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International Journal of Gynaecology... Aug 2023Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009....
INTRODUCTION
Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009. Substantially more outcome and biological behavior data are now available regarding the several histological types. Molecular and genetic findings have accelerated since the publication of The Cancer Genome Atlas (TCGA) data and provide improved clarity on the diverse biological nature of this collection of endometrial cancers and their differing prognostic outcomes. The goals of the new staging system are to better define these prognostic groups and create substages that indicate more appropriate surgical, radiation, and systemic therapies.
METHODS
The FIGO Women's Cancer Committee appointed a Subcommittee on Endometrial Cancer Staging in October 2021, represented by the authors. Since then, the committee members have met frequently and reviewed new and established evidence on the treatment, prognosis, and survival of endometrial cancer. Based on these data, opportunities for improvements in the categorization and stratification of these factors were identified in each of the four stages. Data and analyses from the molecular and histological classifications performed and published in the recently developed ESGO/ESTRO/ESP guidelines were used as a template for adding the new subclassifications to the proposed molecular and histological staging system.
RESULTS
Based on the existing evidence, the substages were defined as follows: Stage I (IA1): non-aggressive histological type of endometrial carcinoma limited to a polyp or confined to the endometrium; (IA2) non-aggressive histological types of endometrium involving less than 50% of the myometrium with no or focal lymphovascular space invasion (LVSI) as defined by WHO criteria; (IA3) low-grade endometrioid carcinomas limited to the uterus with simultaneous low-grade endometrioid ovarian involvement; (IB) non-aggressive histological types involving 50% or more of the myometrium with no LVSI or focal LVSI; (IC) aggressive histological types, i.e. serous, high-grade endometrioid, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types without any myometrial invasion. Stage II (IIA): non-aggressive histological types that infiltrate the cervical stroma; (IIB) non-aggressive histological types that have substantial LVSI; or (IIC) aggressive histological types with any myometrial invasion. Stage III (IIIA): differentiating between adnexal versus uterine serosa infiltration; (IIIB) infiltration of vagina/parametria and pelvic peritoneal metastasis; and (IIIC) refinements for lymph node metastasis to pelvic and para-aortic lymph nodes, including micrometastasis and macrometastasis. Stage IV (IVA): locally advanced disease infiltrating the bladder or rectal mucosa; (IVB) extrapelvic peritoneal metastasis; and (IVC) distant metastasis. The performance of complete molecular classification (POLEmut, MMRd, NSMP, p53abn) is encouraged in all endometrial cancers. If the molecular subtype is known, this is recorded in the FIGO stage by the addition of "m" for molecular classification, and a subscript indicating the specific molecular subtype. When molecular classification reveals p53abn or POLEmut status in Stages I and II, this results in upstaging or downstaging of the disease (IICm or IAm ).
SUMMARY
The updated 2023 staging of endometrial cancer includes the various histological types, tumor patterns, and molecular classification to better reflect the improved understanding of the complex nature of the several types of endometrial carcinoma and their underlying biologic behavior. The changes incorporated in the 2023 staging system should provide a more evidence-based context for treatment recommendations and for the more refined future collection of outcome and survival data.
Topics: Female; Humans; Peritoneal Neoplasms; Neoplasm Staging; Endometrial Neoplasms; Prognosis; Carcinoma, Endometrioid; Retrospective Studies
PubMed: 37337978
DOI: 10.1002/ijgo.14923 -
The New England Journal of Medicine Jul 2023Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain.
METHODS
We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects.
RESULTS
From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy.
CONCLUSIONS
In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).
Topics: Adult; Humans; Anal Canal; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Chemotherapy, Adjuvant; Disease-Free Survival; Fluorouracil; Leucovorin; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Organ Sparing Treatments; Oxaliplatin; Rectal Neoplasms; Preoperative Care; Preoperative Period
PubMed: 37272534
DOI: 10.1056/NEJMoa2303269 -
European Urology Aug 2023Bladder cancer (BC) is common worldwide and poses a significant public health challenge. External risk factors and the wider exposome (totality of exposure from external... (Review)
Review
CONTEXT
Bladder cancer (BC) is common worldwide and poses a significant public health challenge. External risk factors and the wider exposome (totality of exposure from external and internal factors) contribute significantly to the development of BC. Therefore, establishing a clear understanding of these risk factors is the key to prevention.
OBJECTIVE
To perform an up-to-date systematic review of BC's epidemiology and external risk factors.
EVIDENCE ACQUISITION
Two reviewers (I.J. and S.O.) performed a systematic review using PubMed and Embase in January 2022 and updated it in September 2022. The search was restricted to 4 yr since our previous review in 2018.
EVIDENCE SYNTHESIS
Our search identified 5177 articles and a total of 349 full-text manuscripts. GLOBOCAN data from 2020 revealed an incidence of 573 000 new BC cases and 213 000 deaths worldwide in 2020. The 5-yr prevalence worldwide in 2020 was 1 721 000. Tobacco smoking and occupational exposures (aromatic amines and polycyclic aromatic hydrocarbons) are the most substantial risk factors. In addition, correlative evidence exists for several risk factors, including specific dietary factors, imbalanced microbiome, gene-environment risk factor interactions, diesel exhaust emission exposure, and pelvic radiotherapy.
CONCLUSIONS
We present a contemporary overview of the epidemiology of BC and the current evidence for BC risk factors. Smoking and specific occupational exposures are the most established risk factors. There is emerging evidence for specific dietary factors, imbalanced microbiome, gene-external risk factor interactions, diesel exhaust emission exposure, and pelvic radiotherapy. Further high-quality evidence is required to confirm initial findings and further understand cancer prevention.
PATIENT SUMMARY
Bladder cancer is common, and the most substantial risk factors are smoking and workplace exposure to suspected carcinogens. On-going research to identify avoidable risk factors could reduce the number of people who get bladder cancer.
Topics: Humans; Vehicle Emissions; Risk Factors; Urinary Bladder Neoplasms; Smoking; Tobacco Smoking; Occupational Exposure
PubMed: 37198015
DOI: 10.1016/j.eururo.2023.03.029 -
The New England Journal of Medicine Feb 2024Retrospective data suggest that the incidence of parametrial infiltration is low in patients with early-stage low-risk cervical cancer, which raises questions regarding... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Retrospective data suggest that the incidence of parametrial infiltration is low in patients with early-stage low-risk cervical cancer, which raises questions regarding the need for radical hysterectomy in these patients. However, data from large, randomized trials comparing outcomes of radical and simple hysterectomy are lacking.
METHODS
We conducted a multicenter, randomized, noninferiority trial comparing radical hysterectomy with simple hysterectomy including lymph-node assessment in patients with low-risk cervical cancer (lesions of ≤2 cm with limited stromal invasion). The primary outcome was cancer recurrence in the pelvic area (pelvic recurrence) at 3 years. The prespecified noninferiority margin for the between-group difference in pelvic recurrence at 3 years was 4 percentage points.
RESULTS
Among 700 patients who underwent randomization (350 in each group), the majority had tumors that were stage IB according to the 2009 International Federation of Gynecology and Obstetrics (FIGO) criteria (91.7%), that had squamous-cell histologic features (61.7%), and that were grade 1 or 2 (59.3%). With a median follow-up time of 4.5 years, the incidence of pelvic recurrence at 3 years was 2.17% in the radical hysterectomy group and 2.52% in the simple hysterectomy group (an absolute difference of 0.35 percentage points; 90% confidence interval, -1.62 to 2.32). Results were similar in a per-protocol analysis. The incidence of urinary incontinence was lower in the simple hysterectomy group than in the radical hysterectomy group within 4 weeks after surgery (2.4% vs. 5.5%; P = 0.048) and beyond 4 weeks (4.7% vs. 11.0%; P = 0.003). The incidence of urinary retention in the simple hysterectomy group was also lower than that in the radical hysterectomy group within 4 weeks after surgery (0.6% vs. 11.0%; P<0.001) and beyond 4 weeks (0.6% vs. 9.9%; P<0.001).
CONCLUSIONS
In patients with low-risk cervical cancer, simple hysterectomy was not inferior to radical hysterectomy with respect to the 3-year incidence of pelvic recurrence and was associated with a lower risk of urinary incontinence or retention. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov number, NCT01658930.).
Topics: Female; Humans; Canada; Carcinoma, Squamous Cell; Hysterectomy; Lymph Nodes; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Retrospective Studies; Urinary Incontinence; Urinary Retention; Uterine Cervical Neoplasms
PubMed: 38416430
DOI: 10.1056/NEJMoa2308900 -
Trends in Endocrinology and Metabolism:... Aug 2023Cancer remains the second leading cause of mortality, with nearly 10 million deaths worldwide in 2020. In many cases, radiotherapy is used for its anticancer effects.... (Review)
Review
Cancer remains the second leading cause of mortality, with nearly 10 million deaths worldwide in 2020. In many cases, radiotherapy is used for its anticancer effects. However, radiation causes healthy tissue toxicity as a side effect. In intra-abdominal and pelvic malignancies, the healthy bowel is inevitably included in the radiation field, causing radiation-induced enteritis and dramatically affecting the gut microbiome. This condition is associated with significant morbidity and mortality that impairs cancer patients' and survivors' quality of life. This Review provides a critical overview of the main drivers in modulating the gut microenvironment in homeostasis, disease, and injury, focusing on gut microbial metabolites and microorganisms that influence epithelial regeneration upon radiation injury.
Topics: Humans; Gastrointestinal Microbiome; Quality of Life; Enteritis; Radiation Injuries; Neoplasms; Regeneration; Tumor Microenvironment
PubMed: 37336645
DOI: 10.1016/j.tem.2023.05.006 -
ACTL6A protects gastric cancer cells against ferroptosis through induction of glutathione synthesis.Nature Communications Jul 2023Gastric cancer (GC), one of the most common malignant tumors in the world, exhibits a rapid metastasis rate and causes high mortality. Diagnostic markers and potential...
Gastric cancer (GC), one of the most common malignant tumors in the world, exhibits a rapid metastasis rate and causes high mortality. Diagnostic markers and potential therapeutic targets for GCs are urgently needed. Here we show that Actin-like protein 6 A (ACTL6A), encoding an SWI/SNF subunit, is highly expressed in GCs. ACTL6A is found to be critical for regulating the glutathione (GSH) metabolism pathway because it upregulates γ-glutamyl-cysteine ligase catalytic subunit (GCLC) expression, thereby reducing reactive oxygen species (ROS) levels and inhibiting ferroptosis, a regulated form of cell death driven by the accumulation of lipid-based ROS. Mechanistic studies show that ACTL6A upregulates GCLC as a cotranscription factor with Nuclear factor (erythroid-derived 2)-like 2 (NRF2) and that the hydrophobic region of ACTL6A plays an important role. Our data highlight the oncogenic role of ACTL6A in GCs and indicate that inhibition of ACTL6A or GCLC could be a potential treatment strategy for GCs.
Topics: Humans; Reactive Oxygen Species; Stomach Neoplasms; Ferroptosis; Transcription Factors; Glutathione; NF-E2-Related Factor 2; Actins; Chromosomal Proteins, Non-Histone; DNA-Binding Proteins
PubMed: 37443154
DOI: 10.1038/s41467-023-39901-8 -
Cell Reports. Medicine Oct 2023Neoadjuvant chemotherapy (NAC) for rectal cancer (RC) shows promising clinical response. The modulation of the tumor microenvironment (TME) by NAC and its association...
Neoadjuvant chemotherapy (NAC) for rectal cancer (RC) shows promising clinical response. The modulation of the tumor microenvironment (TME) by NAC and its association with therapeutic response remain unclear. Here, we use single-cell RNA sequencing and spatial transcriptome sequencing to examine the cell dynamics in 29 patients with RC, who are sampled pairwise before and after treatment. We construct a high-resolution cellular dynamic landscape remodeled by NAC and their associations with therapeutic response. NAC markedly reshapes the populations of cancer-associated fibroblasts (CAFs), which is strongly associated with therapeutic response. The remodeled CAF subsets regulate the TME through spatial recruitment and crosstalk to activate immunity and suppress tumor progression through multiple cytokines, including CXCL12, SLIT2, and DCN. In contrast, the epithelial-mesenchymal transition of malignant cells is upregulated by CAF_FAP through MIR4435-2HG induction, resulting in worse outcomes. Our study demonstrates that NAC inhibits tumor progression and modulates the TME by remodeling CAFs.
Topics: Humans; Cancer-Associated Fibroblasts; Neoadjuvant Therapy; Transcriptome; Rectal Neoplasms; Cell Proliferation; Tumor Microenvironment
PubMed: 37852187
DOI: 10.1016/j.xcrm.2023.101231 -
International Journal of Gynecological... Jul 2023As part of its mission to improve the quality of care for women with gynecological cancers across Europe, the European Society of Gynaecological Oncology (ESGO) first...
BACKGROUND
As part of its mission to improve the quality of care for women with gynecological cancers across Europe, the European Society of Gynaecological Oncology (ESGO) first published in 2017 evidence-based guidelines for the management of patients with vulvar cancer.
OBJECTIVE
To update the ESGO guidelines based on the new evidence addressing the management of vulvar cancer and to cover new topics in order to provide comprehensive guidelines on all relevant issues of diagnosis and treatment of vulvar cancer.
METHODS
The ESGO Council nominated an international development group comprised of practicing clinicians who provide care to vulvar cancer patients and have demonstrated leadership through their expertize in clinical care and research, national and international engagement and profile as well as dedication to the topics addressed to serve on the expert panel (18 experts across Europe). To ensure that the statements were evidence-based, new data identified from a systematic search were reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Prior to publication, the guidelines were reviewed by 206 international practitioners in cancer care delivery and patient representatives.
RESULTS
The updated guidelines cover comprehensively diagnosis and referral, staging, pathology, pre-operative investigations, surgical management (local treatment, groin treatment, sentinel lymph node procedure, reconstructive surgery), (chemo)radiotherapy, systemic treatment, treatment of recurrent disease (vulvar, inguinal, pelvic, and distant recurrences), and follow-up. Management algorithms are also defined.
Topics: Female; Humans; Europe; Gynecology; Plastic Surgery Procedures; Vulvar Neoplasms
PubMed: 37369376
DOI: 10.1136/ijgc-2023-004486 -
Journal of Clinical Oncology : Official... Sep 2023The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate...
PURPOSE
The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC).
METHODS
Data of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier's methodology and log-rank tests.
RESULTS
A total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε (mut EC). In mismatch repair-deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; < .0001).
CONCLUSION
The molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in mut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control.
Topics: Female; Humans; Radiation Oncology; Endometrial Neoplasms; Brachytherapy; Combined Modality Therapy
PubMed: 37487144
DOI: 10.1200/JCO.23.00062 -
Gut Feb 2024Metastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain...
OBJECTIVE
Metastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain largely undiscovered.
DESIGN
We performed single-cell RNA sequencing and spatial transcriptomic analysis in primary colorectal cancer (CRC) and metastases in the liver (lCRC) or ovary (oCRC). We also conducted immunofluorescence staining and functional experiments to examine the mechanism.
RESULTS
Integrative analyses of epithelial cells reveal a stem-like cell cluster with high () and () expression as the metastatic culprit. This cell cluster comprising distinct subpopulations shows distinct liver or ovary metastatic preference. Population 1 (P1) cells with high and expression are enriched in primary CRC and oCRC, thus may be associated with ovarian metastasis. P3 cells having a similar expression pattern as cholangiocytes are found mainly in primary CRC and lCRC, presuming to be likely the culprits that specifically metastasise to the liver. Stem-like cells interacted with cancer-associated fibroblasts and endothelial cells via the DLL4-NOTCH signalling pathway to metastasise from primary CRC to the ovary. In the oCRC microenvironment, myofibroblasts provide cancer cells with glutamine and perform a metabolic reprogramming, which may be essential for cancer cells to localise and develop in the ovary.
CONCLUSION
We uncover a mechanism for organ-specific CRC metastasis.
Topics: Female; Humans; Colorectal Neoplasms; Endothelial Cells; Liver Neoplasms; Gene Expression Profiling; Signal Transduction; Gene Expression Regulation, Neoplastic; Neoplasm Metastasis; Tumor Microenvironment; Basic Helix-Loop-Helix Transcription Factors
PubMed: 38050068
DOI: 10.1136/gutjnl-2023-330243