Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer.

Background: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described. Patient and methods: Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated. Results: Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04). Conclusions: Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.

Radiochemical analysis of Tc-99m human serum albumin with high-pressure liquid chromatography: concise communication.

High-pressure liquid chromatography (HPLC) can be performed with an aqueous size-exclusion column to separate proteins or other macromolecules on the basis of molecular size. An HPLC system with a Spherogel-TSK SW column was modified to detect simultaneously uv absorption and radioactivity. Characteristic retention times (RT) were determined for pure human serum albumin (HSA) (RT = 17 min) and pertechnetate (RT = 28.5 min). When analysis was performed on Tc-99m HSA preparations, Tc-99m radioactivity was resolved into five different peaks, with RT ranging from 10.2 to 28.5 min. Less than 2% radioactivity was associated with the pertechnetate peak, whereas the remaining Tc-99m was protein bound. Most of the activity (90%) corresponded to the albumin peak, and 7% was bound to contaminants of high molecular weight with RTs of 10.2 and 14 min. Rapid separation of various radiochemical components differing in molecular size provides an improved basis for understanding the biodistribution of a Tc-99m HSA preparation. This technique would be useful for the preparation and analysis of various radiolabeled macromolecules such as enzymes, immunoglobulins, and other proteins.

Noninvasive predictors of patency for infrapopliteal PTFE bypasses with combined arteriovenous fistula and vein interposition technique.

BACKGROUND: Despite recent increased indications for infrapopliteal prosthetic bypass grafts with complementary arteriovenous fistulas, objective documentation of improved perfusion to the foot is lacking. In addition, the value of post operative noninvasive testing in the prediction of bypass success remains unclear. PATIENTS AND METHODS: Over a 3-year period, 41 patients with limb-threatening ischemia were treated with 41 infrapopliteal 6-mm polytetrafluoroethylene (PTFE) bypasses with a complementary arteriovenous fistula at our institution. Twenty-four patients were men and 17 were women, with an average age 71.3 +/- 8.6 years. Thirty-one patients (76%) had undergone at least 1 previous failed ipsilateral arterial bypass. Preoperative and early postoperative (less than 1 month) pulse-volume recordings of transmetatarsal amplitude (TMA) were available for analysis in 28 patients. Postoperative duplex evaluations of graft velocity, fistula patency, and prograde distal arterial flow were performed in 26 of the original 41 patients. These data were correlated to early graft failure in an attempt to identify specific noninvasive predictors. RESULTS: Cumulative primary patency rates of the original 41 patients were 79.0%, 69.2%, and 63.8% at 1, 2, and 3 years, respectively. The early postoperative TMA values ranged from 3 to 50 mm with a mean of 21.6 +/- 14.8 mm (P < 0.001). Twenty-one patients (75%) had patent grafts on follow-up of 2 to 37 months (mean 18.6). The early postoperative TMA in this group of patients was 26.5 +/- 12.4 mm compared with 3.3 +/- 2.8 mm in the 6 patients whose grafts failed within 6 months (P < 0.001). A TMA of < 5 mm was 83% sensitive and 95% specific for the prediction of early graft failure. Of the graft examined by duplex ultrasonography, 21 (81%) remained patent during the follow-up period. The midgraft peak systolic velocity (PSV) of these grafts was 109 +/- 8.0 cm/s compared with 74.2 +/- 15.3 cm/s for the 5 initially patent bypasses that subsequently failed at any time during the follow-up period (P < 0.05). PSV of < 70 cm/s was 60% sensitive and 86% specific in predicting early graft failure. The combination of early postoperative TMA < 5 mm and early midgraft PSV < 70 cm/s was 100% sensitive and 100% specific for the prediction of early graft failure. CONCLUSIONS: These data show that infrapopliteal PTFE arterial bypasses with complementary arteriovenous fistulas significantly improve arterial perfusion at the level of the foot in the majority of patients. Also, both the postoperative TMA and midgraft PSV appear to be reliable predictors of graft outcome. Further experience with the noninvasive surveillance of these bypasses may become as rewarding as it is in standard vein bypasses.

Twelve-lead electrocardiographic analysis and pharmacotherapy in centenarians.

The prevalence of electrocardiographic anomalies has been assessed in a selected group of centenarians recruited in Western Sicily (49 subjects, 15 males and 34 females) with an average age of 101.5 years (range 100-109); the findings were analyzed in correlation with the state of health of the subjects, the drugs used and the presence of specific heart diseases and immobility. These subjects have rare signs of heart diseases, they do not show any electrolytic disorder, in spite of using many drugs sometimes in an inconsistent way. Particularly interesting is to note the moderate prevalence of sinus rhythm and the extremely low number of subjects with sinus respiratory arrhythmia as compared to the known literary data for the over-sixties. There occur, however, frequent, but almost asymptomatic troubles of the intraventricular conduction, especially left anterior hemiblock and ectopic beats. Atrial fibrillation and bradyarrhythmias are rare, while left axis deviation with scarce signs of left ventricular hypertrophy and alterations of the repolarization phase are frequent. The most used drugs are digitalis and vasodilators, especially angiotensin converting enzyme (ACE) inhibitors. The observed data prove that heart functions of the centenarians are in good conditions; the alterations of them are less serious than those of the somewhat younger old age classes, where the electrocardiographic anomalies are of higher extent and severity.

[Appropriateness of referral to the emergency department through a telecardiology service. "Boario Home-Care" researchers]. / Appropriatezza dell'invio in Pronto Soccorso mediante un servizio di telecardiologia sul territorio. Ricercatori "Boario Home-Care".

BACKGROUND: The use of telemedicine appears particularly promising in cardiovascular diseases; it may reduce the decisional time during an acute myocardial infarction, which is the greater part of the so-called "avoidable delay" and the inappropriate admission to the Emergency Department with the possibility of ruling out an acute pathology. The aim of our study was to show the diagnostic accuracy of a telecardiology service in the daily activity of general practitioners. METHODS: From February 1998 to February 1999, 150 general practitioners received a portable electrocardiographer (Card-Guard 7100) transferring, by a mobile or fixed telephone, a 12-lead ECG to a receiving station, where a cardiologist was available for the reporting and interactive teleconsultation. RESULTS: During 1 year 3456 calls took place. At the time of the ECG recording 44% of patients were symptomatic. Chest pain was present in 669 patients (44%), dyspnea in 21%, palpitation in 18%, dizziness in 7%, and asthenia in 13%. ECG and teleconsultation solved all the problems for 2452 patients (71%) and further diagnostic tests were requested in 862 patients (25%); 142 patients (4%) were sent to the Emergency Department. Cardiological diagnosis was confirmed in 95 patients (73%), while anxiety or gastritis were presumed in 35 patients (27%). In the group of patients (n = 3314) for whom the cardiologist solved the problem without admission to the Emergency Department, there were 5 patients who were admitted to the Emergency Department for myocardial ischemia in the following 48 hours after the teleconsultation. Telecardiology service showed versus Emergency Department admission a sensitivity of 95%, a specificity of 97.5%, and a diagnostic accuracy of 92.5%. CONCLUSIONS: These data confirm a good diagnostic value to the service and a useful support to the general practitioners' activity.

Superior vena caval Greenfield filters: indications, techniques, and results.

PURPOSE: This study assessed the clinical feasibility of placement of the titanium Greenfield filter within the superior vena cava (SVC) in patients with upper extremity deep venous thrombosis and evaluated the short-term results. METHODS: During the past 14 months, we have encountered 6 patients who had upper extremity central venous thrombosis in whom anticoagulation was deemed either contraindicated or ineffective in preventing recurrent pulmonary embolism. All patients underwent percutaneous insertion of a Greenfield filter into the SVC for prophylaxis for pulmonary embolism. Two of these patients had already undergone insertion of an inferior vena cava filter and two other patients had simultaneous insertion of SVC and inferior vena caval filters. RESULTS: No complications such as filter migration, misplacement, excessive hemorrhage, or pneumothorax occurred. Two patients subsequently underwent uncomplicated insertion of a Swan-Ganz catheter despite the presence of the filter. Two patients died of unrelated causes without clinical evidence of complications related to the filter. During the follow-up period from 4 to 14 months, there was no clinical evidence of pulmonary embolism in the remaining four patients. CONCLUSIONS: This procedure can be performed safely and is effective for the prevention of pulmonary embolism in patients with upper extremity venous thrombosis.

Preliminary results of a nonoperative approach to saphenofemoral junction thrombophlebitis.

PURPOSE: A prospective, nonrandomized study was conducted to evaluate the efficacy of a nonoperative approach of anticoagulation therapy to manage saphenofemoral junction thrombophlebitis (SFJT). METHODS: Over a 2-year period between January 1993 and January 1995, 20 consecutive patients with SFJT were entered into the study. They were hospitalized and given a full course of heparin. Duplex ultrasonography was performed before admission, both to establish the diagnosis and to evaluate the deep venous system. Two to 4 days after admission a follow-up scan was obtained to assess resolution of SFJT and to reexamine the deep venous system. Patients with SFJT alone and resolution of SFJT by duplex scanning were maintained on warfarin (Coumadin) for 6 weeks. Those with SFJT and deep venous thrombosis (DVT) were maintained on Coumadin for 6 months. Incidence of concurrent DVT and its location were noted. The efficacy of anticoagulation therapy was evaluated by measuring SFJT resolution, recurrent episodes of SFJT, and occurrence of pulmonary embolism (PE). RESULTS: There was a 40% incidence (eight of 20 patients) of concurrent DVT with SFJT. Of the eight patients, four had unilateral DVT, two had bilateral DVT, and two had development of DVT with anticoagulation. DVT was contiguous with SFJT in five patients and noncontiguous in three patients. Of 13 duplex scans obtained at 2 to 8 months follow-up, seven demonstrated partial resolution of SFJT, five had complete resolution, and one did not demonstrate resolution. There were no episodes of PE, no recurrences, and no complications of anticoagulation at maximum follow-up of 14 months. CONCLUSIONS: Anticoagulation therapy to manage SFJT was effective in achieving resolution, preventing recurrence and preventing PE within our follow-up period. There is a high incidence of DVT associated with SFJT that merits careful evaluation of the deep venous system during the course of management.

The value and limitations of L-arginine infusion on glomerular and tubular function in the ischemic/reperfused kidney.

PURPOSE: The nitric oxide precursor, L-arginine, has been shown to have a salutary effect on ischemia and reperfusion injury in skeletal muscle, skin, and intestines. Because L-arginine also increases renal blood flow, glomerular filtration, and urine flow in experimental animals with normal renal function, we postulated that L-arginine may also improve renal function after renal ischemic injury. METHODS: Eighteen adult New Zealand white rabbits weighing 3 to 3.5 kg were subjected to bilateral normothermic renal ischemia by clamping both renal pedicles for 1 hour followed by 2 hours of reperfusion. The animals were randomized into three groups: group I (control, n = 6) received no additional treatment; group II (pretreatment, n = 6) received systemic intravenous L-arginine at 150 mg/kg over 20 minutes before induction of ischemia; group III (posttreatment, n = 6) received systemic intravenous L-arginine at 150 mg/kg over 20 minutes from the onset of reperfusion. Urine flow, creatinine clearance (CCR), fractional excretion of sodium (FENa), and renal failure index (RFI) were calculated before ischemia and 2 hours after reperfusion, by use of standard formulas. The changes of the various renal parameters were compared among the three groups. RESULTS: Bilateral normothermic renal ischemia for 1 hour produced a significant deterioration of glomerular filtration as evidenced by a CCR decrease from 11.1 +/- 1.8 to 2.49 +/- 0.9 ml/min (p < 0.01), FENa increase from 2.9% +/- 1.0% to 20.8% +/- 1.5% (p < 0.01) and RFI increase from 4.0 +/- 1.3 to 28.8 +/- 2.6 (p < 0.01). Pretreatment with L-arginine (group II) minimized the deleterious effects caused by ischemia on glomerular filtration (CCR of 2.49 +/- 0.9 ml/min in group I vs 4.95 +/- 2.5 ml/min in group II, p < 0.05) and tubular function (FENa of 20.8% +/- 1.5% in group I vs 13.0% +/- 5.6% in group II and RFI of 28.8 +/- 2.6 in group I vs 18.6 +/- 8.0 in group II, p < 0.05). Infusion of L-arginine at the onset of reperfusion (group III) produced a significant diuretic effect (urine flow from 32.6 +/- 13.4 ml/hr in group I to 63.3 +/- 18.8 ml/hr in group III, p < 0.05) and also minimized glomerular damage (CCR from 2.49 +/- 0.9 ml/min in group I to 4.80 +/- 1.2 ml/min in group III, p < 0.05); however, no beneficial effect was observed on tubular function. CONCLUSION: Induction of nitric oxide production by systemic L-arginine infusion can best preserve glomerular and tubular function in the ischemic/reperfused kidney when given before the ischemic insult.

The natural history of the external carotid artery after carotid endarterectomy: implications for management.

PURPOSE: Most surgeons perform some type of endarterectomy of the external carotid artery (ECA) routinely during standard carotid endarterectomy (CEA). This approach has been shown to result in a small percentage of ECA occlusions, the clinical significance of which remains poorly understood. We have modified our approach to the management of the ECA during standard CEA by averting any attempt at external CEA. To evaluate the natural history of the untreated ECA after CEA, we reviewed the preoperative, postoperative, and follow-up duplex scans obtained from 232 CEAs over the past 4 years. METHODS: Preoperative and postoperative carotid artery duplex examinations with specific evaluation of the extent of ECA stenosis were available for review on 114 CEAs performed between January 1991 and July 1994. All CEAs were performed for internal carotid artery stenosis greater than 75% as determined by duplex scanning, which was confirmed by either contrast arteriography or magnetic resonance angiography. RESULTS: Seventy-three (64.0%) procedures were performed for symptomatic lesions, whereas 41 (36.0%) were performed for asymptomatic stenosis. There were no perioperative strokes or transient ischemic attacks in this group, and there was one postoperative death (0.9%). Short- and intermediate-term follow-up demonstrated insignificant changes in ECA diameter after operation, with no cases of ECA occlusion and only five cases progressing to greater than 75% on the 1-year follow up duplex examination. CONCLUSION: We conclude from these data that averting external CEA during standard CEA does not result in significant progression of ECA stenosis or occlusion.

Complementary distal arteriovenous fistula and deep vein interposition: a five-year experience with a new technique to improve infrapopliteal prosthetic bypass patency.

PURPOSE: In an attempt to improve graft patency results of prosthetic bypasses to infrapopliteal arteries, we used a new type of adjunctive technique that combines an arteriovenous fistula and vein interposition (AVF/VI). METHODS: Over the past 5 years, 68 such reconstructions were performed in 62 patients with critical ischemia in whom a totally autogenous vein bypass was not feasible. Forty-seven patients (76%) had one or more failed ipsilateral infrainguinal bypasses. The AVF/VI was performed by transposing the central portion of the adjacent deep vein onto the side of the recipient artery. The distal end of a 6-mm polytetrafluoroethylene (PTFE) ringed graft then was anastomosed to the hood of the AVF. The segment of vein interposed between the PTFE graft and the recipient artery widened the anastomosis and improved the compliance mismatch. Simultaneous pressure measurements of the radial artery and the distal portion of the graft were obtained in all cases. RESULTS: Significant pressure gradients ranging from 35 to 70 mm Hg were detected in 26 bypasses (38%), which led to banding of the venous outflow that decreased the gradient to within 20 mm Hg. A gradient < or = 30 mm Hg was found in 28 bypasses (41%), and no banding was required if the absolute intragraft systolic pressure was > or = 100 mm Hg. Only 14 bypasses (21%) had no detectable pressure gradients. Twenty-six bypasses originated from femoral arteries, 34 from iliac arteries, and 8 from patent proximal grafts. The recipient arteries were the anterior tibial artery in 33 cases, posterior tibial in 17, peroneal in 15, dorsalis pedis in 2, and lateral plantar in 1. All patients began a regimen of heparin 6 to 8 hours after surgery and continued to receive chronic anticoagulation. Cumulative, 3-year assisted primary graft patency rates were 78%, 70%, and 62%, respectively. Cumulative 3-year AVF patency rates were 65%, 57%, and 46%, respectively. The 3-year limb salvage rate was approximately 78%. CONCLUSION: Adjunctive AVF/VI significantly improves infrapopliteal PTFE graft patency and limb salvage rates. The combination of a decreased compliance mismatch at the distal anastomosis and the abolishment of a large pressure gradient at the distal anastomosis while maintaining higher graft flow rates may have contributed to the improved results.