A.
DATA EXTRACTION AND SYNTHESIS
Data regarding the first author, publication year, location, sample size, and rates of PCR, sphincter-preserving surgery, ileostomy, and disease-free and overall survival were extracted using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and pooled using a random-effects model.
MAIN OUTCOMES AND MEASURES
Rates of PCR, sphincter-preserving surgery, ileostomy, and disease-free and overall survival.
RESULTS
After reviewing 2165 reports, 7 unique studies including a total of 2416 unique patients, of whom 1206 received TNT, were selected. The median age for the patients receiving TNT ranged from 57 to 69 years, with 58% to 73% being male. The pooled prevalence of PCR was 29.9% (range, 17.2%-38.5%) in the TNT group and 14.9% (range, 4.2%-21.3%) in the CRT plus A group. Total neoadjuvant therapy was associated with a higher chance of achieving a PCR (odds ratio [OR], 2.44; 95% CI, 1.99-2.98). No statistically significant difference in the proportion of sphincter-preserving surgery (OR, 1.06; 95% CI, 0.73-1.54) or ileostomy (OR, 1.05; 95% CI, 0.76-1.46) between recipients of TNT and CRT plus A was observed. Only 3 studies presented data on disease-free survival, and pooled analysis showed significantly higher odds of improved disease-free survival in patients who received TNT (OR, 2.07; 95% CI, 1.20-3.56; I2 = 49%). Data on overall survival were not consistently reported.
CONCLUSIONS AND RELEVANCE
The findings of this systematic review and meta-analysis suggest that TNT is a promising strategy in locally advanced rectal cancer, with superior rates of PCR compared with standard therapy. However, the long-term effect on disease recurrence and overall survival needs to be explored in future studies.
Topics: Chemoradiotherapy; Humans; Ileostomy; Neoadjuvant Therapy; Neoplasm Micrometastasis; Neoplasm Staging; Proctectomy; Rectal Neoplasms; Survival Analysis
PubMed: 33326026
DOI: 10.1001/jamanetworkopen.2020.30097 -
Developmental Cell Apr 2021Estrogen receptor-positive (ER) breast cancer exhibits a strong bone tropism in metastasis. How the bone microenvironment (BME) impacts ER signaling and endocrine...
Estrogen receptor-positive (ER) breast cancer exhibits a strong bone tropism in metastasis. How the bone microenvironment (BME) impacts ER signaling and endocrine therapy remains poorly understood. Here, we discover that the osteogenic niche transiently and reversibly reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance. As BMMs progress, the ER reduction and endocrine resistance may partially recover in cancer cells away from the osteogenic niche, creating phenotypic heterogeneity in macrometastases. Using multiple approaches, including an evolving barcoding strategy, we demonstrated that this process is independent of clonal selection, and represents an EZH2-mediated epigenomic reprogramming. EZH2 drives ER BMMs toward a basal and stem-like state. EZH2 inhibition reverses endocrine resistance. These data exemplify how epigenomic adaptation to BME promotes phenotypic plasticity of metastatic seeds, fosters intra-metastatic heterogeneity, and alters therapeutic responses. Our study provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies.
Topics: Adaptation, Physiological; Animals; Bone Neoplasms; Bone and Bones; Breast Neoplasms; Cell Communication; Clonal Evolution; Disease Models, Animal; Down-Regulation; Enhancer of Zeste Homolog 2 Protein; Female; Gap Junctions; Genes, Reporter; Green Fluorescent Proteins; Humans; MCF-7 Cells; Mice; Neoplasm Micrometastasis; Osteogenesis; Receptors, Estrogen; Signal Transduction; Tumor Microenvironment
PubMed: 33878299
DOI: 10.1016/j.devcel.2021.03.008 -
Cell Jun 2016Transfer RNAs (tRNAs) are primarily viewed as static contributors to gene expression. By developing a high-throughput tRNA profiling method, we find that specific tRNAs...
Transfer RNAs (tRNAs) are primarily viewed as static contributors to gene expression. By developing a high-throughput tRNA profiling method, we find that specific tRNAs are upregulated in human breast cancer cells as they gain metastatic activity. Through loss-of-function, gain-of-function, and clinical-association studies, we implicate tRNAGluUUC and tRNAArgCCG as promoters of breast cancer metastasis. Upregulation of these tRNAs enhances stability and ribosome occupancy of transcripts enriched for their cognate codons. Specifically, tRNAGluUUC promotes metastatic progression by directly enhancing EXOSC2 expression and enhancing GRIPAP1-constituting an "inducible" pathway driven by a tRNA. The cellular proteomic shift toward a pro-metastatic state mirrors global tRNA shifts, allowing for cell-state and cell-type transgene expression optimization through codon content quantification. TRNA modulation represents a mechanism by which cells achieve altered expression of specific transcripts and proteins. TRNAs are thus dynamic regulators of gene expression and the tRNA codon landscape can causally and specifically impact disease progression.
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Codon; Disease Progression; Exosome Multienzyme Ribonuclease Complex; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lung; Mice; Neoplasm Invasiveness; Neoplasm Micrometastasis; Neoplasm Proteins; RNA, Transfer; RNA-Binding Proteins; Regulatory Sequences, Ribonucleic Acid; Ribosomes; Xenograft Model Antitumor Assays
PubMed: 27259150
DOI: 10.1016/j.cell.2016.05.046 -
JAMA Oncology Jun 2018Treatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which... (Comparative Study)
Comparative Study
IMPORTANCE
Treatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases.
OBJECTIVE
To compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the more recent TNT approach for LARC.
DESIGN, SETTING, AND PARTICIPANTS
A retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified.
EXPOSURES
Of the 811 patients, 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT).
MAIN OUTCOMES AND MEASURES
Treatment and outcome data for the 2 cohorts were compared. Dosing and completion of prescribed chemotherapy were assessed on the subset of patients who received all therapy at MSK.
RESULTS
Of the 628 patients overall, 373 (59%) were men and 255 (41%) were women, with a mean (SD) age of 56.7 (12.9) years. Of the 308 patients in the TNT cohort, 181 (49%) were men and 127 (49%) were women. Of the 320 patients in the chemoRT with planned adjuvant chemotherapy cohort, 192 (60%) were men and 128 (40%) were women. Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort.
CONCLUSIONS AND RELEVANCE
Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer. Our data suggest that TNT facilitates delivery of planned systemic therapy. Long-term follow-up will determine if this finding translates into improved survival. In addition, given its high CR rate, TNT may facilitate nonoperative treatment strategies aimed at organ preservation.
Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoradiotherapy; Chemotherapy, Adjuvant; Combined Modality Therapy; Dose Fractionation, Radiation; Female; Fluorouracil; Humans; Ileostomy; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Micrometastasis; Organoplatinum Compounds; Oxaliplatin; Postoperative Care; Preoperative Care; Proctectomy; Radiotherapy, Conformal; Radiotherapy, Intensity-Modulated; Rectal Neoplasms; Remission Induction; Retrospective Studies
PubMed: 29566109
DOI: 10.1001/jamaoncol.2018.0071 -
Cancer Research May 2022Micrometastases of colorectal cancer can remain dormant for years prior to the formation of actively growing, clinically detectable lesions (i.e., colonization). A...
UNLABELLED
Micrometastases of colorectal cancer can remain dormant for years prior to the formation of actively growing, clinically detectable lesions (i.e., colonization). A better understanding of this step in the metastatic cascade could help improve metastasis prevention and treatment. Here we analyzed liver specimens of patients with colorectal cancer and monitored real-time metastasis formation in mouse livers using intravital microscopy to reveal that micrometastatic lesions are devoid of cancer stem cells (CSC). However, lesions that grow into overt metastases demonstrated appearance of de novo CSCs through cellular plasticity at a multicellular stage. Clonal outgrowth of patient-derived colorectal cancer organoids phenocopied the cellular and transcriptomic changes observed during in vivo metastasis formation. First, formation of mature CSCs occurred at a multicellular stage and promoted growth. Conversely, failure of immature CSCs to generate more differentiated cells arrested growth, implying that cellular heterogeneity is required for continuous growth. Second, early-stage YAP activity was required for the survival of organoid-forming cells. However, subsequent attenuation of early-stage YAP activity was essential to allow for the formation of cell type heterogeneity, while persistent YAP signaling locked micro-organoids in a cellularly homogenous and growth-stalled state. Analysis of metastasis formation in mouse livers using single-cell RNA sequencing confirmed the transient presence of early-stage YAP activity, followed by emergence of CSC and non-CSC phenotypes, irrespective of the initial phenotype of the metastatic cell of origin. Thus, establishment of cellular heterogeneity after an initial YAP-controlled outgrowth phase marks the transition to continuously growing macrometastases.
SIGNIFICANCE
Characterization of the cell type dynamics, composition, and transcriptome of early colorectal cancer liver metastases reveals that failure to establish cellular heterogeneity through YAP-controlled epithelial self-organization prohibits the outgrowth of micrometastases. See related commentary by LeBleu, p. 1870.
Topics: Animals; Colorectal Neoplasms; Humans; Liver Neoplasms; Mice; Neoplasm Micrometastasis; Neoplastic Stem Cells
PubMed: 35570706
DOI: 10.1158/0008-5472.CAN-21-0933 -
The Lancet. Oncology Apr 2013For patients with breast cancer and metastases in the sentinel nodes, axillary dissection has been standard treatment. However, for patients with limited sentinel-node... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
For patients with breast cancer and metastases in the sentinel nodes, axillary dissection has been standard treatment. However, for patients with limited sentinel-node involvement, axillary dissection might be overtreatment. We designed IBCSG trial 23-01 to determine whether no axillary dissection was non-inferior to axillary dissection in patients with one or more micrometastatic (≤2 mm) sentinel nodes and tumour of maximum 5 cm.
METHODS
In this multicentre, randomised, non-inferiority, phase 3 trial, patients were eligible if they had clinically non-palpable axillary lymph node(s) and a primary tumour of 5 cm or less and who, after sentinel-node biopsy, had one or more micrometastatic (≤2 mm) sentinel lymph nodes with no extracapsular extension. Patients were randomly assigned (in a 1:1 ratio) to either undergo axillary dissection or not to undergo axillary dissection. Randomisation was stratified by centre and menopausal status. Treatment assignment was not masked. The primary endpoint was disease-free survival. Non-inferiority was defined as a hazard ratio (HR) of less than 1·25 for no axillary dissection versus axillary dissection. The analysis was by intention to treat. Per protocol, disease and survival information continues to be collected yearly. This trial is registered with ClinicalTrials.gov, NCT00072293.
FINDINGS
Between April 1, 2001, and Feb 28, 2010, 465 patients were randomly assigned to axillary dissection and 469 to no axillary dissection. After the exclusion of three patients, 464 patients were in the axillary dissection group and 467 patients were in the no axillary dissection group. After a median follow-up of 5·0 (IQR 3·6-7·3) years, we recorded 69 disease-free survival events in the axillary dissection group and 55 events in the no axillary dissection group. Breast-cancer-related events were recorded in 48 patients in the axillary dissection group and 47 in the no axillary dissection group (ten local recurrences in the axillary dissection group and eight in the no axillary dissection group; three and nine contralateral breast cancers; one and five [corrected] regional recurrences; and 34 and 25 distant relapses). Other non-breast cancer events were recorded in 21 patients in the axillary dissection group and eight in the no axillary dissection group (20 and six second non-breast malignancies; and one and two deaths not due to a cancer event). 5-year disease-free survival was 87·8% (95% CI 84·4-91·2) in the group without axillary dissection and 84·4% (80·7-88·1) in the group with axillary dissection (log-rank p=0·16; HR for no axillary dissection vs axillary dissection was 0·78, 95% CI 0·55-1·11, non-inferiority p=0·0042). Patients with reported long-term surgical events (grade 3-4) included one sensory neuropathy (grade 3), three lymphoedema (two grade 3 and one grade 4), and three motor neuropathy (grade 3), all in the group that underwent axillary dissection, and one grade 3 motor neuropathy in the group without axillary dissection. One serious adverse event was reported, a postoperative infection in the axilla in the group with axillary dissection.
INTERPRETATION
Axillary dissection could be avoided in patients with early breast cancer and limited sentinel-node involvement, thus eliminating complications of axillary surgery with no adverse effect on survival.
FUNDING
None.
Topics: Adult; Aged; Axilla; Breast Neoplasms; Disease-Free Survival; Female; Follow-Up Studies; Humans; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Neoplasm Grading; Neoplasm Micrometastasis; Sentinel Lymph Node Biopsy; Treatment Outcome
PubMed: 23491275
DOI: 10.1016/S1470-2045(13)70035-4 -
Journal of Clinical Oncology : Official... Nov 2021The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to... (Comparative Study)
Comparative Study
PURPOSE
The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN).
METHODS
GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences.
RESULTS
From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL ( = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL.
CONCLUSION
Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.
Topics: Aged; Female; Humans; Lymph Node Excision; Lymphatic Metastasis; Middle Aged; Neoplasm Micrometastasis; Neoplasm Staging; Prospective Studies; Radiation Dosage; Sentinel Lymph Node; Time Factors; Treatment Outcome; Vulvar Neoplasms
PubMed: 34432481
DOI: 10.1200/JCO.21.00006 -
The Korean Journal of Gastroenterology... May 2017Although the incidence and mortality rate of gastric cancer have been steadily declining, gastric cancer is still the fourth most common cancer in the world and more... (Review)
Review
Although the incidence and mortality rate of gastric cancer have been steadily declining, gastric cancer is still the fourth most common cancer in the world and more than 50% of cases occur in Eastern Asia. In Korea, gastric cancer is the second most common cancer and third cause of cancer related death. The standard surgical procedure for resectable advanced gastric cancer is D2 lymphadenectomy with radical gastrectomy. Even though R0 resection was completed, recurrence is relatively common, and contributes to the limited survival of the patients in gastric cancer. As a clinically relevant factor for detection of the recurrence, the presence of isolating tumor cells has been introduced and it is so called as 'micrometastasis'. Numerous immunohistochemistry and molecular studies have shown that micrometastasis can be demonstrated not only in lymph nodes but also in such body compartments as the bone marrow, peritoneal cavity and blood. Herein, we review the current knowledge and evidence of the prognostic significance of micrometastasis in peritoneal, lymph node, bone marrow. Also, we discuss the current state of research on the circulating tumor cell in peripheral blood.
Topics: Humans; Immunohistochemistry; Lymphatic Metastasis; Neoplasm Metastasis; Neoplastic Cells, Circulating; Peritoneal Neoplasms; Prognosis; Stomach Neoplasms
PubMed: 28539031
DOI: 10.4166/kjg.2017.69.5.270 -
Ugeskrift For Laeger Oct 2018Two recent randomised studies found no survival difference in patients, who had melanoma with metastasis to the sentinel node (SN) and underwent immediate complete lymph... (Review)
Review
Two recent randomised studies found no survival difference in patients, who had melanoma with metastasis to the sentinel node (SN) and underwent immediate complete lymph node dissection (CLND), compared with patients, who were followed closely with ultrasound scans and only underwent CLND if metastases developed. From 2018, the Danish guidelines concur: SN-positive patients will no longer undergo routine CLND, which has high morbidity, but will be followed with ultrasound scans of the SN-positive region(s) at their follow-up visits every third month for two years, then every six month for three years, except if PET-CT is performed.
Topics: Denmark; Humans; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Neoplasm Micrometastasis; Practice Guidelines as Topic; Survival Rate; Ultrasonography; Watchful Waiting
PubMed: 30327078
DOI: No ID Found