Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

Development of a new lingual range-of-motion assessment scale: normative data in surgically treated oral cancer patients.

Surgical resection in oral cancer patients can result in altered speech, swallowing, and patient perception of quality of life (QOL). Oral surgery can result in reduced lingual range of motion (ROM). However, few studies have quantified the degree of lingual restriction after surgery. This pilot study describes a new measurement system to define tongue ROM in surgically treated tongue cancer patients. This measurement system was validated by comparing results in these treated surgical patients versus healthy individuals. This scale was further validated by correlating ROM with performance status, oral outcomes, and patient-rated QOL. Thirty-six patients who underwent oral tongue surgery and 31 healthy individuals were included. Tongue ROM was assessed using a novel ROM assessment system. This novel system was examined in these patients versus healthy subjects. This measurement tool was further validated by correlating tongue ROM in treated patients with performance status, oral outcomes, and patient-rated QOL. Tongue ROM was found to be significantly lower in the surgically treated patients than in the healthy individuals (p = 0.0001). Tongue ROM correlated with performance status, oral outcomes, and all QOL measures. This new tongue ROM measurement system defined tongue deficits in surgically treated oral cancer patients. This tool was validated by comparing results to those in healthy individuals, as well as by correlating tongue ROM to performance status, oral outcomes, and QOL. This measurement tool can be used to define baseline and postsurgery tongue ROM in oral cancer patients, as well as track change over time with recovery and therapy. Future studies should examine use of this measurement tool with other populations demonstrating tongue deficits.

Pre-Transplant Marital Status and Hematopoietic Cell Transplantation Outcomes

Background: Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting. Methods: We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct. Results: We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic (p = 0.58) or autologous (p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99). Conclusions: Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization.

Intraoperative ultrasonic imaging of the carotid artery during carotid endarterectomy.

Intraoperative real-time B-mode ultrasonography was used to evaluate the technical results of 155 carotid endarterectomies in 143 patients. Technical defects created as a result of the endarterectomy were detected in 43 of the 155 endarterectomies (27.7%) and included intimal flaps (73% of defects); strictures (18%); and arterial kinks, residual plaque, and intraluminal thrombi (9% collectively). Eleven of the 43 endarterectomy sites (7% of all endarterectomies) were reentered to correct a defect; none of these patients had neurologic deficits, which suggests that reentering an endarterectomy and correcting a defect does not, in and of itself, lead to a higher incidence of stroke. The incidence of stroke in patients with normal results of intraoperative ultrasonography was 3.8%, whereas the incidence of perioperative stroke in those patients with insignificant and thus uncorrected defects was 3.3%; this suggests that intraoperative ultrasonography is sufficiently sensitive to detect defects that, when left uncorrected, do not lead to a higher than usual incidence of stroke. Because intraoperative ultrasonography is safe and highly sensitive, we believe it is the method of choice for assessing the technical results of carotid endarterectomy.

Early experience with in situ saphenous vein bypass for distal arterial reconstruction.

During a 36-month period 74 patients underwent infrainguinal in situ saphenous vein bypass to the popliteal or tibial vessels. The first 54 operations were performed with standard valvulotomes and valve-cutting scissors, while in the last 20 operations a new intraluminal valve-cutting device was used to incise the valves. Ninety-four percent of bypasses were performed for limb salvage, 80% of all operations were done to the tibial vessels, and 31% of bypasses were done to the ankle vessels. The operation was attempted in 81 patients and completed in 74 patients, for a vein utilization rate of 91%. Fifty-five percent of all veins had a distal diameter of less than 4 mm (average 3.6 mm). The patency rates were 92% at 3 months and 90% at 12 and 36 months for all grafts. There were six failed grafts, all within the first 6 months, and eight diabetic patients required reoperation, two for missed valve leaflets, and three needed revision of the distal anastomosis; however, all these grafts were patent at the time of reexploration. There were four perioperative deaths and two patients had nonfatal postoperative myocardial infarctions. This study demonstrates that in situ saphenous vein grafting provides for a high vein utilization rate and suggests that the technique provides for higher graft patency and limb salvage rates than do more traditional types of procedures.

Modified technique to produce valvular incompetence in in situ saphenous vein arterial bypass.

Methods for producing valvular incompetence in the in situ vein arterial bypass have been either traumatic or tedious. We modified the technique of atraumatically incising the venous valves, rendering them incompetent. Using a specially designed long scissors, the valves are excised by introducing the scissors into the proximal end of the vein or, if necessary, one major branch. This requires minimal manipulation and exposure of the vein, almost no disturbance of the venous bed, and makes the operation less tedious.

Hypertonic mannitol: its use in the prevention of revascularization syndrome after acute arterial ischemia.

Revascularization of acutely ischemic lower limbs is associated with high mortality and high rates of rethrombosis, limb loss, massive edema, and compartment syndrome. These complications may be due to revascularization syndrome. The effects of hypertonic mannitol used during revascularization of acutely ischemic lower extremities were studied. In an isolated canine hind limb model, revascularization of the limb via a Dacron graft after 90 minutes of ischemia resulted in tissue edema and decreased flow. The low flow state (50% of control) for two hours after reperfusion was associated with thrombosis at the anastomosis. Use of hypertonic mannitol reversed the reperfusion syndrome and prevented graft thrombosis. Therefore, 15 consecutive patients with acute lower extremity ischemia and threatened limb loss were treated with hypertonic mannitol during emergency thromboembolectomy. Fourteen patients survived and had excellent results without any rethrombosis. Compartment syndrome was absent. Results of this clinical trial suggests that hypertonic mannitol may be useful in the management of acute arterial ischemia.

Crossover femorofemoropopliteal sequential bypass for combined ipsilateral iliac and femoropopliteal occlusive disease.

We evaluated the effectiveness of crossover femorofemoropopliteal sequential bypass in 13 patients with combined ipsilateral iliac and femoropopliteal disease. Of them, eight underwent bypass grafting for limb salvage, and five, for disabling claudication. Four of the patients with claudication had relief of symptoms and significant increases in treadmill walking time. The cumulative limb salvage rate in the patients operated on for limb salvage was 88%. At 42 months, the cumulative patency rate for the femorofemoral portion of the graft was 91%, and for the distal segment, 63%. Mean ankle-brachial indices increased from 0.37 +/- 0.12 preoperatively to 0.76 +/- 0.16 postoperatively in the recipient limb. Early experience suggests that crossover sequential femorofemoropopliteal bypass grafts are effective in achieving limb salvage and relief of claudication, especially in patients with relative contraindications to major intra-abdominal surgery.

Peripheral vascular trauma from close-range shotgun injuries.

This report summarizes an eight-year experience (1976 to 1983) with 49 close-range shotgun blasts with associated major vascular injuries seen in a large urban hospital. Injuries to the upper extremity (40%), lower extremity (56%), and neck (4%) were seen. A high frequency of associated deep venous injury (82%), nerve injury (37%), fracture (33%), massive soft-tissue loss (43%), and compartmental hypertension (39%) was observed. There were no deaths in this series, and the limb salvage rate was 96%. Neither patient with multiple carotid artery injuries suffered a neurologic deficit. We attribute our success in the management of these complex injuries to rapid fracture immobilization, early and aggressive use of fasciotomy, adequate débridement of devitalized tissue, repair of deep venous injuries, arterial repair with autogenous tissue, and extra-anatomic bypass grafting in selected cases.

Results of arterial reconstruction of the foot.

Sixty-five patients with critical ischemia required bypass to foot vessels. These procedures were performed by five different techniques: (1) femoral-foot bypass with in situ saphenous vein; (2) femoral-foot bypass with reversed autogenous saphenous vein; (3) femoral-foot bypass with polytetrafluoroethylene (PTFE); (4) popliteal-foot bypass with reversed autogenous saphenous vein; and (5) popliteal-foot bypass with PTFE. The two-year patency rate of femoral-foot bypass with in situ vein (96%) was significantly higher than femoral-foot bypass with reversed vein (42%), while both procedures demonstrated significantly higher patency than femoral-foot bypass with PTFE (0%). Popliteal-foot bypass with reversed vein (92%) was superior to both popliteal-foot bypass with PTFE (27%) and femoral-foot bypass with PTFE (0%). Femoral-foot bypass with in situ vein and popliteal-foot bypass with reversed vein have appreciably increased vein utilization, graft patency, and limb salvage.

Internal iliac artery revascularization in the treatment of vasculogenic impotence.

Five impotent men underwent internal iliac artery revascularization in conjunction with end-to-side aortobifemoral bypass after preoperative testing suggested a vasculogenic cause for impotence. All patients had abnormal preoperative penile/brachial arterial pressure indices (mean, 0.42 +/- 0.12). Following operation, all patients regained erectile capability and had normal postoperative penile/brachial indices (mean, 0.80 +/- 0.06). One patient developed retrograde ejaculation, emphasizing the need for meticulous nerve-sparing dissection with this operation. Internal iliac artery revascularization in conjunction with end-to-side aortobifemoral bypass is effective in relieving vasculogenic impotence in properly selected patients.

Pathologic interactions between prosthetic aortic grafts and the gastrointestinal tract. Clinical problems and a new experimental approach.

Twenty-one patients presented with pathologic interactions between the gastrointestinal tract and aortic grafts. Seventeen patients were managed by excision of the graft and axillobifemoral bypass. Six patients died. four deaths were due to disruption of the proximal aortic stump after initial therapy that appeared successful. An experimental model of a seromuscular jejunal patch is presented that may be beneficial for closure of the proximal aortic stump.

Patients evaluated for venous disease may have other pathologic conditions contributing to symptomatology.

Of the more than 200 patients recently evaluated for venous disease, 8 were diagnosed with lower extremity masses. Three patients were referred for superficial phlebitis and four for deep venous obstructive disease. The eighth mass was found during work-up for varicose veins. Five masses were identified by palpation, and three were identified by duplex scan. All were confirmed by magnetic resonance imaging (MRI) or computed tomography (CT). Of the eight masses, three were malignant: a metastatic melanoma, a histiocytoma, and a myxoid liposarcoma. Nonmalignant masses included a hematoma, an inflammatory lesion, a hemangioma, and an intramuscular lipoma. One patient presented with deep venous thrombosis secondary to an occluded popliteal artery aneurysm compressing the popliteal vein. Thus, patients presenting with ostensible venous disease may have other pathologic conditions responsible for symptomatology. Careful physical examination will reveal a mass in a majority of patients who have one. Duplex scanning will identify masses that should be confirmed by MRI or CT. Definitive diagnosis should be made by biopsy, due to the high possibility of malignancy.

Use of ultrasonic venography in the evaluation of venous valve function.

Forty healthy limbs and 31 limbs with suspected deep venous insufficiency were imaged with real-time B-mode ultrasound to determine valve location, anatomic characteristics, and function. Valve function was evaluated by comparison with Doppler ultrasonographic techniques, and the data clearly indicated that ultrasonic venography accurately localized and determined the extent of deep venous reflux. Ascending contrast venography was performed in 15 postphlebitic limbs for assessment of valve location. The results indicate that ultrasonic venography is a more accurate method for visualization of valves in this group of patients. Therefore, ultrasonographic imaging is a valuable technique for evaluating limbs with chronic venous insufficiency.

Origin of deep vein thrombi in an ambulatory population.

Eighty symptomatic ambulatory outpatients with acute deep vein thrombosis were evaluated with ascending contrast venography and ultrasonic imaging to determine the origin and distribution of thrombosis and to analyze clinical risk factors. Isolated calf vein thrombosis was present in 42.5 percent of the limbs, combined calf and proximal deep vein thrombosis in 47.5 percent, and isolated proximal thrombosis in 10 percent of the limbs. Discontinuity of thrombus was present in 55 percent, whereas 45 percent exhibited a continuous column of thrombus. The results of this study indicate that in the ambulatory outpatient population, acute deep vein thrombosis begins segmentally in the calf and proximal vessels and frequently coalesces into a continuous column of thrombus over several days. We believe that all cases of acute deep vein thrombosis should be treated and patients with evidence of previous acute deep vein thrombosis should be closely monitored for possible recurrences.

Popliteal-to-tibial in situ saphenous vein bypass for limb salvage in diabetic patients.

This study has summarized our results with popliteal-tibial in situ saphenous vein bypass in 26 patients, 25 of whom were diabetic, over a 2 year period. Both above- and below-knee popliteal inflow sites were used for bypass of limb-threatening ischemia. Distal calf or pedal outflow sites were required in all but two patients who had sequential bypass performed to tibial sites. Postoperative ankle-brackial indices were calculated. Eleven patients had transcutaneous mapping surrounding the pedal skin envelope injuries. The mean lowest and highest transcutaneous oxygen values have been reported as a guide to successful healing.

Further experience with the saphenous vein used in situ for arterial bypass.

Ongoing experience with use of the saphenous vein in situ as in infrainguinal arterial bypass is presented. One hundred eighty-three bypasses were performed for limb-threatening ischemia, 92 of which were to the popliteal artery, either isolated or in continuity with one or more tibial vessels, and 91 bypasses were carried to single tibial vessels below the termination of the popliteal artery. The results were analyzed by the life table method and show an overall patency rate of 89.8 percent at 3 to 4 years. Separate life table analysis of the tibial bypass group showed a patency rate of 83 percent at 3 to 4 years. Special emphasis is placed on the ability to use veins less than 4 mm in diameter, which comprise 40 percent of those used in these procedures. The superior results provided by the in situ method are explained in part by experimental observations which show that endothelial stability is completely preserved by this method but is severely disturbed during the process of vein removal and reversal.

Use of isovolemic hemodilution in the management of arterial ischemia in patients with polycythemia.

The management of patients with both polycythemia and limb-threatening ischemia presents many difficulties because in this population, vascular surgical procedures carry a particularly high incidence of hemorrhagic and thromboembolic complications. We evaluated the use of acute isovolemic hemodilution in 12 polycythemic patients who required urgent surgery due to severe ischemia and threatened limb loss. Within 48 hours, blood was withdrawn in units of 500 ml and simultaneously replaced with 1,500 ml of lactated Ringer's solution until a hematocrit of 35 to 40 percent was achieved. After hemodilution, two patients had such a marked improvement that no further therapeutic measures were required immediately. Four patients showed definite improvement in pulmonary vascular resistance tracings and segmental Doppler pressures, but ischemia was not fully ameliorated. These patients together with the remaining six patients underwent vascular surgery within 1 to 14 days after hemodilution. A hematocrit of 32 to 40 percent was maintained during the perioperative period. All arterial reconstructions were successfully completed and there were no perioperative failures. No pulmonary emboli, myocardial infarctions, or deaths occurred in this period. These results indicate that in polycythemic patients, urgent vascular surgery can be performed more safely with the concomitant use of acute isovolemic hemodilution.

Clinical use of the seromuscular jejunal patch for protection of the infected aortic stump.

Pathologic interactions between aortic prostheses and the gastrointestinal tract are very difficult problems in vascular surgery. After excision of the graft and proximal aortic closure, the major unsolved problem has been continued sepsis of the proximal aortic stump with subsequent fatal disruption. To provide healthy tissue for protection of this crucial area, we have devised a method in which a piece of jejunum on its vascular pedicle is opened along its antimesenteric border, the mucosa is removed, and the vascularized muscular wall is anchored to the aortic stump. This seromuscular jejunal patch was used clinically in three patients. Postmortem examinations in two of these patients 4 and 45 days postoperatively revealed no signs of infection, hematoma, or mucocele, and no histologic abnormalities; instead, the examinations did reveal firm tissue adherence between the aortic stumps and the seromuscular patches. The third patient is alive and well 1 year after this procedure. The three patients have demonstrated the feasibility of secure aortic stump protection by placement of well-prepared, vascularized seromuscular jejunal tissue over the potentially infected aortic stump. This technique may prevent postoperative stump dissolution and thus far appears to be a reasonable solution to this usually lethal problem.

Ankle bypass: should we go the distance?

This report reviewed the results of 47 distal arterial reconstructions to or below the level of the malleolus. The operations were performed by the techniques of popliteal-to-distal bypass (20 procedures) and in situ bypass (27 procedures). Seventy-five percent of patients had gangrene of ischemic ulceration, and all procedures were performed for limb salvage. Seventy-three percent of all patients were diabetic. The patency rates for popliteal-to-distal bypass with reversed saphenous vein were 92 percent at 24 months and 57 percent at 60 months, with a limb salvage rate of 70 percent at 60 months; the patency rates for popliteal-to-distal bypass with PTFE were 53 percent at 12 months and 0 at 36 months, with a limb salvage rate of 53 percent at 36 months; and the patency rate for in situ saphenous vein bypass was 96 percent at 24 months, with a limb salvage rate of 80 percent at 24 months. Early results are promising for ankle bypass using the techniques of popliteal-to-distal and in situ bypass.