Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial.

BACKGROUND: TGF-ß is an immunosuppressive cytokine that is upregulated in colorectal cancer. TGF-ß blockade improved response to chemoradiotherapy in preclinical models of colorectal adenocarcinoma. We aimed to test the hypothesis that adding the TGF-ß type I receptor kinase inhibitor galunisertib to neoadjuvant chemoradiotherapy would improve pathological complete response rates in patients with locally advanced rectal cancer. METHODS: This was an investigator-initiated, single-arm, phase 2 study done in two medical centres in Portland (OR, USA). Eligible patients had previously untreated, locally advanced, rectal adenocarcinoma, stage IIA-IIIC or IV as per the American Joint Committee on Cancer; Eastern Cooperative Oncology Group status 0-2; and were aged 18 years or older. Participants completed two 14-day courses of oral galunisertib 150 mg twice daily, before and during fluorouracil-based chemoradiotherapy (intravenous fluorouracil 225 mg/m2 over 24 h daily 7 days per week during radiotherapy or oral capecitabine 825 mg/m2 twice per day 5 days per week during radiotherapy; radiotherapy consisted of 50·4-54·0 Gy in 28-30 fractions). 5-9 weeks later, patients underwent response assessment. Patients with a complete response could opt for non-operative management and proceed to modified FOLFOX6 (intravenous leucovorin 400 mg/m2 on day 1, intravenous fluorouracil 400 mg/m2 on day 1 then 2400 mg/m2 over 46 h, and intravenous oxaliplatin 85 mg/m2 on day 1 delivered every 2 weeks for eight cycles) or CAPEOX (intravenous oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks for four cycles). Patients with less than complete response underwent surgical resection. The primary endpoint was complete response rate, which was a composite of pathological complete response in patients who proceeded to surgery, or clinical complete response maintained at 1 year after last therapy in patients with non-operative management. Safety was a coprimary endpoint. Both endpoints were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02688712, and is active but not recruiting. FINDINGS: Between Oct 19, 2016, and Aug 31, 2020, 38 participants were enrolled. 25 (71%) of the 35 patients who completed chemoradiotherapy proceeded to total mesorectal excision surgery, five (20%) of whom had pathological complete responses. Ten (29%) patients had non-operative management, three (30%) of whom ultimately chose to have total mesorectal excision. Two (67%) of those three patients had pathological complete responses. Of the remaining seven patients in the non-operative management group, five (71%) had clinical complete responses at 1 year after their last modified FOLFOX6 infusion. In total, 12 (32% [one-sided 95% CI ≥19%]) of 38 patients had a complete response. Common grade 3 adverse events during treatment included diarrhoea in six (16%) of 38 patients, and haematological toxicity in seven (18%) patients. Two (5%) patients had grade 4 adverse events, one related to chemoradiotherapy-induced diarrhoea and dehydration, and the other an intraoperative ischaemic event. No treatment-related deaths occurred. INTERPRETATION: The addition of galunisertib to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer improved the complete response rate to 32%, was well tolerated, and warrants further assessment in randomised trials. FUNDING: Eli Lilly via ExIST program, The Providence Foundation.

Fecal incontinence: help for patients who suffer silently.

Once you've identified patients with this embarrassing condition, achieving optimal outcomes hinges on your familiarity with advances like sacral nerve stimulation.

Construct domain analysis of patient health-related quality of life: physical and mental trajectory profiles following open versus endovascular repair of abdominal aortic aneurysm.

PURPOSE: Many clinical trials comparing the outcomes of open surgical repair (OSR) versus endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms (AAAs) have been conducted, with varying results. Surprisingly, few outcomes studies have closely examined perceived physical and mental health-related quality of life (HRQOL) factors through a validated survey tool. The purpose of this prospective observational study was to describe the trajectory of HRQOL measures, from baseline to 1 year after surgery, in patients undergoing OSR or EVAR for AAA, and to explore for differences in physical and mental composite scores and their construct domains (subscales) using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36(®)) tool. PATIENTS AND METHODS: Over an 18-month period, a small sample of patients undergoing elective AAA repair in a community hospital setting were prospectively enrolled. Fifteen patients undergoing OSR and twenty patients undergoing EVAR were studied. Physical and mental HRQOL parameters were assessed using the SF-36. RESULTS: No significant differences in demographic and clinical variables were found between the OSR and EVAR groups. In the multivariable linear models with repeated measures, both groups showed a significant decline in physical health composite scores 30 days after the surgical procedure (P < 0.01). However, although the OSR group showed a statistically significant decline in three of the four physical health domains, the EVAR group declined in only one physical health domain. Only the OSR group showed a significant decline in three of the four mental health domains at 30 days; however, the decline of these domains was not reflected in the group's mental health composite scores. By 90 days after surgery, both groups were not significantly different from their baseline in physical or mental health composite scores, or in any of their respective physical health domains. CONCLUSION: In this small sample of patients undergoing AAA repair, EVAR resulted in less physical and emotional decline than OSR in the early postoperative period. However, patients in both groups may return to near baseline status at 90 days.

Spatiotemporal expression profiling of proteins in rat sciatic nerve regeneration using reverse phase protein arrays.

BACKGROUND: Protein expression profiles throughout 28 days of peripheral nerve regeneration were characterized using an established rat sciatic nerve transection injury model. Reverse phase protein microarrays were used to identify the spatial and temporal expression profile of multiple proteins implicated in peripheral nerve regeneration including growth factors, extracellular matrix proteins, and proteins involved in adhesion and migration. This high-throughput approach enabled the simultaneous analysis of 3,360 samples on a nitrocellulose-coated slide. RESULTS: The extracellular matrix proteins collagen I and III, laminin gamma-1, fibronectin, nidogen and versican displayed an early increase in protein levels in the guide and proximal sections of the regenerating nerve with levels at or above the baseline expression of intact nerve by the end of the 28 day experimental course. The 28 day protein levels were also at or above baseline in the distal segment however an early increase was only noted for laminin, nidogen, and fibronectin. While the level of epidermal growth factor, ciliary neurotrophic factor and fibroblast growth factor-1 and -2 increased throughout the experimental course in the proximal and distal segments, nerve growth factor only increased in the distal segment and fibroblast growth factor-1 and -2 and nerve growth factor were the only proteins in that group to show an early increase in the guide contents. As expected, several proteins involved in cell adhesion and motility; namely focal adhesion kinase, N-cadherin and ß-catenin increased earlier in the proximal and distal segments than in the guide contents reflecting the relatively acellular matrix of the early regenerate. CONCLUSIONS: In this study we identified changes in expression of multiple proteins over time linked to regeneration of the rat sciatic nerve both demonstrating the utility of reverse phase protein arrays in nerve regeneration research and revealing a detailed, composite spatiotemporal expression profile of peripheral nerve regeneration.

Role of the sagittal view of computed tomography in evaluation of the nasofrontal ducts in frontal sinus fractures.

PURPOSE: Frontal sinus fractures are relatively uncommon due to the high-impact force required to produce these. However, their management is quite complex, with the treatment algorithm incorporating many factors in which the status of the nasofrontal ducts is critically important. Traditionally, this has been evaluated by both axial and coronal computed tomographic (CT) scan views. Anatomically, we propose that this is better evaluated by coronal and sagittal CT views. We evaluated the role of sagittal CT scan views in determining the status of the nasofrontal ducts in patients with frontal sinus fractures. METHODS: A retrospective analysis examining 8 patients with frontal sinus fractures, from August 2004 to January 2008, was performed. Axial, coronal, and sagittal CT scan views were obtained routinely as part of the facial trauma workup. These views were assessed to determine the status of the nasofrontal ducts. The operative findings were also reviewed. RESULTS: Five of the 8 patients had displaced anterior and posterior table frontal sinus fractures. Of these, 4 required surgical intervention that included addressing the nasofrontal ducts. Two of the 8 patients had displaced anterior table fractures that required no intervention of the nasofrontal ducts. One patient had nondisplaced anterior and posterior table fractures and did not require surgery. The sagittal CT view clearly demonstrated the anatomy of the nasofrontal ducts in all 8 patients, including patients in whom the axial and/or coronal views were questionable. Intraoperatively, where the patency of the nasofrontal ducts was directly evaluated, there was a direct correlation with the sagittal image findings. CONCLUSIONS: The sagittal CT view provides invaluable information for evaluating the patency of the nasofrontal ducts in frontal sinus fractures. The ability to evaluate the frontal sinus in an anteroposterior dimension (the usual vector of the injury) and in a superoinferior dimension (the anatomic pathway of the ducts) is the reason for this imaging advantage.

Role of sagittal reformatted computed tomographic images in the evaluation of orbital floor fractures.

BACKGROUND: The sagittal plane computed tomographic (CT) scan has been proposed as the most important radiologic view in the diagnosis of orbital floor fractures. Before the advent of high-resolution CT, several articles were published in the radiology literature debating the need for direct sagittal views, which required cumbersome patient positioning. Today, the ability to easily create high-quality sagittal reformations requires reassessment of the importance of this view in the evaluation of orbital floor fractures. MATERIALS AND METHODS: Computed tomographic studies of 24 orbital floor fractures for which coronal and sagittal images were available were included. Five independent reviewers evaluated all image sets and recorded maximum fracture width, depth, posterior shelf length (PSL), and presence of medial wall fracture and of trap door deformity. Direct fracture width measurements were obtained via coronal images, whereas depth and PSL were measured directly in the sagittal plane. Indirect measurements in a given plane were obtained by counting the number of slices in which the fracture was present and multiplying by the slice thickness. Cronbach alpha analysis was used to provide an intraclass correlation coefficient, where greater values signify less interreviewer variability. RESULTS: The Cronbach alpha values for width, depth, and PSL were 64%, 59%, and 85% in the coronal view and 76%, 55%, and 51% in the sagittal view, respectively. The alpha values for presence/absence of medial wall fracture and trap door deformity were greater in the coronal view at 73% and 55%, respectively. The intrareviewer variability was not significantly correlated with the degree of patient rotation or CT scan slice thickness. The interreviewer variability was significantly less among attending reviewer then resident reviewers. CONCLUSIONS: There was less interreviewer variability when the measured variables were assessed indirectly (width was best assessed in the sagittal plane, and depth and PSL were best assessed in the coronal view). These findings support the idea that additional views aid the surgeon's ability to further define fracture anatomy than might be possible with any single view, thereby improving preoperative planning and reconstructive strategies.

Duration of smoking cessation and its impact on skin flap survival.

BACKGROUND: Empirical and experimental evidence abounds as to the negative effects of smoking on skin flaps. The ideal duration of preoperative smoking cessation is unclear. The present study evaluates the effect of various durations of smoking cessation on skin flap survival in a rat model. METHODS: Forty smoke-exposed and 10 non-smoke-exposed Sprague-Dawley rats were divided into five groups: controls and 0 days, 2 weeks, 4 weeks, and 8 weeks of smoking cessation. All animals had a dorsally based random pattern flap created and either bilateral pure axial superficial inferior epigastric (superficial inferior epigastric) flaps or a unilaterally superficial inferior epigastric axial with random component flap. The percentage of flap necrosis was assessed 2 weeks postoperatively. RESULTS: The mean amount of random skin flap necrosis was 16.6 +/- 13.0 percent, 30.3 +/- 8.4 percent, 27.6 +/- 7.9 percent, 27.1 +/- 6.1 percent, and 29.7 +/- 10.3 percent, respectively. There was significantly less flap necrosis in the controls than in all other groups (p < 0.03). There was no necrosis of any of the pure axial superficial inferior epigastric flaps. The mean amount of superficial inferior epigastric axial with random component skin flap necrosis was 11.1 +/- 6.2 percent, 31.1 +/- 6.0 percent, 36.0 +/- 8.4 percent, 21.7 +/- 4.0 percent, and 19.1 +/- 6.3 percent, respectively. All smoke-exposed groups had significantly greater flap necrosis than controls, with the exception of the 8-week group (p < 0.02). CONCLUSIONS: Smoking irreversibly increases the risk of flap necrosis in a random pattern flap out to 2 months of preoperative cessation. Preoperative smoking does not result in any necrosis of pure axial flaps. In axial with random component flaps, significant decreases in skin flap necrosis are not seen until 4 weeks of preoperative cessation.

Evaluation of a novel reverse thermosensitive polymer for use in microvascular surgery.

Microvascular clamps have several potential shortcomings, including the risk of vessel injury. LeGoo, a novel reverse thermosensitive polymer (Pluromed Inc., Woburn, MA), is investigated as a substitute to vascular clamping in a microsurgical model and the technical details are described. Femoral vessels of Sprague Dawley rats were used to evaluate the usefulness of this polymer for performing end-to-end arterioarterial (AA), venovenous (VV), and end-to-side arteriovenous (AV) microvascular anastomoses. The ability to obtain and maintain hemostasis was assessed. Secondary endpoints, including polymer volume, concentration, temperature, infusion technique, ability to reinfuse, blood vessel stenting effect, polymer dissolution characteristics, and reestablishment of flow, were also noted. Initial hemostasis occurred in every case. Mean duration of efficacy (hemostasis) after initial injection was 17.8 minutes (4 minutes to 44.5 minutes) for AA anastomoses and 31.8 minutes (13 minutes to 46 minutes) for VV anastomoses. Mean volume of polymer initially injected was 0.11 mL (0.01 mL to 0.20 mL) and 0.07 mL (0.06 mL to 0.10 mL) for AA and AV arteries, respectively, and 0.14 mL (0.10 mL to 0.20 mL) and 0.20 mL (0.15 mL to 0.27 mL) for VV and AV veins. Use of LeGoo in veins was clearly superior to arterial use with regard to the technical aspects of injecting LeGoo and reestablishing hemostasis, as well as greater vessel stenting effect and less vessel retraction. This novel polymer showed promise for its ability to allow for hemostasis while performing microvascular anastomoses. Improvements were made with regard to injection techniques, appropriate volumes, ability to reliably determine gel plug dissolution, and final vessel patency. Preliminary results demonstrate that this polymer may be a viable substitute for microvascular clamps.

Evaluation of a new 4-strand flexor tendon repair in a cadaveric porcine model.

PURPOSE: Numerous flexor tendon repairs have been described. The ideal core flexor tendon repair optimizes strength characteristics while minimizing factors felt to contribute to adhesion formation. The present study compares ultimate tensile strength, gap strength, and surgical time in the Lahey repair, a new 4-strand flexor tendon repair, to 2 previously described techniques. METHODS: The flexor digitorum profundus tendons of 30 porcine forelimbs were repaired in situ using 1 of 3 flexor tendon repair techniques. The techniques compared included the 4-strand Kessler repair, the cruciate repair, and the experimental Lahey repair (4-strand Kessler with cruciate modification). Biomechanical testing was conducted in order to obtain initial gap strength and ultimate tensile strength. RESULTS: Although not significantly different from the 4-strand Kessler, the ultimate tensile strength of the Lahey repair was significantly greater than that of the cruciate repair. CONCLUSIONS: The Lahey flexor tendon repair has significantly greater ultimate tensile strength than the cruciate repair. These findings suggest that the Lahey repair can be considered a biomechanically favorable 4-strand technique for the repair of flexor tendon lacerations.

Disruption of graft endothelium correlates with early failure after off-pump coronary artery bypass surgery.

BACKGROUND: Saphenous vein graft failure after coronary artery bypass surgery may be as high as 5% to 10% in the first postoperative week. We hypothesized that identifying damage sustained by saphenous vein endothelium before grafting predicts early graft attrition after off-pump coronary artery bypass graft surgery. METHODS: Intraoperative graft flow, platelet function, and endothelial integrity were analyzed in 125 patients undergoing off-pump coronary artery bypass graft surgery. Endothelial integrity was assessed in an excess vein segment from each graft using immunohistochemistry (CD31 staining). Platelet function was monitored just before and immediately after revascularization and on postoperative days 1 and 3 using whole blood aggregometry, thrombelastography, and platelet activated clotting time. Platelet activation was monitored using flow cytometry. Intraoperative conduit blood flow, measured by transit time ultrasonography, was used to detect and rectify anastomotic problems. Early graft patency was determined on postoperative day 5 using gated multichannel computed tomography angiography. RESULTS: In 106 patients undergoing postoperative computed tomography evaluation, 10 vein grafts in 10 patients were discovered to have developed early thrombosis, representing 4% (10 of 217) of all vein grafts. Endothelial integrity was 10.75% +/- 17.56% in 10 grafts that failed early compared with 51.45% +/- 36.29% in patent grafts (p = 0.04). Perioperative platelet function and graft flow did not differ significantly between the two groups. CONCLUSIONS: Although endothelial disruption predicts early failure of bypass grafts, the importance of a hypercoaguable state and low graft flow as a cause of early graft thrombosis after off-pump coronary artery bypass graft surgery was not supported by our preliminary results. A means to assess, prevent, and treat intraoperative vein graft damage will likely improve early graft patency.