Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the capacity to deliver small molecules as drug cargoes. We utilized the sigma-2-based drug delivery concept to convert Erastin, a clinically underperforming drug, into a potent pancreatic cancer therapeutic. The Erastin derivative des-methyl Erastin (dm-Erastin) was chemically linked to sigma-2 ligand SV119 to create SW V-49. Conjugation increased the killing capacity of dm-Erastin by nearly 35-fold in vitro and reduced the size of established tumors and doubled the median survival in syngeneic and patient-derived xenograft models when compared to non-targeted dm-Erastin. Mechanistic analyses demonstrated that cell death was associated with robust reactive oxygen species production and could be efficiently antagonized with antioxidants. Mass spectrometry was employed to demonstrate selective uptake into pancreatic cancer cells. Thus, targeted delivery of dm-Erastin via conjugation to the sigma-2 ligand SV119 produced efficient tumor control and prolonged animal survival with minimal off-target toxicities, and SW V-49 represents a promising new therapeutic with the potential to advance the fight against pancreatic cancer.
BACKGROUND: The National Accreditation Program for Rectal Cancer (NAPRC) emphasizes a multidisciplinary approach for treating rectal cancer and has developed performance measures to ensure that patients receive standardized care. We hypothesized that rectal cancer patients receiving care at multiple centers would be less likely to receive timely and appropriate care. STUDY DESIGN: A single institution retrospective review of a prospectively maintained database was performed. All patients undergoing proctectomy and ≤1 other treatment modality (eg radiation and/or chemotherapy) for Stage II/III rectal adenocarcinoma were included. Unified care was defined as receiving all modalities of care at our institution, and fragmented care was defined as having at least 1 treatment modality at another institution. RESULTS: From 2009 to 2019, 415 patients met inclusion criteria, with 197 (47.5%) receiving fragmented care and 218 (52.5%) receiving unified care. The unified cohort patients were more likely to see a colorectal surgeon before starting treatment (89.0% vs 78.7%, p < 0.01) and start definitive treatment within 60 days of diagnosis (89.0% vs 79.7%, p = 0.01). On adjusted analysis, unified care patients were 2.78 times more likely to see a surgeon before starting treatment (95% CI 1.47–5.24) and 2.63 times more likely to start treatment within 60 days (95% CI 1.35–5.13). There was no difference in 90-day mortality or 5-year disease-free survival. CONCLUSIONS: This retrospective cohort study suggests patients with rectal cancer receiving fragmented care are at an increased risk of delays in care without any impact on disease-free survival. These findings need to be considered within the context of ongoing regionalization of rectal cancer care to ensure all patients receive optimal care, irrespective of whether care is delivered across multiple institutions.
To report long-term follow up of a phase II, single-center, single-arm trial of resectable pancreatic ductal adenocarcinoma (PDAC) treated with adjuvant interferon-based chemoradiation followed by gemcitabine to determine survival, recurrence, and complications. Methods From 2002 to 2005, 53 patients with PDAC underwent pancreaticoduodenectomy and received adjuvant interferon-based chemoradiation consisting of external-beam irradiation and simultaneous 3-drug chemotherapy of continuous daily 5-fluorouracil infusion, weekly intravenous bolus cisplatin, and subcutaneous interferon-α, followed by two 4-week courses of weekly intravenous gemcitabine. Results Actual overall survival for the 5- and 10-year periods were 26% and 10%, respectively, with a median overall survival of 25 months (95% CI: 16.4–38.5). Adverse prognostic factors on multivariate analysis were positive tumor margin (p<0.035), lymphovascular invasion (p<0.015), and perineural invasion (p<0.026). Median time to recurrence was 11 months. Positive tumor margin was associated with lymph node involvement (p<0.005), portal vein resection (p<0.038), and distant recurrence/metastases (p<0.018). Late complications were frequent and predominated by gastrointestinal and infectious complications. Conclusions Adjuvant interferon-based chemoradiation for PDAC improves long-term survival compared to standard therapy. However, recurrence rates and long-term complications remain high, thus further studies are indicated to assess patient characteristics that indicate a favorable treatment profile.
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