Colorectal cancer primarily metastasizes to the liver and globally kills over 600,000 people annually. By functionally screening 661 microRNAs (miRNAs) in parallel during liver colonization, we have ...identified miR-551a and miR-483 as robust endogenous suppressors of liver colonization and metastasis. These miRNAs convergently target creatine kinase, brain-type (CKB), which phosphorylates the metabolite creatine, to generate phosphocreatine. CKB is released into the extracellular space by metastatic cells encountering hepatic hypoxia and catalyzes production of phosphocreatine, which is imported through the SLC6A8 transporter and used to generate ATP—fueling metastatic survival. Combinatorial therapeutic viral delivery of miR-551a and miR-483-5p through single-dose adeno-associated viral (AAV) delivery significantly suppressed colon cancer metastasis, as did CKB inhibition with a small-molecule inhibitor. Importantly, human liver metastases express higher CKB and SLC6A8 levels and reduced miR-551a/miR-483 levels relative to primary tumors. We identify the extracellular space as an important compartment for malignant energetic catalysis and therapeutic targeting.
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•miR-551a and miR-483-5p suppress colon cancer metastasis by targeting CKB•CKB promote metastatic survival by modulating intra- and extracellular energetics•miRNAs and CKB can be therapeutically targeted by AAV and small molecule delivery
The tumor microenvironment is a rich source of metabolic substrates that could be utilized by cancer cells. Colon cancer cells secrete a kinase that acts extracellularly to generate one such metabolite, phosphocreatinine, that directly fuels tumor growth and metastasis to the liver.
Background This study evaluated the feasibility, safety, and effectiveness of endovascular interventions for common femoral artery (CFA) occlusive disease. Methods Using a prospectively maintained ...multicenter database, we analyzed outcomes in 167 consecutive patients who underwent percutaneous CFA interventions for Rutherford class 3 to class 6 (R3-R6) disease. The standardized treatment approach included primary percutaneous transluminal angioplasty (PTA) only, atherectomy + PTA, and provisional stenting. Outcomes included technical failure rate, recurrence, complications, and major or minor amputation rate. Data were analyzed using multivariate regression analysis. Results During a 7-year period, 167 patients with R3 (n = 91 54.5%) and R4 to R6 (n = 76 45.5%) disease underwent CFA interventions that included PTA only (n = 114 68.2%), atherectomy ± PTA (n = 38 22.8%), and provisional stenting (n = 15 9.0%) for failed atherectomy ± PTA. Procedure-related complications included pseudoaneurysm (n = 1 0.6%), thrombosis (n = 1 0.6%), distal embolization (n = 1 0.6%), and death (R6, n = 1 0.06%). CFA restenosis was observed in 34 (20.4%) patents; these underwent further percutaneous (n = 18 10.8%) or surgical (n = 17 10.2%) revascularization that included CFA endarterectomy ± femoral distal bypass. Major or minor amputations were observed in none of the R3 patients and in only three (3.9%) and five (6.5%) of the R4 to R6 patients, respectively. Compared with the atherectomy + PTA group, patients in the PTA-only group had a significantly lower patency. Furthermore, during long-term mean follow-up of 42.5 months, the CFA provisional stent group had a 100% primary patency, which was significantly better than the primary patency in the CFA nonstent groups combined (77.0%; P = .0424). Conclusions Data from this study to date would suggest that percutaneous CFA interventions in select patients are relatively safe and effective. In the long term, CFA stenting has significantly better primary patency than CFA atherectomy and PTA combined. CFA atherectomy + PTA has significantly better primary patency than CFA PTA-only at midterm, especially in patients with claudication. Future randomized controlled trials are warranted.
Purpose This study evaluated the outcomes of secondary procedures after endovascular aneurysm repair (EVAR). Methods From 2002 to 2009, 1768 patients underwent EVAR for treatment of 1662 elective ...(94%) and 106 emergent (6%) infrarenal abdominal aortic aneurysm (AAA) with a variety of Food and Drug Administration-approved and commercially available stent grafts. Postoperative follow-up included clinical examination, pulse volume recording, duplex ultrasound imaging, and computed tomography and magnetic resonance angiography at 1, 6, and 12 months, and yearly thereafter. Patients with type I and III endoleaks, unexplained endotension, limb occlusion, stent graft migration, with and without type I endoleak, and aneurysm rupture underwent secondary interventions. Type II endoleak at >6 months without a decrease in the aneurysm sac underwent translumbar embolization. Data were prospectively collected. Results EVAR was performed in 1768 patients. During a mean follow-up of 34 (SD, 30.03) months, 339 patients (19.2%) required additional secondary procedures for aneurysm-related complications, including type I (n = 51, 15.0%), type II (n = 136, 40.1%), and type III (n = 5, 1.5%) endoleaks; endotension (n = 8, 2.4%), stent graft migration proximal fixation site (n = 46, 13.6%), stent graft iliac limb thrombosis or stenosis (n = 25, 7.4%), subsequent iliac aneurysm formation (n = 39, 11.5%), or aneurysm rupture after EVAR (n = 29, 8.6%). The mean age was 74 (SD, 9.15) years. Mean AAA size was 5.7 (SD 3.24) cm. Compared with secondary procedures for AAA rupture, the nonrupture patients had a significantly lower mortality (1.6% vs 17.2%, P < .05) and a higher likelihood of being managed by endovascular means (98.8% vs 44.8%, P < .05). When nonruptured EVAR patients required urgent secondary procedures for type I endoleaks and stent graft migration or limb thrombosis, the mortality was 6.0% vs 0.5% for elective procedures ( P < .05). Conclusions Our long-term EVAR experience indicates that 18% of patients require additional secondary procedures, and most of these patients can be managed by endovascular means with an acceptable overall mortality of 2.9%. Most type I and II endoleaks can be successfully treated by transluminal embolization, and most patients with delayed aneurysm rupture after EVAR can be successfully managed by endovascular or open surgical repair.
Background Women have a lower chance of surviving elective open abdominal aortic repair. The reasons for this are not clear. Endovascular repair has clearly reduced early and midterm morbidity and ...mortality for patients with large abdominal aortic aneurysms (AAAs). However, most patients are male. It is unclear whether there has been any reduction in elective morbidity for females or what the extent of that reduction has been. We prospectively analyzed outcomes for elective endovascular aneurysm repair (EVAR) in women at our center and compared results with those for elective open surgery and emergent open and endovascular repair. Methods All patients undergoing elective and emergency AAA from 2002 to 2009 were prospectively entered into a database. Demographic details, including gender, were tabulated. Outcome measures were operative blood loss, incidence of type 1 endoleaks, length of in-hospital stay, postoperative complications, 30-day all-cause mortality, and secondary interventions during the follow-up period. Statistical analysis was performed using Fischer exact test and Student t test. A multivariate analysis was also performed. Results From 2002 to 2009, there were 2631 abdominal aortic aneurysms (AAA) open and endovascular repairs performed in our center (1698 endovascular aneurysm repairs EVARs, 933 “open”). Males comprised 1995 (76%) of patients; females 636 (24%). There were 1592 elective EVARs (1248 male, 344 female) and 106 emergency EVARs (73 male, 33 female). Elective open repair was performed in 788 patients (579 male, 209 female) and emergency open repair in 149 (73 male, 76 female). For women, elective EVAR resulted in significantly greater mortality rates than men (3.2% vs 0.96%, P < .005). There was a greater incidence of intraoperative aortic neck or iliac artery rupture (4.1% vs 1.2% P = .002) and use of Palmaz stents for type 1 endoleaks (16.1% vs 8%, P = .0009). Mean blood loss was greater in females (327 mL vs 275 mL, P = .038). Perioperative complications were also more frequent in women: leg ischemia (3.5% vs 0.6%, P = .003) and colon ischemia requiring colectomy (0.9% vs 0.2%, P = .009). Mean hospital stay was also longer (3.7 days vs 2.2 days, P = .0001). In contrast, there were no gender differences for any of these outcome measures for elective open repair or emergency open surgery or EVAR. There was no significant difference in death rates between EVAR and open repair in women (3.2% vs 5.7%). In males, the 30-day mortality was 0.96% for elective EVAR and 4.7% for elective open surgery. Following logistic regression, female gender remains a significant risk even when the effects of aneurysm size and age are considered (odds ratio 3.4, P < .01). Conclusions Mortality for females undergoing elective EVAR is significantly greater than for males. It is also more hazardous. Colon ischemia, native arterial rupture, and type 1 endoleaks are more frequent. Elective endovascular aneurysm repair benefits men more than women.
Although neoadjuvant chemoradiotherapy achieves low local recurrence rates in clinical stages II to III rectal cancer, it delays administration of optimal chemotherapy. We evaluated preoperative ...infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/bevacizumab with selective rather than consistent use of chemoradiotherapy.
Thirty-two patients with clinical stages II to III rectal cancer participated in this single-center phase II trial. All were candidates for low anterior resection with total mesorectal excision (TME). Patients were to receive six cycles of FOLFOX, with bevacizumab included for cycles 1 to 4. Patients with stable/progressive disease were to have radiation before TME, whereas responders were to have immediate TME. Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX × 6 was recommended, but adjuvant regimens were left to clinician discretion. The primary outcome was R0 resection rate.
Between April 2007 and December 2008, 32 (100%) of 32 study participants had R0 resections. Two did not complete preoperative chemotherapy secondary to cardiovascular toxicity. Both had preoperative chemoradiotherapy and then R0 resections. Of 30 patients completing preoperative chemotherapy, all had tumor regression and TME without preoperative chemoradiotherapy. The pathologic complete response rate to chemotherapy alone was 8 of 32 (25%; 95% CI, 11% to 43%). The 4-year local recurrence rate was 0% (95% CI, 0% to 11%); the 4-year disease-free survival was 84% (95% CI, 67% to 94%).
For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes. Preoperative Radiation or Selective Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROSPECT), a randomized phase III trial to validate this experience, is now open in the US cooperative group network.
Strategies to stage and treat cancer rely on a presumption of either localized or widespread metastatic disease. An intermediate state of metastasis termed oligometastasis(es) characterized by ...limited progression has been proposed. Oligometastases are amenable to treatment by surgical resection or radiotherapy.
We analyzed microRNA expression patterns from lung metastasis samples of patients with ≤ 5 initial metastases resected with curative intent.
Patients were stratified into subgroups based on their rate of metastatic progression. We prioritized microRNAs between patients with the highest and lowest rates of recurrence. We designated these as high rate of progression (HRP) and low rate of progression (LRP); the latter group included patients with no recurrences. The prioritized microRNAs distinguished HRP from LRP and were associated with rate of metastatic progression and survival in an independent validation dataset.
Oligo- and poly- metastasis are distinct entities at the clinical and molecular level.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective Endovascular aneurysm repair (EVAR) decreases 30-day mortality for patients with ruptured abdominal aortic aneurysms (r-AAAs) compared with open surgical repair (OSR). However, which ...patients benefit or whether there is any long-term survival advantage is uncertain. Methods From 2002 to 2011, 283 patients with r-AAA underwent EVAR (n = 120 42.4%) or OSR (n = 163 57.6%) at Albany Medical Center. All data were collected prospectively. Patients were analyzed on an intention-to-treat basis, and outcomes were evaluated by a logistic regression multivariable model. Kaplan-Meier analysis was used to compare long-term survival. Results The EVAR patients had a significantly lower 30-day mortality than did the OSR patients (29/120 24.2% vs 72/163 44.2%; P < .005) and better cumulative 5-year survival (37% vs 26%; P < .005). Men benefited more from EVAR (mortality: 20.9% for EVAR vs 44.3% for OSR; P < .001) than did women (mortality: 32.4% vs 43.9%; P = .39). Age ≥80 years was a significant predictor of death for EVAR (odds ratio OR, 1.07; P = .003) but not for OSR (OR, 1.04; P = .056). Preexisting hypertension was a significant predictor of survival for both EVAR (OR, 0.17; P < .001) and OSR (OR, 0.48; P = .021). Almost one fourth of EVAR patients (21/91 23.1%) required secondary interventions. Survival advantage was maintained for EVAR patients to 5 years. Conclusions For r-AAA, EVAR reduces the 30-day mortality and improves long-term survival up to 5 years. However, whereas open survivors require few graft-related interventions, up to 23% of EVAR patients will require reintervention for endoleaks or graft migration. Close follow-up of all EVAR survivors is mandatory.
Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited.
In this ...prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival.
Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates.
Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.
Colorectal cancer Paty, Philip B.; Garcia‐Aguilar, Julio
Journal of surgical oncology,
October 2022, 2022-10-00, 20221001, Letnik:
126, Številka:
5
Journal Article
Recenzirano
Although surgery is the established standard and mainstay for treatment of colorectal cancer, advances in technology and clinical trials over the past 50 years have dramatically expanded and improved ...the detection, staging, treatment, and understanding of this disease. This review highlights contributions by surgeons, oncologists, gastroenterologists, engineers, and scientists to increase postsurgical recurrence‐free survival, reduce the time and toxicity of treatment, and improve the quality of life for patients over the past half‐century.
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