Application of nitroxoline in urologic oncology - a review of evidence.

The persistence of high incidence and mortality rates associated with urologic cancers underscores the urgent need for effective and safe treatments. Conventional chemotherapy regimens are often limited by their high toxicity, the cancer's drug resistance, and the challenge of managing independently evolving multifocal spread. In this context, a repurposing strategy is particularly enticing. It allows for the introduction of a drug with a known safety profile, thus significantly reducing the costs and time necessary to introduce a new treatment. Nitroxoline (NIT), a drug with a well-established pharmacokinetic profile known for over 50 years and utilised in treating uncomplicated urinary tract infections, has recently garnered attention for its potential oncologic applications. Given the pharmacokinetic properties of NIT, our focus was specifically on urologic cancers in which its excretion profile is most advantageous. We examined all available studies, demonstrating significant effectiveness of NIT in inhibiting angiogenesis, tissue invasion, metastasis formation, and counteracting multidrug resistance. The efficacy and mechanism of action of NIT were found to vary across different cell lines. The findings to date are promising, suggesting that NIT or its derivatives could play a role in oncology, although further research is necessary to fully understand its potential and applicability in cancer treatment.

Immune activation- and regulation-related patterns in stable hand transplant recipients.

We assessed cell subsets and expression of a set of genes related to the T-cell populations in peripheral blood mononuclear cells to elucidate whether immune status of stable hand transplant recipients (HTx) differs from stable kidney transplant recipients (KTx). The study was conducted on five HTx 4.8 ± 1.7 years after transplantation and 30 stable KTx 7.9 ± 2.4 years after transplantation as well as 18 healthy volunteers. The research involved PBMC gene expression analysis of CD4, CD8, CTLA4, GZMB, FOXP3, IL10, IL4, ILR2A, NOTCH, PDCD1, PRF1, TGF-B, and TNF-A genes on a custom-designed low-density array (TaqMan) as well as flow cytometry assessment of lymphocyte subpopulations. HTx presented significantly increased expression of immunomodulatory genes (TNF, IL10, GITR, and PDCD1) compared to KTx and controls. HTx revealed a proinflammatory molecular pattern with higher expression of NOTCH and CD8 compared to KTx and controls. KTx showed a reduced level of regulatory T cells compared to controls and HTx. Both HTx and KTx presented an increased number of CD8+ and CD8+ CD28- T cells compared to controls. Stable hand transplant recipients exhibit persistent immune activation with rejection-related gene expression pattern counterbalanced by secondary induction of regulatory mechanisms.

Functional and Psychosocial Outcomes of Hand Transplantation Compared with Prosthetic Fitting in Below-Elbow Amputees: A Multicenter Cohort Study.

BACKGROUND: Hand-transplantation and improvements in the field of prostheses opened new frontiers in restoring hand function in below-elbow amputees. Both concepts aim at restoring reliable hand function, however, the indications, advantages and limitations for each treatment must be carefully considered depending on level and extent of amputation. Here we report our findings of a multi-center cohort study comparing hand function and quality-of-life of people with transplanted versus prosthetic hands. METHODS: Hand function in amputees with either transplant or prostheses was tested with Action Research Arm Test (ARAT), Southampton Hand Assessment Procedure (SHAP) and the Disabilities of the Arm, Shoulder and Hand measure (DASH). Quality-of-life was compared with the Short-Form 36 (SF-36). RESULTS: Transplanted patients (n = 5) achieved a mean ARAT score of 40.86 ± 8.07 and an average SHAP score of 75.00 ± 11.06. Prosthetic patients (n = 7) achieved a mean ARAT score of 39.00 ± 3.61 and an average SHAP score of 75.43 ± 10.81. There was no significant difference between transplanted and prosthetic hands in ARAT, SHAP or DASH. While quality-of-life metrics were equivocal for four scales of the SF-36, transplanted patients reported significantly higher scores in "role-physical" (p = 0.006), "vitality" (p = 0.008), "role-emotional" (p = 0.035) and "mental-health" (p = 0.003). CONCLUSIONS: The indications for hand transplantation or prosthetic fitting in below-elbow amputees require careful consideration. As functional outcomes were not significantly different between groups, patient's best interests and the route of least harm should guide treatment. Due to the immunosuppressive side-effects, the indication for allotransplantation must still be restrictive, the best being bilateral amputees.

The Physical and Psychosocial Benefits of Upper-Limb Transplantation: A Case Series of 5 Polish Patients.

BACKGROUND: Although upper-limb transplantation is not a life-saving procedure, every year more and more patients are ready to undergo this surgery. Conventional methods of treatment performed earlier have not brought the expected functional and aesthetic results. Patients who have received upper-limb transplantation (HTx) enjoy, in addition to the physical benefits associated with good functional effect, numerous benefits of a psychological and social nature. Investigation of these benefits was the aim of this interdisciplinary research. CASE REPORT: The wide spectrum of physical, psychological, and social benefits derived by recipients of limb transplantation include: improved physical fitness, recovery of the complete body form, corporeal well-being, enhanced self-esteem, recovery of self-confidence, a stable feeling of personal and social identity, higher integration of the body with performed social roles, greater confidence in the ability to act and have control over life, a feeling of greater security, the ability to return to work, restoration of social position, and positive personality changes. CONCLUSIONS: Potential benefits which may be derived by future upper limb recipients are manifested in the good functional effect of the transplantation, enhanced life satisfaction, and better functioning in society. It does not mean, however, restoration of 100% of fitness or absolutely problem-free functioning in everyday life, which is extremely important in the context of prevention of possible disappointment to future limb recipients.

Assessment of vascular function of hand allografts.

BACKGROUND: Insufficiency of blood vessels supplying a limb allograft may lead to loss of the extremity. Thus, a regular evaluation of perfusion of transplants seems a reasonable approach. The purpose of the present study was assessment of allograft perfusion by means of non-invasive methods. MATERIAL/METHODS: Six hand allografts transplanted in 5 patients were included in the study group. The transplant procedure occurred on average 45 months before. The study group comprised 2 allografts at forearm level, 2 transplants of the arm, and 1 bilateral transplant of the forearm. Parameters of blood flow using Doppler ultrasonography, impedance plethysmography, Doppler measurement of segmental pressures, optical pulse oscillography (OPO), and thermography were performed in all participants. RESULTS: DUS revealed increased resistive index in ulnar arteries of transplant hands compared to native hands and an altered blood supply was confirmed by IP. Flow-mediated dilatation within the transplanted extremity was abnormal in most patients and was inversely correlated with number of episodes of acute rejection. Analysis of oscillographic spectrum revealed flattening of the dicrotic notch in transplant hands. A tendency for lower temperature of the skin of transplanted hands compared to native extremities was also observed. CONCLUSIONS: In asymptomatic patients after limb transplantation, non-invasive methods disclosed discreet abnormalities of graft perfusion. Thus, regular measurement of perfusion parameters using these methods appears to be a promising approach to detect early and potentially reversible disturbances of blood supply. Further observational studies are required to determine its clinical significance.

Humoral immunity in hand transplantation: anti-HLA and non-HLA response.

UNLABELLED: Antibodies against donor's HLA antigens and B cell activity are recognized modulators of immune response to allograft. The role of both anti-HLA and non-HLA antibodies is understood in solid organ transplantation, but has not been addressed in composite tissue allografts. AIM: We decided to evaluate the presence and role of anti-HLA and non-HLA antibodies after hand transplantation. METHODS: We assayed anti-HLA and non-HLA antibodies in 5 consecutive hand transplant patients. The presence of anti-HLA antibodies was tested by flow-PRA method (One Lambda). Non-HLA antibodies were defined as anti-endothelial cell (AECA), anti-angiotensin II type 1 receptor (anti-AT1R), anti-endothelin receptor antibodies (anti-ETAR). RESULTS: Anti-HLA antibodies were present in 1 patient in class I and in another one in class II. Both patients developed one episode of acute rejection. AECA were present in only one recipient with borderline activity. Both anti-AT1R and Anti-ETAR were found strongly positive in one patient who repeatedly developed acute rejection episodes. CONCLUSION: The presence of non-HLA antibodies (anti-AT1R and anti-ETAR) and the occurrence of multiple rejection episodes found in one patient here require further investigation into a possible association and role of humoral immunity in composite tissue rejection.

Result of arm-level upper-limb transplantation in two recipients at 19- and 30-month follow-up.

BACKGROUND: Arm transplantation (ATx) is a novelty in the field of upper-limb transplantation, with only 7 procedures performed world-wide. CASE REPORT: In this paper we report on early results of unilateral arm transplantation recipients. Patient 1, a 30-year-old man, examined 30 months post-transplant, is able to actively flex the elbow, has 160 degree of ROM in the fingers of the grafted limb, and scored 92 points in the DASH questionnaire and 62 points in the Comprehensive Functional Score System (CFSS). The post-transplant period was complicated with 1 acute rejection episode due to CMV infection, and delayed bony union. Patient 2, a 55-year-old woman, examined 19 months post-transplant, is able to actively flex the elbow, has 180 degree of ROM in the fingers of the grafted limb, and scored 89 points in the DASH questionnaire and 64 points in the Comprehensive Functional Score System (CFSS). CONCLUSIONS: The post-transplant period was complicated with a delayed bony union. The ATx seems to be a valuable reconstructive therapeutic modality.

First Polish forearm transplantation - final report (outcome after 4 years).

BACKGROUND: Hand transplantation (HTx) presents an exceptional reconstructive solution for hand amputees. Relatively few patients qualify for such an operation - generally healthy patients suffering from a serious disturbance of body integrity. CASE REPORT: We present a patient 48 months after unilateral transplantation of an allogenic forearm. Clinical course, laboratory results, function of the graft, and quality of life of the patient are analyzed. These findings are compared with those achieved by 2 other patients - recipients of allograft forearm transplanted on the same zone in Lyon 2002, and Louisville 2001. The patient suffered no post-transplantation infections, had 1 episode of rejection - I degrees . Except for mild diabetes, no disturbances of internal organs were observed. Total active motions of fingers (TAM) equaled 53% of fingers of unaffected hand. The functional evaluation by SF 36 is 53; by DASH - 92; Chen's score system rates our patient as II (good); CFSS score system - 84 points (excellent result). His functional result is similar to that achieved by 2 others mid-forearm recipients. CONCLUSIONS: The upper limb transplant performed on a functionally unfavorable zone of the mid-forearm has greatly increased patient's quality of life.

Unsuccessful attempt of forearm transplantation--case report.

BACKGROUND: The technique of hand transplantation is similar to that of hand replantation. Although the rate of failure of hand replantation tantamount to 15% on average, depending mostly on mechanism of amputation, until now no data have been published concerning the failure of attempts of hand transplantation. CASE REPORT: A 42-year-old male is presented who was the recipient of a hand transplant. The patient had an amputation of his left, dominant forearm (result of a circular-saw accident) 8 years prior to the transplantation. He was generally healthy, very dedicated to the operation. The limb was obtained in another hospital from a 49-year-old woman, victim of an accident and multi visceral donor.The donor was matched for blood group (0 positive), bone size, texture, with the recipient. There was 4 HLA antigen mismatch; the lymphocytotoxic cross-match was negative. The operation was performed in a sequence as follows: bones--muscles--nerves--veins--arteries--skin. The induction IT consisted of Simulect, Prograff, Cell-Cept, and steroids; the pharmacotherapy was standard as for a forearm replantation. The cold ischemia time was 9 hours. Soon after the transplantation the disturbances of blood circulation in the transplanted forearm were to be seen. High doses of macromolecular heparin were applied resulting in temporary improvement. During following hours despite various precautions the symptoms of ischemia of the hand up to 1/3 distal part of the forearm dramatically increased. The revision (performed 12 hrs after completing the transplantation) proved a massive thrombosis of hand arteries, and a large clot of the radial artery in locus of it's cannulation for invasive blood pressure measurement. The limb had to be re-amputated. As it came clear the arterial catheter was removed 6 hours prior to procurement. CONCLUSIONS: The hand transplant are not free from non-immunological typical vascular complications. The arterial catheters should not be applied in limbs destined for procurement.

Hand transplant - outcome after 6 months, preliminary report.

BACKGROUND: Hand transplant still remains a partly experimental procedure because of the small number of patients and short follow-up (not longer than 10 years). Most hand transplantations have been performed at the distal forearm level. MATERIAL AND METHOD: The transplant recipient was a 29-year-old man who had lost his dominant right hand 3 years before in a milling machine accident; the donor was a 52-year-old woman. The procurement and transport of the limb were performed according to standard procedures. Preparation of the donor limb and the patient's stump was performed simultaneously by two surgical teams. Anastomoses were done in the following order : bones-tendons-nerves-veins-artery. The radial artery and 3 large veins were anastomosed. The operative wound was closed without a skin graft. Ischemia time was 9 hours. Pharmacological treatment was similar to that usually administered to replantation patients; immunotherapy consisted of Simulect, Prograf, Cell-Cept, and steroids. Physiotherapy was started on the second postoperative day; it consisted of early protective active motion (EPM), continuous passive motion (CPM), splinting, and sensory stimulation. The function of internal organs was monitored; the early outcome was evaluated at 6 months after the transplantation. RESULTS: The function of internal organs remained undisturbed, no rejection episodes were observed. Bony union was achieved after 11 weeks and progressed steadily, as did the range of motion and reinnervation. On the day of the preliminary assessment, the active range of motion was 200 degrees , 2PD exceeded 15 mm, and electromyography demonstrated temperature sensation and hypothenar muscle function. Functional assessment according to the DASH questionnaire was rated at 67 points, and a quality of life evaluation with the SF-36 questionnaire produced a score of 110 points. CONCLUSION: The distal third of the forearm is a replantation zone promoting early functional recovery.

Composite allotransplantations of knee joint, larynx, uterus, abdominal wall, face and penis.

One of the most important and most spectacular achievements in the field of medicine in the past 10 years are new possibilities of tissue reconstruction with help of composite tissue transplantation. As long as the upper limb transplantation can be considered as standard therapeutic procedures, the status of other composite tissue transplantations is still unclear. The aim of the work is to present a review of the actual situation in the field.