Abstract Ovarian carcinoma is the most lethal gynaecologic malignancy. Despite wide initial sensibility to chemotherapy especially to platinum-based regimens, the vast majority of patients with ...advanced stages of the disease develop recurrences and subsequent resistance to treatments. Ovarian cancer is actually considered as a heterogeneous disease at the clinical, histological and molecular level. In this review, the mechanisms of intrinsic sensitivity or resistance to treatment, especially to platinum-based chemotherapy are considered with particular reference to the significance of tumour heterogeneity. The molecular features involved in acquired resistance are reviewed and the current hypotheses are discussed. In particular, potential disruptions of the DNA reparation pathways are highlighted.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemotherapy and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic ...markers. We previously generated the nonligand competing anti‐HER3 antibody 9F7–F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7–F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody‐drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE‐based HER3 antibody‐drug conjugate (HER3‐ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3‐positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3‐ADC decreased the clonogenic survival of irradiated cells by increasing DNA double‐strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3‐ADC favored the inhibition of the AKT‐induced survival pathway, together with more efficient caspase 3/PARP‐mediated apoptosis. Incubation with HER3‐ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3‐ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient‐derived xenografts, and reduced proliferation (KI67‐positive cells). Combining auristatin radiosensitizer delivery via an HER3‐ADC with radiotherapy is a new promising therapeutic strategy in PDAC.
What's new?
In pancreatic ductal adenocarcinoma (PDAC), chemoradiation is prescribed to patients with borderline resectable lesions to make surgery possible. The HER3 receptor is a key signaling hub in PDAC. Here, the authors developed a novel antibody‐drug conjugate targeting HER3 (HER3‐ADC) that enhanced radiosensitivity of PDAC by arresting cells in G2/M. HER3‐ADC increased radiation response in mice xenografted with PDAC cells, through inhibition of cell survival and induction of DNA break formation and apoptosis. Combining auristatin radiosensitizer delivery via an HER3‐ADC with radiotherapy could help increase the rate of resection for patients with borderline resectable pancreatic cancer.
Poly(N-acryloyl glycinamide) is a neutral polymer that can form gel–sol thermoresponsive systems with upper critical solution temperature in aqueous media. The temperature of the reversible gel–sol ...transition depends on the molar mass and the concentration of macromolecules. These parameters were combined to adjust the transition temperature slightly above body temperature for the sake of respecting living tissues during the sol form injection using a classical syringe. On contact with local tissues, the injected sol turned rapidly to a gel. The simplicity of the process makes it exploitable to administrate and deliver neutral or ionic drug and especially those that are soluble in aqueous media. The versatility was exemplified from formulations with cobalt acetate, small polymers (MW~2000g/mol), tartrazine and methylene blue dyes and albumin. The model compounds were allowed to diffuse in an isotonic pH=7.4 buffered medium at 37°C. All the release profiles were typical of diffusion control with 100% release within 2 to 3weeks and no obvious burst. The in vitro release of methylene blue from a gel formulation was checked prior to injection in the peritoneal cavity of mice where the release of the dye was monitored visually through tissue and organ colorations. A comparable polymer-free dye solution was used as control. Coloration appeared rapidly in tissues and organs and it was still detectable 52h post injection of the gel whereas it was no longer present at 24h in control mice.
Display omitted
Background
Resectability of pancreatic carcinoma (PC) is directly linked to vascular extension (Tempero MA et al. in J Natl Compr Canc Netw 15(8):1028–1061, 2017.
...https://doi.org/10.6004/jnccn.2017.0131
; Isaji S et al. in Pancreatology 18(1):2–11, 2018.
https://doi.org/10.1016/j.pan.2017.11.011
). Involvement of the celiac axis (CA) is typically a contraindication to surgery. High postoperative morbidity and subsequent poor prognosis have been observed in this case, especially for contact > 180° requiring arterial resection (Tempero MA et al. 2017). Recent medical advances in PC treatment, such as FOLFIRINOX-based chemotherapy eventually followed by chemoradiation therapy, offer the potential to select tumour for surgery and to obtain a negative-margin resection even in case of unresectable PC at diagnosis (Suker M et al. in Lancet Oncol 17(6):801–10, 2016.
https://doi.org/10.1016/s1470-2045(16)00172-8
; Pietrasz D et al. in Ann Surg Oncol 26(1):109–117, 2019.
https://doi.org/10.1245/s10434-018-6931-6
). A major pathologic response has been observed in more than 20% of patients after this treatment and is associated with an improved survival (Suker M et al. 2016; Pietrasz D et al. 2019). This evolution allows aggressive surgical strategies with the possibility of long-term disease control for patients showing a good response to induction treatment.
Patient
This video presents the case of a 66-year-old man diagnosed with a locally advanced ductal adenocarcinoma of the pancreatic body with a 360° involvement of the CA and the hepatic artery. After eight courses of FOLFIRINOX chemotherapy and a capecitabin-based chemoradiation, a surgical exploration was planned for potential resection.
Technique
The key steps of the procedure are presented, i.e. surgical exposition, assessment of resectability with frozen sections of peri-arterial tissues,
en bloc
resection (Strasberg SM et al. in Surgery 133(5):521–527, 2003.
https://doi.org/10.1067/msy.2003.146
), and primary end-to-end arterial reconstruction.
Conclusion
A modified Appleby operation for locally advanced PC is a technically challenging but feasible procedure in experienced teams. It offers the possibility of
en
bloc R0 resection of a locally advanced PC with the potential of long-term disease local control. This video may help surgeons to perform this complex intervention.
Objective
The aim of this study is to compare robotic total mesorectal excision (R-TME) with laparoscopic TME (L-TME) in a series of consecutive rectal cancer patients.
Background
R-TME and L-TME ...have drawn contradictory reports. A recent phase III trial (ROLARR) concluded that R-TME performed by surgeons with varying experience did not confer an advantage in rectal cancer resection.
Patients and Methods
In this retrospective single-center cohort study (8/2008 to 4/2015), data were prospectively registered. A total of 200 L-TME and 200 R-TME were operated consecutively without selection. The primary outcome was the conversion rate to open laparotomy or transanal TME. The secondary endpoints were type of anastomosis, operative time, postoperative morbidity, circumferential radial (CRM) and distal margins, quality of life, bladder and sexual dysfunction, and oncological outcomes.
Results
Baseline characteristics were well balanced. Type of anastomosis colo-anal anastomosis (CAA) 40% vs 49%;
p
< 0.001, transanal TME (5% vs 13%;
p
= 0.005), and conversion rate (2% vs 9.5%; odd ratio (OR): 0.19 95% confidence interval (CI): 0.05–0.60) were significantly different. Intersphincteric resection (39% vs 47%), diverting stoma (66.5% vs 68%), CRM involvement, median operative time (243 vs 232 min), and R0 resection rate were similar. Conversion risk was lower for R-TME in male patients and those with small tumors (< 5 cm). The 3-year overall survival rate was 84.1% 77.3–88.9% and 88.4% 82.9–92.2% in the R-TME and L-TME group. No significant differences were reported in quality of life, and urinary or sexual function.
Conclusions
R-TME is less likely to be converted to open surgery than L-TME; operative time and curative pathologic criteria are equivalent. Future prospective trial should compare standardized procedures performed by experienced surgeons for subgroups of high-risk patients.
In ovarian carcinoma, anti-Müllerian hormone (AMH) type II receptor (AMHRII) and the AMH/AMHRII signaling pathway are potential therapeutic targets. Here, AMH dose-dependent effect on signaling and ...proliferation was analyzed in four ovarian cancer cell lines, including sex cord stromal/granulosa cell tumors and high grade serous adenocarcinomas (COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN). As previously shown, incubation with exogenous AMH at concentrations above the physiological range (12.5-25 nM) decreased cell viability. Conversely, physiological concentrations of endogenous AMH improved cancer cell viability. Partial AMH depletion by siRNAs was sufficient to reduce cell viability in all four cell lines, by 20% (OVCAR8 cells) to 40% (COV434-AMHRII cells). In the presence of AMH concentrations within the physiological range (5 to 15 pM), the newly developed anti-AMH B10 antibody decreased by 25% (OVCAR8) to 50% (KGN) cell viability at concentrations ranging between 3 and 333 nM. At 70 nM, B10 reduced clonogenic survival by 57.5%, 57.1%, 64.7% and 37.5% in COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN cells, respectively. In the four cell lines, B10 reduced AKT phosphorylation, and increased PARP and caspase 3 cleavage. These results were confirmed in ovarian cancer cells isolated from patients' ascites, demonstrating the translational potential of these results. Furthermore, B10 reduced COV434-MISRII tumor growth in vivo and significantly enhanced the median survival time compared with vehicle (69 vs 60 days; p = 0.0173). Our data provide evidence for a novel pro-survival autocrine role of AMH in the context of ovarian cancer, which was targeted therapeutically using an anti-AMH antibody to successfully repress tumor growth.
PDF
