UBC9, the sole E2-conjugating enzyme required for SUMOylation, is a key regulator of essential cellular functions and, as such, is frequently altered in cancers. Along these lines, we recently ...reported that its expression gradually increases during early stages of human papillomavirus (HPV)-mediated cervical lesions transformation. However, a better understanding of how UBC9 is exploited by transforming viral oncoproteins is still needed. In the present study, we show that in human samples HPV drives UBC9 up-regulation also in very early steps of head and neck tumorigenesis, pointing to the important role for UBC9 in the HPV-mediated carcinogenic program. Moreover, using HPV-infected pre-cancerous tissues and primary human keratinocytes as the natural host of the virus, we investigate the pathological meaning and the cellular mechanisms responsible for UBC9 de-regulation in an oncoviral context. Our results show that UBC9 overexpression is promoted by transforming viral proteins to increase host cells' resistance to apoptosis. In addition, ultrastuctural, pharmacological and genetic approaches crucially unveil that UBC9 is physiologically targeted by autophagy in human cells. However, the presence of HPV E6/E7 oncoproteins negatively impacts the autophagic process through selective inhibition of autophagosome-lysosome fusion, finally leading to p53 dependent UBC9 accumulation during viral-induced cellular transformation. Therefore, our study elucidates how UBC9 is manipulated by HPV oncoproteins, details the physiological mechanism by which UBC9 is degraded in cells, and identifies how HPV E6/E7 impact on autophagy. These findings point to UBC9 and autophagy as novel hallmarks of HPV oncogenesis, and open innovative avenues towards the treatment of HPV-related malignancies.
Skin-sparing (SSM) and nipple-sparing (NSM) mastectomies are relatively new conservative surgical approaches to breast cancer. In SSM most of the breast skin is conserved to create a pocket that ...facilitates immediate breast reconstruction with implant or autologous graft to achieve a quality cosmetic outcome. NSM is closely similar except that the nipple-areola complex (NAC) is also conserved. Meta-analyses indicate that outcomes for SSM and NSM do not differ from those for non-conservative mastectomies. Recurrence rates in the NAC after NSM are acceptably low (0–3.7%). Other studies indicate that NSM is associated with high patient satisfaction and good psychological adjustment.
Indications are carcinoma or DCIS that require mastectomy (including after neoadjuvant chemotherapy). NSM is also suitable for women undergoing risk-reducing bilateral mastectomy.
Tumor not less than 2 cm from the NAC is recommended, but may be less important than no evidence of nipple involvement on mandatory intraoperative nipple margin assessment. A positive margin is an absolute contraindication for nipple preservation. Other contraindications are microcalcifications close to the subareolar region and a positive nipple discharge.
Complication rates are similar to those for other types of post-mastectomy reconstructions. The main complication of NSM is NAC necrosis, however as surgeon experience matures, frequency declines. Factors associated with complications are voluminous breast, ptosis, smoking, obesity, and radiotherapy.
Since the access incision is small, breast tissue may be left behind, so only experienced breast surgeons should do these operations in close collaboration with the plastic surgeon. For breast cancer patients requiring mastectomy, NSM should be the option of choice.
Summary Background Intraoperative radiotherapy with electrons allows the substitution of conventional postoperative whole breast irradiation with one session of radiotherapy with the same equivalent ...dose during surgery. However, its ability to control for recurrence of local disease required confirmation in a randomised controlled trial. Methods This study was done at the European Institute of Oncology (Milan, Italy). Women aged 48–75 years with early breast cancer, a maximum tumour diameter of up to 2·5 cm, and suitable for breast-conserving surgery were randomly assigned in a 1:1 ratio (using a random permuted block design, stratified for clinical tumour size <1·0 cm vs 1·0–1·4 cm vs ≥1·5 cm) to receive either whole-breast external radiotherapy or intraoperative radiotherapy with electrons. Study coordinators, clinicians, and patients were aware of the assignment. Patients in the intraoperative radiotherapy group received one dose of 21 Gy to the tumour bed during surgery. Those in the external radiotherapy group received 50 Gy in 25 fractions of 2 Gy, followed by a boost of 10 Gy in five fractions. This was an equivalence trial; the prespecified equivalence margin was local recurrence of 7·5% in the intraoperative radiotherapy group. The primary endpoint was occurrence of ipsilateral breast tumour recurrences (IBTR); overall survival was a secondary outcome. The main analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01849133. Findings 1305 patients were randomised (654 to external radiotherapy and 651 to intraoperative radiotherapy) between Nov 20, 2000, and Dec 27, 2007. After a medium follow-up of 5·8 years (IQR 4·1–7·7), 35 patients in the intraoperative radiotherapy group and four patients in the external radiotherapy group had had an IBTR (p<0·0001). The 5-year event rate for IBRT was 4·4% (95% CI 2·7–6·1) in the intraoperative radiotherapy group and 0·4% (0·0–1·0) in the external radiotherapy group (hazard ratio 9·3 95% CI 3·3–26·3). During the same period, 34 women allocated to intraoperative radiotherapy and 31 to external radiotherapy died (p=0·59). 5-year overall survival was 96·8% (95% CI 95·3–98·3) in the intraoperative radiotherapy group and 96·9% (95·5–98·3) in the external radiotherapy group. In patients with data available (n=464 for intraoperative radiotherapy; n=412 for external radiotherapy) we noted significantly fewer skin side-effects in women in the intraoperative radiotherapy group than in those in the external radiotherapy group (p=0·0002). Interpretation Although the rate of IBTR in the intraoperative radiotherapy group was within the prespecified equivalence margin, the rate was significantly greater than with external radiotherapy, and overall survival did not differ between groups. Improved selection of patients could reduce the rate of IBTR with intraoperative radiotherapy with electrons. Funding Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, and Umberto Veronesi Foundation.
The aim of the present systematic review was to evaluate the hypothesis of an association between periodontitis and the development of cancer.
Two reviewers independently screened electronic and ...manual sources for pertinent articles. Primary outcome measures were the occurrence of neoplasm diagnosis in exposed and non-exposed groups, reported to evaluate association between cancer and periodontitis.
Of the 490 initially retrieved papers 10 were included in the qualitative synthesis and eight in the quantitative synthesis; the eight papers covered six studies. Considering hazard ratios, a statistically significant association was found for all cancers studied (1.14; CI 95%: 1.04, 1.24), digestive tract cancer (1.34; CI 95%: 1.05, 1.72), pancreatic cancer (1.74; CI 95%: 1.21, 2.52), prostate cancer (1.25; CI 95%: 1.04, 1.51), breast cancer (1.11; CI 95%: 1.00, 1.23), corpus uteri cancer (2.20; CI 95%: 1.16, 4.18), lung cancer (1.24; CI 95%: 1.06, 1.45), hematological cancer (1.30; CI 95%: 1.11, 1.53), esophagus / oropharyngeal cancer pooled together (2.25; CI 95%: 1.30, 3.90) and Non-Hodgkin lymphoma (1.30; CI 95%: 1.11, 1.52).
Despite the sparse scientific evidence and considering the low statistical power of the results, this systematic review revealed a substantial lack of studies with standardized and comparable methods to speculate about the association between periodontitis and cancer; more studies are need in order to explore further the scientific evidence of such correlation.
The increased use of neoadjuvant chemotherapy (NACT) has changed the approach to breast surgery. NACT allows de-escalation of surgery by both increasing breast conservation rates (up to 40%), the ...initial goal of this chemotherapy, and in particular it permits reduces axillary surgery. Furthermore, in relation to the molecular characteristics of the tumor we can have a pathological complete response (pCR) ranging from 20 to 80%.
In clinically node positive (cN+) patients who converted to clinically node-negative (cN0) various prospective studies have demonstrated that the false negative rate (FNR) of the sentinel node biopsy (SNB) were higher than the acceptable 10% and strategies to reduce the FNR in cN + patients are being investigated.
But all the effort to reduce the FNR does not have clinical prognostic significance. This has already been demonstrated in the literature in different randomized trials with long term follow up.
The 10-year follow-up of our study confirmed our preliminary data that the use of standard SNB without the use of clip is acceptable in cN1/2 patients who become cN0 after NAT and will not translate into a worse outcome.
In fact, the axillary recurrences were less than 2%. Similar positive data with different follow up were also confirmed by other studies that used SNB alone without TAD. All these studies, with encouraging results on the follow up, confirm that SN surgery alone for selected patients who have an excellent response to NACT is rationale and not oncologically inferior to AD during a short- and long-term follow-up.
•Sentinel node biopsy alone (SNB) without the use of clip is acceptable in cN + patients who become cN0 NACT•SNB alone post NACT will not translate into a worse outcome.•Different studies with SNB alone demonstrate good outcome.
Background
Robotic nipple-sparing mastectomy (RNSM) may allow for more precise anatomic dissection and improved cosmetic outcomes over conventional open nipple-sparing mastectomy; however, data ...regarding the feasibility and safety of the procedure are limited.
Objective
The aim of this study was to present and discuss perioperative surgical outcomes and early oncologic follow-up data on consecutive patients undergoing RNSM from June 2014 to January 2019.
Methods
Patients underwent RNSM and immediate robotic breast reconstruction through an axillary incision at a single institution. Perioperative data, complications at 3 months postoperatively, pathological data, and adjuvant therapies were recorded. Local recurrence-free, disease-free, and overall survival were analyzed.
Results
Overall, 73 women underwent 94 RNSM procedures. Indications were invasive breast cancer in 39 patients, ductal carcinoma in situ in 17 patients, and BRCA mutation in 17 patients. Mean surgery time was 3 h and 32 min. One-step reconstruction with implant occurred in 89.4% of procedures. The rate of complications requiring reoperation was 4.3%, and the rate of flap or nipple necrosis was 1.1%. Median follow-up was 19 months (range 3.1–44.8). No local recurrences occurred. Overall survival at 12, 24, or 60 months was 98% (95% confidence interval 86–100%).
Conclusion
We observed a low complication rate in 94 consecutive RNSM procedures, demonstrating the procedure is technically feasible and safe. We found no early local failures at 19 months follow-up. Long-term follow-up is needed to confirm oncologic safety. Future clinical trials to study the advantages and disadvantages of RNSM are warranted.
Metformin is associated with reduced breast cancer risk in observational studies in patients with diabetes, but clinical evidence for antitumor activity is unclear. The change in Ki-67 between ...pretreatment biopsy and post-treatment surgical specimen has prognostic value and may predict antitumor activity in breast cancer.
After tumor biopsy, we randomly allocated 200 nondiabetic women with operable breast cancer to either metformin 850 mg/twice per day (n = 100) or placebo (n = 100). The primary outcome measure was the difference between arms in Ki-67 after 4 weeks adjusted for baseline values.
Overall, the metformin effect on Ki-67 change relative to placebo was not statistically significant, with a mean proportional increase of 4.0% (95% CI, -5.6% to 14.4%) 4 weeks apart. However, there was a different drug effect depending on insulin resistance (homeostasis model assessment HOMA index > 2.8, fasting glucose mmol/L × insulin mU/L/22.5; P(interaction) = .045), with a nonsignificant mean proportional decrease in Ki-67 of 10.5% (95% CI, -26.1% to 8.4%) in women with HOMA more than 2.8 and a nonsignificant increase of 11.1% (95% CI, -0.6% to 24.2%) with HOMA less than or equal to 2.8. A different effect of metformin according to HOMA index was noted also in luminal B tumors (P(interaction) = .05). Similar trends to drug effect modifications were observed according to body mass index (P = .143), waist/hip girth-ratio (P = .058), moderate alcohol consumption (P = .005), and C-reactive protein (P = .080).
Metformin before surgery did not significantly affect Ki-67 overall, but showed significantly different effects according to insulin resistance, particularly in luminal B tumors. Our findings warrant further studies of metformin in breast cancer with careful consideration to the metabolic characteristics of the study population.
Background
The latest National Comprehensive Cancer Network Breast Cancer Guidelines still discourage repeat sentinel node biopsy (SNB) after mastectomy, and the largest multicentric study available ...reports only 35 cases in the absence of previous axillary dissection (AD).
Methods
From January 2003 to November 2018, 89 patients of the European Institute of Oncology with local recurrence of breast cancer after mastectomy, free of distant metastases, with a clinically negative axilla and a negative axillary ultrasound, in absence of AD, underwent lymphatic mapping before wide local excision.
Results
During surgery, SNB was successful for 99% of the patients, with 14% being metastatic. Additional metastatic nodes removed by AD after a positive sentinel node occurred in 82% of cases. After a medium follow-up period of 3.7 years, the overall survival rate was 96.7%, and the disease-free survival rate was 84.4%. No axillary relapse after AD was recorded. One patient who refused human epidermal growth factor receptor 2 (HER2)-targeted treatment experienced ipsilateral axillary recurrence after a negative repeat SNB. The first axillary level was never directly irradiated because all the patients with positive repeat SNB underwent AD. For invasive luminal-like HER2-negative recurrences, the metastatic sentinel node was significantly associated with the choice to prescribe adjuvant chemotherapy (
p
= 0.003).
Conclusions
In specialized centers, repeat axillary SNB for patients with local recurrence after mastectomy in the absence of previous AD can represent a safe option for detection and removal of occult axillary disease that would otherwise not be excised/irradiated to achieve better local control and could possibly influence the choice of adjuvant treatments.
Background
Breast cancer during pregnancy (PrBC) is a rare condition known for its aggressive clinical behavior. The presence of tumor-infiltrating lymphocytes (TILs) has been shown to have a ...significant impact on the prognosis of these patients. Despite some biological characteristics of the tumor that may differ depending on the gestational age, little is known about the dynamics of the immune landscape within the tumor microenvironment (TME) in PrBC. Therefore, in this study, our objective was to gain comprehensive insights into the relationship between gestational age at breast cancer diagnosis and the composition of the TME.
Methods
n
= 108 PrBC were selected from our institutional registry and categorized based on the gestational age by trimester. For all cases, TILs were profiled according to the International TILs Working Group recommendations, and subtyped by CD4, CD8, and forkhead box P3 (FOXP3) immunohistochemistry. PD-L1 was tested according to the combined positive score (CPS) using the IHC 22C3 pharmDx assay, with a cutoff value of ≥10 for positivity. The statistical approach encompassed Fisher’s and Chi-squared tests, with appropriate adjustments for multiple comparisons, logistic regression models, and survival analyses based on the Kaplan–Meier method.
Results
The proportion of patients with poorly differentiated (G3) neoplasms increased as the gestational age advanced (first trimester,
n
= 25, 56.8%; second trimester,
n
= 27, 69.2%; third trimester,
n
= 21, 87.5%;
p
= 0.03). The histologic subtypes as well as the hormone receptor (HR) and HER2 status did not show significant changes across different pregnancy trimesters. In the HR+/HER2– subtype, there was a higher proportion of tumors with high/moderate TILs in the early phases of pregnancy, similar to FOXP3 expression (TILs: first trimester,
n
= 10, 35.7%; second trimester,
n
= 2, 10.5%; third trimester,
n
= 0;
p
= 0.02; FOXP3: first trimester,
n
= 10, 40%; second trimester,
n
= 3, 15.8%; third trimester,
n
= 0;
p
= 0.03). The median follow-up for our cohort was 81 months. Patients who relapsed after a breast cancer diagnosis during the first trimester were more frequently PD-L1-negative, unlike those with no disease recurrence (
n
= 9, 100% vs.
n
= 9, 56.3%;
p
= 0.03; hormone therapy and
n
= 9, 100% vs.
n
= 7, 53.9%;
p
= 0.02; chemotherapy). No statistically significant differences were seen among the three trimesters in terms of survival outcome.
Conclusion
The TME dynamics of HR+/HER2− PrBC vary based on gestational age, suggesting that immune tolerance expression during later gestational age could explain the increased aggressiveness of tumors diagnosed at that stage.
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