Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.     

<Emphasis Type="Italic">GSTP1</Emphasis> and <Emphasis Type="Italic">MDR1</Emphasis> Genotypes and Central Nervous System Relapse in Childhood Acute Lymphoblastic Leukemia

The probability of event-free survival of childhood acute lymphoblastic leukemia (ALL) approaches 80% or more with the use of modern multiagent chemotherapeutic regimens. One major contribution to this success has been reduction of the rate of central nervous system (CNS) relapses to less than 5%. However, heterogeneity is observed with regard to the incidence of CNS relapse in homogenously treated patient populations. One potential explanation for this heterogeneity is variation in the genetic background of these populations. Glutathione S-transferase P1 and P-glycoprotein are implicated in resistance to a variety of chemotherapeutic agents and have been localized to the blood-brain barrier. In a matched case-control study, we investigated the associations between CNS relapse in childhood ALL and the presence of phenotypically relevant single nucleotide polymorphisms within the GSTP1 (codon 105 and 114) and MDR1 genes (ABCB1; coding for Pgp; exon 26, C3435T). Significant reductions in risk of CNS relapse were observed for patients homozygous for the GSTP1 Val105 allele as well as for patients with the MDR1 3435T/T or C/T genotype. For both genotypes, the effect was restricted to patients at intermediate or high risk of treatment failure. These results suggested a modulating role for host genetic variation in the development of CNS relapse in childhood ALL treated according to Berlin-Frankfurt-Münster protocols.     

Platelets modulate the proteolysis of factor VIII:C protein by plasmin

Factor VIII coagulant protein (VIII:C) functions as a critical cofactor with factor IXa, calcium ions, and phospholipid during the activation of factor X. In the course of this reaction, the activity of VIII:C is first increased and then is destroyed by one or more serine proteases that are part of the coagulation sequence. In this study, we have investigated the influence of platelets on the inactivation of VIII:C by plasmin. Platelets were separated from plasma proteins in the presence of granule release inhibitors and were incubated with plasmin and isolated VIII:C or the complex of purified VIII:C/von Willebrand factor (vWF); VIII:C activity and antigen levels were assessed over time. In the presence of platelets, the isolated VIII:C showed an initial increase in VIII:C activity that was not present when platelets were absent, and the VIII:C/vWF showed an increase in VIII:C activity over that seen when platelets were absent. In addition, platelets stabilized VIII:C activity over a one-hour time course when compared with buffer. The VIII:C antigen did not increase and decreased slowly whether platelets were present or absent. Preincubating the platelets with ristocetin, collagen, or plasmin did not alter the results, and experiments using platelets from a patient with severe von Willebrand's disease also showed a pattern similar to that seen with normal platelets. Experiments using fixed platelets or phospholipid vesicles showed that they did not support the activation reaction or delay the inactivation reaction. These studies demonstrate that platelets modulate the activation and inactivation of VIII:C by plasmin, apparently by a mechanism that is independent of the platelet release reaction.     

Toward the development of peptide nanofilaments and nanoropes as smart materials

Protein design studies using coiled coils have illustrated the potential of engineering simple peptides to self-associate into polymers and networks. Although basic aspects of self-assembly in protein systems have been demonstrated, it remains a major challenge to create materials whose large-scale structures are well determined from design of local protein-protein interactions. Here, we show the design and characterization of a helical peptide, which uses phased hydrophobic interactions to drive assembly into nanofilaments and fibrils ("nanoropes"). Using the hydrophobic effect to drive self-assembly circumvents problems of uncontrolled self-assembly seen in previous approaches that used electrostatics as a mode for self-assembly. The nanostructures designed here are characterized by biophysical methods including analytical ultracentrifugation, dynamic light scattering, and circular dichroism to measure their solution properties, and atomic force microscopy to study their behavior on surfaces. Additionally, the assembly of such structures can be predictably regulated by using various environmental factors, such as pH, salt, other molecular crowding reagents, and specifically designed "capping" peptides. This ability to regulate self-assembly is a critical feature in creating smart peptide biomaterials.     

Der Schlaganfall beim Diabetespatienten

Diabetes and stroke are important clinical conditions from epidemiological and economical points of view. An interdisciplinary approach is always indicated to diagnose and treat these diseases optimally. Diabetes elevates the risk of stroke between two- and four-fold. Diabetic stroke patients need longer in-patient treatment, have a higher mortality rate and recover less well during the rehabilitation process. Approximately 20%-30% of first-ever stroke patients reveal an impaired glucose tolerance or even manifest diabetes. Already in the prediabetic phase, vessel damage can be seen in the form of endothelial dysfunction and early arteriosclerosis. Measurements of microalbuminuria and intima-media thickness of the common carotid artery enable an assessment of the vascular system. Hyperglycemia represents a serious risk during the acute treatment phase, as it diminishes the effect of thrombolysis and worsens the ischemic parenchymal lesion. Specific neurological signs and symptoms complicate the acute phase of stroke treatment, which should always be carried out in a stroke unit. For secondary prevention purposes, risk-adapted platelet inhibition and statins are recommended.     

Racial/ethnic disparities among women receiving intrauterine transfusions for alloimmunization at a single fetal treatment center

Disparities are prevalent in numerous areas of healthcare. We sought to investigate whether there were racial/ethnic disparities among pregnant women with the most severe form of alloimmunization who require intrauterine transfusions (IUT). We reviewed patients who underwent IUT for alloimmunization at a single fetal treatment center between 2015 and 2020. This “IUT cohort” was compared to an “Alloimmunization cohort”: patients seen at our institution with a diagnosis of alloimmunization during pregnancy, who did not receive IUT. We collected maternal demographics including self-identified race/ethnicity and primary language, transfusion, and antibody characteristics. The cohorts were compared using unpaired t-tests, Mann-Whitney tests, and Fischer's exact tests, as appropriate. The IUT cohort included 43 patients and the alloimmunization cohort included 1049 patients. Compared to the alloimmunization cohort, there were significantly more patients of Latina descent in the IUT cohort (23.3% vs. 3.4%, p < .0001), and more non-English speakers (18.6% vs. 4.6%, p = .001). Twenty-one percent (9/43) of patients had immigrated to the United States, all of whom had pregnancies or miscarriages in their country of origin. A third of patients had new antibodies identified on serial screens during the current pregnancy. Significantly more women of Latina ethnicity and non-English speakers required IUTs compared to the cohort of women with alloimmunization. Insufficient access to care prior to arriving in the United States and among racial and ethnic minorities in the United States may contribute to these findings. Providers should be cognizant of potential, racial, and ethnic inequalities among women receiving intrauterine transfusions.     

PSA bounce after <Superscript>125</Superscript>I-brachytherapy for prostate cancer as a favorable prognosticator

Background

Permanent low-dose-rate brachytherapy (BT) with iodine 125 is an established curative treatment for localized prostate cancer. After treatment, prostate-specific antigen (PSA) kinetics may show a transient rise (PSA bounce). Our aim was to investigate the association of PSA bounce with biochemical control.

Patients and methods

Patients treated with BT in Switzerland were registered in a prospective database. Only patients with a follow-up of at least 2 years were included in our analysis. Clinical follow-up and PSA measurements were assessed after 1.5, 3, 6, and 12 months, and annually thereafter. If PSA increased, additional follow-up visits were scheduled. Cases of PSA bounce were defined as a rise of at least 0.2 ng/ml above the initial PSA nadir with a subsequent decline to or below the initial nadir without treatment. Biochemical failure was defined as a rise to nadir +?2 ng/ml.

Results

Between March 2001 and November 2010, 713 patients with prostate cancer undergoing BT with at least 2 years of follow-up were registered. Median follow-up time was 41 months. Biochemical failure occurred in 28 patients (3.9?%). PSA bounce occurred in 173 (24.3?%) patients; only three (1.7?%) patients with PSA bounce developed biochemical failure, in contrast to 25 (4.6?%) patients without previous bounce (p?<?0.05). The median time to bounce was 12 months, the median time to biochemical failure was 30 months. The median bounce increase was 0.78 ng/ml. Twenty-eight patients with bounce (16.5?%) had a transient PSA rise of +?2 ng/ml above the nadir.

Conclusion

In most cases, an early increase in PSA after BT indicates PSA bounce and is associated with a lower risk of biochemical failure.

     

Relative Femoral Neck Lengthening Improves Pain and Hip Function in Proximal Femoral Deformities With a High-riding Trochanter

BackgroundComplex proximal femoral deformities, including an elevated greater trochanter, short femoral neck, and aspherical head-neck junction, often result in pain and impaired hip function resulting from intra-/extraarticular impingement. Relative femoral neck lengthening may address these deformities, but mid-term results of this approach have not been widely reported.Questions/purposesDo patients who have undergone relative femoral neck lengthening show (1) less hip pain and greater function; (2) improved radiographic parameters; (3) significant complications requiring subsequent surgery; and (4) progression of osteoarthrosis (OA) or conversion to total hip arthroplasty (THA) at mid-term followup?MethodsWe retrospectively reviewed 40 patients (41 hips) with isolated relative femoral neck lengthening between 1998 and 2006 with sequelae of Legg-Calvé-Perthes disease (38 hips [93%]), slipped capital femoral epiphysis (two hips [5%]), and postseptic arthritis (one hip [2%]). During this time, the general indications for this procedure included a high-riding greater trochanter with a short femoral neck with abductor weakness and symptomatic intra-/extraarticular impingement. Mean patient followup was 8 years (range, 5–13 years), and complete followup was available in 38 patients (39 hips [95%]). We evaluated pain and function with the impingement test, limp, abductor force, Merle d’Aubigné-Postel score, and range of motion. Radiographic parameters included trochanteric height, alpha angle, and progression of OA. Subsequent surgeries, complications, and conversion to THA were summarized.ResultsThe proportion of positive anterior impingement tests decreased from 93% (38 of 41 hips) preoperatively to 49% (17 of 35 hips) at latest followup (p = 0.002); the proportion of limp decreased from 76% (31 of 41 hips) to 9% (three of 35 hips; p < 0.001); the proportion of normal abductor strength increased from 17% (seven of 41 hips) to 91% (32 of 35 hips; p < 0.001); mean Merle d’Aubigné-Postel score increased from 14 ± 1.7 (range, 9–17) to 17 ± 1.5 (range, 13–18; p < 0.001); mean internal rotation increased to 25° ± 15° (range, 0°–60°; p = 0.045), external rotation to 32° ± 14° (range, 5°–70°; p = 0.013), and abduction to 37° ± 13° (range, 10°–50°; p = 0.004). Eighty percent of hips (33 of 41 hips) showed normal trochanteric height; alpha angle improved to 42° ± 10° (range, 27°–90°). Two hips (5%) had subsequent surgeries as a result of lack of containment; four of 41 hips (10%) had complications resulting in reoperation. Fourteen of 35 hips (40%) showed progression of OA; four of 40 hips (10%) converted to THA.ConclusionsRelative femoral neck lengthening in hips with combined intra- and extraarticular impingement results in reduced pain, improved function, and improved radiographic parameters of the proximal femur. Although lack of long-term complications is gratifying, progression of OA was not prevented and remains an area for future research.

Level of Evidence

Level IV, therapeutic study.

Electronic supplementary material

The online version of this article (doi:10.1007/s11999-014-4032-9) contains supplementary material, which is available to authorized users.     

2015 Marshall Urist Young Investigator Award: Prognostication in Patients With Long Bone Metastases: Does a Boosting Algorithm Improve Survival Estimates?

Background

Survival estimation guides surgical decision-making in metastatic bone disease. Traditionally, classic scoring systems, such as the Bauer score, provide survival estimates based on a summary score of prognostic factors. Identification of new factors might improve the accuracy of these models. Additionally, the use of different algorithms—nomograms or boosting algorithms—could further improve accuracy of prognostication relative to classic scoring systems. A nomogram is an extension of a classic scoring system and generates a more-individualized survival probability based on a patient’s set of characteristics using a figure. Boosting is a method that automatically trains to classify outcomes by applying classifiers (variables) in a sequential way and subsequently combines them. A boosting algorithm provides survival probabilities based on every possible combination of variables.

Questions/purposes

We wished to (1) assess factors independently associated with decreased survival in patients with metastatic long bone fractures and (2) compare the accuracy of a classic scoring system, nomogram, and boosting algorithms in predicting 30-, 90-, and 365-day survival.

Methods

We included all 927 patients in our retrospective study who underwent surgery for a metastatic long bone fracture at two institutions between January 1999 and December 2013. We included only the first procedure if patients underwent multiple surgical procedures or had more than one fracture. Median followup was 8 months (interquartile range, 3-25 months); 369 of 412 (90%) patients who where alive at 1 year were still in followup. Multivariable Cox regression analysis was used to identify clinical and laboratory factors independently associated with decreased survival. We created a classic scoring system, nomogram, and boosting algorithms based on identified variables. Accuracy of the algorithms was assessed using area under the curve analysis through fivefold cross validation.

Results

The following factors were associated with a decreased likelihood of survival after surgical treatment of a metastatic long bone fracture, after controlling for relevant confounding variables: older age (hazard ratio [HR], 1.0; 95% CI, 1.0–1.0; p < 0.001), additional comorbidity (HR, 1.2; 95% CI, 1.0–1.4; p = 0.034), BMI less than 18.5 kg/m² (HR, 2.0; 95% CI, 1.2–3.5; p = 0.011), tumor type with poor prognosis (HR, 1.8; 95% CI, 1.6–2.2; p < 0.001), multiple bone metastases (HR, 1.3; 95% CI, 1.1–1.6; p = 0.008), visceral metastases (HR, 1.6; 95% CI, 1.4–1.9; p < 0.001), and lower hemoglobin level (HR, 0.91; 95% CI, 0.87–0.96; p < 0.001). The survival estimates by the nomogram were moderately accurate for predicting 30-day (area under the curve [AUC], 0.72), 90-day (AUC, 0.75), and 365-day (AUC, 0.73) survival and remained stable after correcting for optimism through fivefold cross validation. Boosting algorithms were better predictors of survival on the training datasets, but decreased to a performance level comparable to the nomogram when applied on testing datasets for 30-day (AUC, 0.69), 90-day (AUC, 0.75), and 365-day (AUC, 0.72) survival prediction. Performance of the classic scoring system was lowest for all prediction periods.

Conclusions

Comorbidity status and BMI are newly identified factors associated with decreased survival and should be taken into account when estimating survival. Performance of the boosting algorithms and nomogram were comparable on the testing datasets. However, the nomogram is easier to apply and therefore more useful to aid surgical decision making in clinical practice.

Level of Evidence

Level III, prognostic study.

Electronic supplementary material

The online version of this article (doi:10.1007/s11999-015-4446-z) contains supplementary material, which is available to authorized users.