Colorectal peritoneal carcinomatosis (PC) is commonly treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). There is an ongoing international debate about ...which intraperitoneal chemotherapeutic agent is preferred, Mitomycin C (MMC) or oxaliplatin. We questioned whether the type of chemotherapeutic agent influenced postoperative complication rates or short-term survival.
In this retrospective cohort study patients with colorectal PC who underwent CRS-HIPEC between January 2010 and December 2016 were included. Until March 2014 patients had preferentially been treated with MMC and thereafter with oxaliplatin in an iso-osmotic glucose/electrolyte dialysis (Dianeal®) carrier solution. Main outcomes were postoperative complications, disease free survival (DFS) and overall survival (OS). Survival analyses and multivariable analyses were performed.
One hundred four patients received MMC and 73 patients oxaliplatin. Postoperative complications did not differ between groups (44.2% (MMC) versus 43.8% (oxaliplatin); P = 0.958). Median DFS was 12.5 months (IQR 6.4–32.4) in the MMC-group and 13.1 months (IQR 6.1-NA) in the oxaliplatin-group (P = 0.669). Median OS was 37.2 months (IQR 17.2-NA) in the MMC-group and 29.4 months (IQR 17.0-NA) in the oxaliplatin-group (P = 0.764). The type of chemotherapeutic agent did not influence OS in multivariable analysis (oxaliplatin versus MMC HR 1.09 (95%CI 0.58–2.06)). The HIPEC-phase was shorter for oxaliplatin (median 32 (IQR 31–34) versus 91 min (IQR 90–92) for MMC (P < 0.001)).
Intraperitoneal oxaliplatin reduced the chemoperfusion time when compared to intraperitoneal MMC without adversely influencing complication rates or short-term survival. It may therefore be the preferential drug in CRS-HIPEC procedures for colorectal PC.
Caspase‐3 (CASP3) is a major mediator of apoptosis activated during cellular exposure to cytotoxic drugs, radiotherapy or immunotherapy. It is often used as a marker for efficacy of cancer therapy. ...However, recent reports indicate that caspase‐3 has also non‐apoptotic roles such as promotion of tumor relapse and tumor angiogenesis. Therefore, the roles of caspase‐3 in tumor progression remain to be defined clearly. In our study, we established caspase‐3 knockout (KO) colon cancer cell lines by use of the CRISPR technology. In vitro, caspase‐3 knockout HCT116 cells were significantly less clonogenic in soft agar assays. They were also significantly less invasive and more sensitive to radiation and mitomycin C than control cells. In vivo, CASP3KO cells formed tumors at rates similar to control cells but were significantly more sensitive to radiotherapy. They were also less prone to pulmonary metastasis when inoculated either subcutaneously or intravenously. At the mechanistic level, caspase‐3 gene knockout appeared to cause reduced EMT phenotypes when compared to parental HCT116 cells. Indeed, they showed significantly increased E‐cadherin expression, reduced N‐cadherin, Snail, Slug and ZEB1 expression than control cells. Therefore, therapeutic targeting of caspase‐3 may not only increase the sensitivity of cancer cell to chemotherapy and radiotherapy, but also inhibit cancer cell invasion and metastasis.
What's new?
The main function of caspase‐3 is to eliminate damaged cells. Following activation, it cleaves proteins vital to cell function, thereby fueling apoptosis. As a result, caspase‐3 generally is thought to be a beneficial factor in cancer therapy. This study shows, however, that caspase‐3 plays important roles in promoting colon cancer cell invasion and metastasis. Compared to control cells, caspase‐3 knockout colon cancer cells (CASP3KO) demonstrated significantly reduced invasive potential in vitro. In vivo, tumors formed by CASP3KO cells exhibited increased sensitivity to radiotherapy and reduced metastatic tendency. The findings suggest that caspase‐3 is a potential target for colon cancer therapy.
Purpose
To assess surgical success and the post‐operative development of intraocular pressure between XEN45® gelstent, Preserflo® MicroShunt and trabeculectomy with mitomycin C.
Methods
Data from 105 ...eyes from 105 patients of matched cases with refractory open‐angle glaucoma, who underwent surgery between January 2019, and August 2020, were evaluated. Patients underwent either stand‐alone XEN gelstent insertion with Mitomycin C, stand‐alone Preserflo with Mitomycin C or trabeculectomy with Mitomycin C. The primary outcome was the proportion of complete surgical success at 6 months post‐operatively (i.e. intraocular pressure between 5mmHg and 18mmHg, no revision surgery, no loss of light perception and no post‐operative pharmaceutical antiglaucomatous treatment). The reduction of intraocular pressure after 6 months, the classes of antiglaucomatous medication used post‐operatively, best‐corrected visual acuity, spherical refractive errors and astigmatism were assessed as secondary outcomes.
Results
We included 35 eyes in each group. After 6‐month follow‐up, complete success was 73.5% 95%‐CI: 57.9%–89.2% in the trabeculectomy group, 51.4% 95%‐CI: 34.0%–68.8% in the XEN group and 74.2% 95%‐CI: 57.9%–90.5% in the Preserflo group (p = 0.08). Regarding secondary outcomes, the reduction of intraocular pressure was 12.1 ± 7.9 mmHg in the trabeculectomy group and was thereby 5.8 95%‐CI: 2.2–9.6 mmHg greater compared with the XEN group (p < 0.001) and 4.8 95%‐CI: 0.9–8.7 mmHg higher than the Preserflo group (p = 0.01).
Conclusions
No statistically significant differences were found between trabeculectomy, XEN45® gelstent implantation and Preserflo® MicroShunt implantation regarding surgical success after 6 months. Yet reduction in intraocular pressure was significantly higher in the trabeculectomy group. However, all three interventions resulted in sufficiently low post‐operative intraocular pressure and may therefore be considered individually for glaucoma treatment.
Systemic absorbtion of topically applied mitomycin C (MMC) during trabeculectomy needs to be evaluated to look for any systemic toxicity, which might be a major concern in certain conditions like ...pregnancy.
After obtaining ethical committee clearance, female patients in the reproductive age group undergoing trabeculectomy with MMC were included. Pregnant/lactating patients, patients with any systemic illness were excluded. During trabeculectomy, 0.02% MMC was applied subconjunctivally for 2 min and then washed. Blood samples were withdrawn at 1, 2, 4, 8, 12, and 24 hrs after the surgery and analyzed of MMC levels using Liquid chromatography-tandem mass spectroscopy (LC-MS/MS).
The mean age of the participants was 29 ± 12 years. MMC was not detected in any of the plasma samples analyzed as it was less than the detection limit (<1.56 ng/mL) of the employed LC-MS/MS assay.
It can be deduced that the systemic absorption of MMC is negligible or the plasma concentration is less than 1.56 ng/ml (1000 times less than the concentration where systemic toxicity was not observed).
Ocular Surface Squamous Neoplasia (OSSN) is an umbrella term that includes a broad spectrum of conjunctival and corneal malignancies, ranging from mild epithelial dysplasia to invasive squamous cell ...carcinoma. These are uncommon ocular surface lesions but harbour the potential to cause significant ocular morbidity and rarely mortality. Human Papilloma Viruses (HPV) and Ultraviolet-B light (UV) have been identified as important risk factors in aetiopathogenesis. The present OSSN patient is a 48- year-old male with redness, growth, and a foreign body sensation in his left eye over the past four months. Examination of the left eye revealed a growth in the nasal limbus with a feeder vessel measuring 0.9x0.3x0.1 cm in size. Diagnosis was confirmed by anterior segment Optical Coherence Tomography (OCT). The patient was admitted for an excision biopsy accompanied by intraoperative Mitomycin-C. The lesion’s histopathology revealed grade 2 in situ carcinoma with spheroidal formation. This case is considered rare due to the infrequent association between Conjunctival Intraepithelial Neoplasia (CIN) and spheroidal degeneration.
Background
Definitive chemoradiotherapy (CRT) with 5-fluorouracil plus mitomycin-C is a standard treatment for stage II/III squamous cell carcinoma of the anal canal (SCCA). We performed this ...dose-finding and single-arm confirmatory trial of CRT with S-1 plus mitomycin-C to determine the recommended dose (RD) of S-1 and evaluate its efficacy and safety for locally advanced SCCA.
Methods
Patients with clinical stage II/III SCCA (UICC 6th) received CRT comprising mitomycin-C (10 mg/m
2
on days 1 and 29) and S-1 (60 mg/m
2
/day at level 0 and 80 mg/m
2
/day at level 1 on days 1–14 and 29–42) with concurrent radiotherapy (59.4 Gy). Dose-finding used a 3 + 3 cohort design. The primary endpoint of the confirmatory trial was 3-year event-free survival. The sample size was 65, with one-sided alpha of 5%, power of 80%, and expected and threshold values of 75% and 60%, respectively.
Results
Sixty-nine patients (dose-finding, n = 10; confirmatory, n = 59) were enrolled. The RD of S-1 was determined as 80 mg/m
2
/day. Three-year event-free survival in 63 eligible patients who received the RD was 65.0% (90% confidence interval 54.1–73.9). Three-year overall, progression-free, and colostomy-free survival rates were 87.3%, 85.7%, and 76.2%, respectively; the complete response rate was 81% on central review. Common grade 3/4 acute toxicities were leukopenia (63.1%), neutropenia (40.0%), diarrhea (20.0%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). No treatment-related deaths occurred.
Conclusions
Although the primary endpoint was not met, S-1/mitomycin-C chemoradiotherapy had an acceptable toxicity profile and favorable 3-year survival and could be a treatment option for locally advanced SCCA.
Clinical trial information
jRCTs031180002.
Several liposome products have been approved for the treatment of cancer. In all of them, the active agents are encapsulated in the liposome water phase passively or by transmembrane ion gradients. ...An alternative approach in liposomal drug delivery consists of chemically modifying drugs to form lipophilic prodrugs with strong association to the liposomal bilayer. Based on this approach, we synthesized a mitomycin c-derived lipidic prodrug (MLP) which is entrapped in the bilayer of PEGylated liposomes (PL-MLP, Promitil®), and activated by thiolytic cleavage. PL-MLP is stable in plasma with thiolytic activation of MLP occurring exclusively in tissues and is more effective and less toxic than conventional chemotherapy in various tumor models. PL-MLP has completed phase I clinical development where it has shown a favorable safety profile and a 3-fold reduction in toxicity as compared to free mitomycin c. Clinical and pharmacokinetic studies in patients with advanced colo-rectal carcinoma have indicated a significant rate of disease stabilization (39%) in this chemo-refractory population and significant prolongation of median survival in patients attaining stable disease (13.9 months) versus progressive disease patients (6.35 months). The pharmacokinetics of MLP was typically stealth with long T½ (~1 day), slow clearance and small volume of distribution. Interestingly, a longer T½, and slower clearance were both correlated with disease stabilization and longer survival. This association of pharmacokinetic parameters with patient outcome suggests that arrest of tumor growth is related to the enhanced tumor localization of long-circulating liposomes and highlights the importance of personalized pharmacokinetic evaluation in the clinical use of nanomedicines. Another important area where PL-MLP may have an added value is in chemoradiotherapy, where it has shown a strong radiosensitizing effect in animal models based on a unique mechanism of enhanced prodrug activation and encouraging results in early human testing.
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Purpose
To analyze the effect of uneventful cataract surgery on intraocular pressure (IOP) in pseudoexfoliation glaucoma (PXG) eyes with and without a history of Mitomycin C-augmented trabeculectomy.
...Methods
Eyes with PXG that had underwent uneventful cataract surgery were enrolled. The IOP and the medication numbers before cataract surgery, and 1, 3, 6, 12, 18, 24 months after cataract surgery, and at the last visit were recorded in PXG with and without previous trabeculectomy. Failure was defined as IOP > 21 or ≤ 21 mmHg with additional medication or surgery. In the postoperative first 24 h, IOP > 50% above baseline was defined as an IOP spike.
Results
In the trabeculectomized eyes (
n
= 37), the increase in the mean IOP (
p
= 0.024) and the increase in the mean number of medications (
p
= 0.007) was significant at the last visit when compared with baseline. In the non-trabeculectomized eyes (
n
= 42) there was a significant decrease in the mean IOP (
p
= 0.016) and in the mean number of medications (
p
= 0.038) at the last visit. Twelve eyes (32.4%) in trabeculectomized group and six (14.3%) in the non-trabeculectomized group experienced failure. An IOP spike was seen in one eye in the trabeculectomized group, in 15 eyes in the non-trabeculectomized group (
p
< 0.0001). The IOP spike was a significant risk factor for failure (
p
= 0.027).
Conclusion
Uneventful cataract surgery may have significant negative effect on the IOP control in the trabeculectomized PXG eyes. After cataract surgery, the non-trabeculectomized PXG eyes had a higher risk of IOP spike and an IOP spike may be a risk factor for failure.
Abstract
Colonial ascidians are the only chordates able to undergo whole body regeneration (WBR), during which entire new bodies can be regenerated from small fragments of blood vessels. Here, we ...show that during the early stages of WBR in
Botrylloides diegensis
, proliferation occurs only in small, blood-borne cells that express
integrin-alpha-6 (IA6), pou3
and
vasa
. WBR cannot proceed when proliferating IA6+ cells are ablated with Mitomycin C, and injection of a single IA6+ Candidate stem cell can rescue WBR after ablation. Lineage tracing using EdU-labeling demonstrates that donor-derived IA6+ Candidate stem cells directly give rise to regenerating tissues. Inhibitors of either Notch or canonical Wnt signaling block WBR and reduce proliferation of IA6+ Candidate stem cells, indicating that these two pathways regulate their activation. In conclusion, we show that IA6+ Candidate stem cells are responsible for whole body regeneration and give rise to regenerating tissues.
Various cyclin-dependent kinase (Cdk) complexes have been implicated in the regulation of transcription. In this study, we identified a 70-kDa Cyclin K (CycK) that binds Cdk12 and Cdk13 to form two ...different complexes (CycK/Cdk12 or CycK/Cdk13) in human cells. The CycK/Cdk12 complex regulates phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II and expression of a small subset of human genes, as revealed in expression microarrays. Depletion of CycK/Cdk12 results in decreased expression of predominantly long genes with high numbers of exons. The most prominent group of down-regulated genes are the DNA damage response genes, including the critical regulators of genomic stability: BRCA1 (breast and ovarian cancer type 1 susceptibility protein 1), ATR (ataxia telangiectasia and Rad3-related), FANCI, and FANCD2. We show that CycK/Cdk12, rather than CycK/Cdk13, is necessary for their expression. Nuclear run-on assays and chromatin immunoprecipitations with RNA polymerase II on the BRCA1 and FANCI genes suggest a transcriptional defect in the absence of CycK/Cdk12. Consistent with these findings, cells without CycK/Cdk12 induce spontaneous DNA damage and are sensitive to a variety of DNA damage agents. We conclude that through regulation of expression of DNA damage response genes, CycK/Cdk12 protects cells from genomic instability. The essential role of CycK for organisms in vivo is further supported by the result that genetic inactivation of CycK in mice causes early embryonic lethality.
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