Exploratory analysis of clinical benefit of ipilimumab and nivolumab treatment in patients with metastatic melanoma from a single institution.

PURPOSE: We retrospectively analysed overall survival (OS) and potential predictive biomarkers of OS in patients with metastatic melanoma treated with ipilimumab plus nivolumab in a single institution. METHODS AND PATIENTS: Electronic medical records of patients with advanced melanoma receiving ≥ 1 dose of a combined ipilimumab plus nivolumab regimen between March 3, 2016 and March 7, 2020 in a single institution, were reviewed. OS was analysed using the Kaplan-Meier method. Sub-group analyses were conducted to examine several endpoints according to relevant clinical, molecular and pathological variables using logistic and Cox models. RESULTS: Forty-four cases were reviewed, 38 (86.4%), of whom had cutaneous melanoma, 21 (47.7%) were BRAF mutant, 21 (47.7%) presented high lactate dehydrogenase (LDH) values, 23 (52.3%) had ≥ 3 disease sites, and 10 (22.7%) patients had brain metastases. The median follow-up was 37.7 months, and the median OS was 21.1 months (95% CI 8.2-NR). In the multivariate analysis, the OS was significantly longer in patients with an Eastern Cooperative Oncology Group (ECOG) score of 0, LDH ≤ upper limit of normal, absence of liver metastases and neutrophil-to-lymphocyte ratio (NLR) < 5 (all p ≤ 0.05, log-rank test). These factors allowed the classification of patients into three prognostic risk groups (low/intermediate/high risk) for death. CONCLUSION: Overall survival of real-world patients from our cohort receiving ipilimumab plus nivolumab was lower than in previous studies. The ECOG score, LDH values, the presence of liver metastases and the NLR were independent prognostic factors for survival.

How to Choose between the Implant Materials Steel and Titanium in Orthopedic Trauma Surgery: Part 2 - Biological Aspects.

BIOLOGICAL ASPECTS OF STEEL AND TITANIUM AS IMPLANT MATERIAL IN ORTHOPEDIC TRAUMA SURGERY The following case from the ICUC database, where a titanium plate was implanted into a flourishing infection, represents the clinical experience leading to preferring titanium over steel. (Fig. 1) (6). Current opinions regarding biological aspects of implant function. The "street" opinions regarding the biological aspects of the use of steel versus titanium as a surgical trauma implant material differ widely. Statements of opinion leaders range from "I do not see any difference in the biological behavior between steel and titanium in clinical application" to "I successfully use titanium implants in infected areas in a situation where steel would act as foreign body "sustaining" infection." Furthermore, some comments imply that clinical proof for the superiority of titanium in human application is lacking. The following tries to clarify the issues addressing the different aspects more through a practical clinical approach than a purely scientific one, this includes simplifications. Today's overall biocompatibility of implant materials is acceptable but: As the vast majority of secondary surgeries are elective procedures this allows the selection of implant materials with optimal infection resistance. The different biological reactions of stainless steel and titanium are important for this segment of clinical pathologies. Biological tole - rance (18) depends on the toxicity and on the amount of soluble implant material released. Release, diffusion and washout through blood circulation determine the local concentration of the corrosion products. Alloying components of steel, especially nickel and chromium, are less than optimal in respect to tissue tolerance and allergenicity. Titanium as a pure metal provides excellent biological tolerance (3, 4, 16). Better strength was obtained by titanium alloys like TiAl6V4. The latter found limited application as surgical implants. It contains Vanadium (9). Today's high strength titanium alloys contain well tolerated alloying components1 like Zr, Nb, Mo and Ta (ISO 5832-14) (7, 15). The corrosion rate of surgical implants is kept low by the passive layer formed when immerged in body fluids (13, 14). The passive layer may be locally destroyed, for instance, by mechanical fretting or by local corrosion conditions like in pitting; it is renewed by an electrochemical corrosion process which releases alloying components like Ni and Cr (Fig. 2) (10). The amount of soluble component may vary markedly depending on the local electrochemical conditions (see below).

How to Choose between the Implant Materials Steel and Titanium in Orthopedic Trauma Surgery: Part 1 - Mechanical Aspects.

When choosing between metal implants of different materials the surgeon mainly needs to balance the pros and cons of steel and titanium. Economic constraints often do not permit both to be kept in stock and it is necessary to decide beforehand which to choose. The arguments for the use of the "preferred metal" vary. The present paper elucidates the practical aspects based on the complex scientific background that has identified the differences between the two metals in their mechanical, electrochemical, biological and application behavior. The data presented here are intended to help the surgeon when he is confronted with different and often complex clinical situations and problems. The following is an overview of different aspects to help with selection of the proper material for the clinical application. The first part concerns mechanical aspects the second part the biological aspects. Both aspects are discussed with the practical application in mind. Nonmetallic implant materials have seen an increasing interest in the recent past. Plastic materials needed improvement to achieve good strength and avoid creep with loss of e.g. compression and minimizing leakage of chemicals.

Biomechanical and biological aspects of defect treatment in fractures using helical plates.

The clinical case of figure 1 through figure 11 shows a series of impressive failures of plate fixation. The plates were repeatedly applied bridging a comminuted bone segment in a heavy patient. The biomechanical analysis elaborates why this happened and proposes an unconventional procedure to prevent this failure with a minimally invasive procedure. A plate bridging an open gap or a defect in a long bone diaphysis is exposed to full functional load. According to clinical observations such plate application often fails even without external load such as weight bearing. The plate risks to break through fatigue when exposed during a long time to cyclic loading. This type of failure has been observed even with broad plates as well in femoral as in tibiae. The first option to avoid such failure consists in protecting the plate by installing load sharing between plate and either bone or an additional implant. This reduces the load carried by the plate to a safe level. Load sharing with bone may be installed at surgery by establishing solid mechanical bridge between the two main fragments of the fractured bone. The optimal load sharing relies on a solid compressed contact between the main fragments. It can be established because the bone is able to take a large load which results in optimal protection of the plate. In the case of an extended comminuted bone segment it may be very difficult, traumatizing and inefficient to reconstruct the bone. In the present case it was impossible to establish load sharing through the bone. The second option protecting the plate is provided by callus bridging of the gap or defect. The formation of a solid callus bridge takes time but the fatigue failure of the plate also takes time. Therefore, the callus bridge may prevent a late fatigue failure. The surgeon may select one of several options: - Replacing the lack of bone support using a second plate which immediately alleviates plate loading. The drawback of application of a second conventional plate is the extent of surgical trauma at the critical site of healing. - Shingling and/or applying an autologous cancellous bone graft: This procedure provides initially no relevant load sharing but will do so after a couple of weeks. The mechanical coupling of the comparably soft graft and the main fracture fragments presents little problems. Applying a cortical bone graft: Such a graft does provide initial only small load sharing and does a less good job inducing callus than a cancellous graft. Furthermore, the coupling by callus between a somewhat rigid bone graft and the mobile main fracture fragments requires a solid maintained contact. If the cortical graft is fixed using implants with small contact area to the graft such as screws or cerclage loops, the local stress may be critical and the graft may break. When the cortical graft is fixed with cerclage wires the procedure must take into account the limited strength of the individual cerclage. Therefore multiple and well-spaced cerclages are required and may lead to success especially if an intramedullary component of the implant contributes to protection (6). The degree of unloading depends apparently on the stiffness of the material of the protecting splint. Though, more important is the effect of the dimensions of the splint. While titanium as a material is about 50% less stiff than steel, the thickness of the implant changes the stiffness with the third power. That is doubling the thickness results in eightfold increased stiffness. When considering the unloading by application of a second plate the leverage of the second plate plays an important role. The larger the distance between the axis of bending and the second implant the larger the protecting effect. The helical plate (2, 3, 7) as introduced by A.A.D. Fernandez offers biological and mechanical advantages. It can be applied without touching the fracture site maintaining the critical biology intact and provides mechanically efficient unloading. Its application is fairly simple: The helical plate is modified conventional long and small plate that is twisted between its ends about 90 degrees. The twist is applied using "bending irons" (4, 5, 8) whereby the force required is small and the exact degree of twist is not critical. Therefore the twist is applicable operating bending irons by hand. Assuming a situation where a plate bridging a defect or non-union has failed the broken plate is replaced by a similar implant: At the distal end of the bone fracture and opposite to the surgical approach a small incision allows to slide in the helical plate in such a way that proximally the plate ends on the same side of the limb as the replaced plate. Ideally the two plate ends meet and the application of the helical plate does not ask for an additional surgical exposure at this location. Otherwise a small minimally invasive exposure is required. The helical plate is then fixed to the main bone fragments using a couple of locked screws. The following case demonstrates the use and efficiency of the helical plate saving a situation where multiple attempts using conventional plates had failed. The successful final treatment of this case was performed by A. A. D. Fernandez.

A cancer-causing gene is positively correlated with male aggression in Xiphophorus cortezi.

The persistence of seemingly maladaptive genes in organisms challenges evolutionary biological thought. In Xiphophorus fishes, certain melanin patterns form malignant melanomas because of a cancer-causing gene (Xiphophorus melanoma receptor kinase; Xmrk), which arose several millions years ago from unequal meiotic recombination. Xiphophorus melanomas are male biased and induced by androgens however male behaviour and Xmrk genotype has not been investigated. This study found that male X. cortezi with the spotted caudal (Sc) pattern, from which melanomas originate, displayed increased aggression in mirror image trials. Furthermore, Xmrk males (regardless of Sc phenotype) bit and performed more agonistic displays than Xmrk deficient males. Male aggressive response decreased when males viewed their Sc image as compared with their non-Sc image. Collectively, these results indicate that Xmrk males experience a competitive advantage over wild-type males and that intrasexual selection could be an important component in the evolutionary maintenance of this oncogene within Xiphophorus.

External fixation of the leg using unilateral biplanar frames.

A simple and reliable method is described for testing the stability of external fixators under stresses similar to those found in clinical practice. Unilateral uniplanar, unilateral biplanar, and bilateral uniplanar frames were used. It seemed important to measure deformations under bending stresses in different planes, because we have found a variable rigidity in some of the frames in the different planes. Our results show that a unilateral biplanar frame without transfixation pins can be set up with an overall rigidity as good as that of a bilateral frame. Using this on the leg, one can avoid putting pins through the anterolateral compartment.

Practical applications of radioimmunoassay theory. A simple procedure yielding linear calibration curves.

The fundamental equation describing radioimmunoassays under equilibrium conditions has been recast into a "working equation" in a form more directly applicable to the requirements of the analytical laboratory. Plotting total counts over counts bound vs. ligand concentration, which is conveniently linear over most of its course, is shown readily to yield quantitative data relative to binding site concentration and the equilibrium constant and to provide a means for deriving apparent labeled ligand concentration. Such data are helpful in establishing optimum assay conditions and can serve a continuing quality-control function. The working equation also characterizes the binder and tracer reagents used in the assay. The determination of working-equation parameters has been illustrated for the vitamin B-12 assay. Data are presented for seven different assay procedures, involving more than 600 calibration curves and 100 different lots of binding agent and tracer reagent, showing a consistently high correlation coefficient (r greater than 0.990), between ligand concentration and the response variable.