Soft and tissue repair of the hand and digital reconstruction.

This article summarizes the current views and proposed approaches to treating soft tissue defects of the hand. The article also outlines some key considerations of digital reconstruction. There are many options in treating soft tissue defects. For defects of the hand, local flaps are primarily considered if the defects are small or moderate in size. A vascularized free flap is only considered for a defect of large size (3 cm long or larger). Thumb reconstruction is of primary importance, while reconstruction of two fingers is necessary when all fingers are lost. Reconstructions of a missing distal part of a finger or reconstruction of an entire finger if only one finger is lost are cosmetic restorations; functionally these defects do not need reconstruction. Sensation is of great importance in repair or reconstruction of the tip of the thumb or finger. Therefore, sensory evaluation is a key factor in assessing and selecting the best options of surgery.

Telehealth for Cancer Care in Veterans: Opportunities and Challenges Revealed by COVID.

The Veterans Health Administration system is one of the largest integrated health care providers in the United States, delivering medical care to > 9 million veterans. Barriers to delivering efficient health care include geographical limitations as well as long wait times. Telehealth has been used as a solution by many different health care services. However, it has not been as widely used in cancer care. In 2018, the US Department of Veterans Affairs (VA) Pittsburgh Healthcare System expanded the use of telehealth to provide antineoplastic therapies to rural patients by creating a clinical video telehealth clinic of the Virtual Cancer Care Network. This allows oncologists located at the tertiary center to virtually deliver care to remote sites. The recent COVID-19 pandemic forced oncologists across the VA system to adopt telehealth to provide continuity of care. On the basis of our review and personal experience, we have outlined opportunities for telehealth to play a role in every step of the cancer care journey from diagnosis to therapy to surveillance to clinical trials for medical, surgical, and radiation oncology. There are many advantages, such as decreased travel time and potential cost savings; however, there continues to be challenges with veterans having access to devices and the Internet as well as understanding how to use telehealth equipment. The lessons learned from this assessment of the VA telehealth system for cancer care can be adopted and integrated into other health systems. In the future, there needs to be evaluation of how telehealth can be further incorporated into oncology, satisfaction of veterans using telehealth services, overcoming telehealth barriers, and defining metrics of success.

Small molecule inhibition of DDAH1 significantly attenuates triple negative breast cancer cell vasculogenic mimicry in vitro.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a key enzyme involved in the metabolism of the endogenous nitric oxide synthase (NOS) inhibitors asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA). Increased DDAH1 expression and subsequent increased NO production have been recently linked to cancer. Specifically, DDAH1 is implicated in establishment of a vascular network by tumour cells, vasculogenic mimicry (VM), which is strongly associated with tumour progression and poor patient prognosis. The use of DDAH1 inhibitors as potential therapeutic agents thus represents a growing field of interest. Here we describe a UPLC-MS assay to quantify stability and intracellular concentration of two small molecule DDAH1 inhibitors synthesised by our group, ZST316 and ZST152, following incubation with MDA-MB-231 breast cancer cells. In an in vitro assay of VM, both DDAH1 inhibitors significantly attenuated formation of capillary-like tube structures in a dose-dependent fashion. This was not due to cell toxicity or altered cell proliferation, but may be due in part to inhibition of cell migration. Mechanistically, we demonstrate significant modulation of the endogenous DDAH/ADMA/NO pathway following exposure of 100 µM ZST316 or ZST152: a 40% increase in the DDAH1 substrate ADMA, and a 38% decrease in the DDAH1 product l-citrulline. This study represents the first evidence for therapeutic inhibition of DDAH1 by small molecules in breast cancer.

The Combination of Metformin and Valproic Acid Has a Greater Anti-tumoral Effect on Prostate Cancer Growth In Vivo than Either Drug Alone.

BACKGROUND/AIM: The hypoglycemic drug metformin (MET) and the anti-epileptic drug valproic acid (VPA) have individually shown anti-tumor effects in prostate cancer in vitro. The present study intended to investigate the efficacy of the combination of MET and VPA in prostate cancer treatment in a pre-clinical xenograft model. MATERIALS AND METHODS: Prostate cancer cell lines (LNCaP and PC-3) were inoculated under the skin of BALB/c nude mice. The mice were treated with 200 µl/ml MET and/or 0.4% (w/v) VPA diluted in drinking water, or with vehicle control, and were monitored until the tumor volume reached 2,000 mm3 Evaluation of toxicity of the drug combination was determined in liver and kidney by histology. RESULTS: In both LNCaP and PC-3 xenografts, MET combined with VPA significantly reduced tumor growth during the first 4 weeks following treatment, and delayed the time-to-tumor volume of 2,000 mm3 by 90 days, as compared to MET or to VPA alone, and to vehicle control. There was no significant difference in total mouse weight, liver or kidney morphology in response to combination treatment (MET+VPA) compared to MET or VPA alone and vehicle control. CONCLUSION: The combination treatment of MET with VPA is more effective at slowing prostate tumor growth in vivo compared to either drug alone, in mouse xenografts. These pre-clinical results support previous in vitro data and also demonstrate the low toxicity of the combination of these drugs, suggesting that this may be a potential new therapy to be investigated in clinical trials for prostate cancer.

Quantitative mass spectrometry to identify protein markers for diagnosis of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a devastating malignancy with a prognosis of <12 months. Even with bans on the use of asbestos in most Western countries, the incidence is still increasing due to the long latency periods between exposure and development of the disease. Diagnosis is often delayed due to invasive biopsies and lack of distinguishable markers. Patients frequently present with pleural effusions months to years before a radiologically detectable mass appears. This study aimed to investigate the proteome of pleural effusions taken from patients with MPM, adenocarcinoma and benign conditions in an attempt to identify a biomarker for early diagnosis. We identified several proteins that may be possible targets and warrant further investigation. Due to the predominance of up regulated proteins involved in VEGF signalling in MPM, we analysed VEGFA levels in effusions and found a strong correlation between VEGFA levels and survival in MPM.

Development of an LC⁻Tandem Mass Spectrometry Method for the Quantitative Analysis of Hercynine in Human Whole Blood.

Given that the peculiar redox behavior of ergothioneine involves a rapid regeneration process, the measurement of its precursor and redox metabolite hercynine could be particularly useful in assessing its role in oxidative stress or other biological processes. Thus, a LC-MS/MS method for the determination of hercynine concentrations in whole blood was developed. After lysis of red blood cells by cold water, samples were filtered on micro concentrators at a controlled temperature of 4 °C. The clear filtered fluid was then treated with diethylpyrocarbonate to derivatize hercynine for the analysis by LC-MS/MS. The derivatized analyte was isocratically separated as a carbethoxy derivative on a C18 column with a mobile phase of an aqueous 0.1% v/v formic acid and acetonitrile (95:5). Effluents were monitored by MRM transitions at m/z 270.28→95 and 273.21→95 for hercynine and its deuterated counterpart, respectively. No cross-talk between MRM transitions was observed and a good linearity was found within a range of 35⁻1120 nmol/L. The LOD and LOQ were, respectively, 10.30 and 31.21 nmol/L with an intraday and intermediate precision below 7%. The average hercynine concentration in whole blood from 30 healthy male volunteers (aged 77 ± 12 years) was 178.5 ± 118.1 nmol/L. Overall, the method is easy to perform, allowing a rapid and accurate assessment of whole blood concentrations of hercynine.

Repair of soft tissue defects in finger, thumb and forearm: less invasive methods with similar outcomes.

We review recent developments in using occlusive dressings, dermal templates, and venous flaps for less invasive approaches to treat soft tissue defects of the forearm and fingers. Occlusive dressings can be used for thumb tip or fingertip trauma with soft tissue defects of small or moderate sizes. They permit skin regeneration without use of skin graft or a flap transfer. This is currently a popular way to treat tip soft tissue defects in European countries. Extensive soft tissue defects in the thumb, fingers, hand and forearm require flap transfers traditionally, but in recent years, surgeons use dermal templates to cover the defect site to allow regeneration of subcutaneous tissues, over which a skin graft is used in lieu of a flap. Transfer of a venous flap is currently a reliable procedure and is less invasive compared with conventional flaps, which usually damage a named artery in the donor. We advocate that less invasive methods should be considered for soft tissue defects in the hand and forearm.

Administering Fixed Oral Doses of Curcumin to Rats through Voluntary Consumption.

Curcumin, a polyphenol derived from turmeric, has a wide variety of therapeutic benefits including antiinflammatory, antioxidative, and chemopreventative effects. Oral gavage is widely performed to administer curcumin in laboratory rodents in several experimental models. Although effective, this method can increase stress in the animal, potentially influencing experimental results. Moreover, oral gavage can result in mortality due to accidental instillation of fluid into the lungs, serious mechanical damage, and gavage-related reflux. Here we describe a method for the administration of fixed dosages of curcumin to rats through voluntary consumption of peanut butter, to reduce gavage-related morbidity and distress to animals and to provide environmental enrichment. Fischer 344 (n = 6) rats received 1100 mg/kg of a commercial curcumin product (equivalent to approximately 200 mg/kg of curcumin) in 8 g/kg of peanut butter daily for 5 wk. Curcumin concentrations in rat plasma were measured by using UPLC-MS at 2 to 4 h after administration. All rats voluntarily consumed the peanut butter-curcumin mixture consistently over the 5-wk period. Total curcumin concentrations in plasma samples collected 2 to 4 h after curcumin consumption were 171 ± 48.4 ng/mL (mean ± 1 SD; range, 103 to 240 ng/mL). This noninvasive curcumin delivery method was effective, eliminated the stress caused by daily oral gavage, and added environmental enrichment.

MiR-193b regulates breast cancer cell migration and vasculogenic mimicry by targeting dimethylarginine dimethylaminohydrolase 1.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is responsible for metabolism of an endogenous inhibitor of nitric oxide synthase (NOS), asymmetric dimethylarginine (ADMA), which plays a key role in modulating angiogenesis. In addition to angiogenesis, tumours can establish a vascular network by forming vessel-like structures from tumour cells; a process termed vasculogenic mimicry (VM). Here, we identified over-expression of DDAH1 in aggressive MDA-MB-231, MDA-MB-453 and BT549 breast cancer cell lines when compared to normal mammary epithelial cells. DDAH1 expression was inversely correlated with the microRNA miR-193b. In DDAH1+ MDA-MB-231 cells, ectopic expression of miR-193b reduced DDAH1 expression and the conversion of ADMA to citrulline. In DDAH1- MCF7 cells, inhibition of miR-193b elevated DDAH1 expression. Luciferase reporter assays demonstrated DDAH1 as a direct target of miR-193b. MDA-MB-231 cells organised into tube structures in an in vitro assay of VM, which was significantly inhibited by DDAH1 knockdown or miR-193b expression. Mechanistically, we found miR-193b regulates cell proliferation and migration of MDA-MB-231 cells, whilst DDAH1 knockdown inhibited cell migration. These studies represent the first evidence for DDAH1 expression, regulation and function in breast cancer cells, and highlights that targeting DDAH1 expression and/or enzymatic activity may be a valid option in the treatment of aggressive breast cancers.

Chemotherapy-related cardiotoxicity: are Australian practitioners missing the point?

BACKGROUND: It has long been established that cardiotoxicity occurs as a result of exposure to certain chemotherapeutics, particularly anthracyclines. Historically, clinicians equate cardiotoxicity with a poor prognosis, in a small percentage of patients and deem long-term surveillance as optional. Emerging evidence suggests that anthracycline cardiotoxicity (ACT) is a life-long risk with an incidence approaching 20%. AIMS: To elucidate the incidence of anthracycline cardiotoxicity within a current paediatric oncology survivor cohort. METHODS: Participants were identified through the Haematology-Oncology database at the Royal Children's Hospital, Melbourne. Patients were identified from a retrospective audit of outpatient attendances between January 2008 and December 2015. Patients with a cancer diagnosis exposed to anthracyclines were eligible for the study. Patient demographics and echocardiogram findings were recorded with patients subcategorised according to degree of ACT. More significant ACT defined as fractional shortening (FS) <24% and less significant if FS 24-28% or a decline in baseline ejection fraction of >10%. RESULTS: Two hundred and eighty-six of a total 481 identified patients were eligible for study inclusion. Twenty patients displayed significant ACT with FS <24%. Ten patients had a FS 24-28% and 25 patients with a decline in ejection fraction from baseline of >10%. Overall, 6.6% demonstrated significant cardiac complications, whilst 19.6 % demonstrated some degree of ACT and decline in myocardial function. When stratified for cumulative anthracycline dose, the incidence of severe cardiac dysfunction was 5.1% (<250 mg/m2 ) and 25% (>250 mg/m2 ) CONCLUSION: This study demonstrates, in keeping with modern literature, the higher incidence of anthracycline associated cardiac toxicity and a need for better surveillance and follow up.

Pushing the Boundaries of Salvage in Mutilating Upper Limb Injuries: Techniques in Difficult Situations.

With the available microsurgical techniques, salvage of the limb can almost always provide a useful upper limb, even in the most complex combined injuries. Having a low threshold for revascularization of doubtfully viable extremities and making full use of the current armamentarium of soft tissue cover techniques, including flow through free flaps, will salvage many limbs. Secondary procedures, including free functioning muscle transfers and toe transfers, further increase the possible functional outcome. Even in the most complex combined injuries, intelligent reconstruction will obtain better outcomes than the best available prosthesis, making the efforts of salvage worthwhile.

Correction of Clinodactyly by Early Physiolysis: 6-Year Results.

PURPOSE: To review results at least 6 years after physiolysis for treatment of the delta phalanx associated with clinodactyly. METHODS: We present 22 cases of clinodactyly treated with physiolysis in which we removed the central part of the epiphysis, which is the portion restricting longitudinal growth unilaterally and inducing progressive finger deviation, and placed a fat graft in the resultant defect. RESULTS: This retrospective study reports the results of early physiolysis in 27 fingers with radial clinodactyly, including 17 fingers from 17 patients previously reported and 10 little fingers from 5 additional patients. All patients had a minimum follow-up of 6 years. Mean preoperative angle was 38° (range, 25° to 47°). At final follow-up, mean angle was 8° (range, 0° to 24°), a mean correction of 79%. Twelve fingers in 9 patients had more than 10° of deformity at final follow-up, whereas 15 fingers in 13 patients had a residual deformity of less than 10°, which is effectively full correction of a clinodactyly. No patient required a closing wedge osteotomy later for insufficient correction. CONCLUSIONS: These accumulative findings confirm our previous preliminary report. Early physiolysis is a quick and simple procedure that allows for growth and partial but often adequate correction of the clinodactyly. The correction occurs slowly over a period of years, which can be seen as a disadvantage, and requires careful counseling of the parents. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Repair and reconstruction of thumb and finger tip injuries: a global view.

In this review, an international group of senior hand surgeons was asked to provide their currently used methods, views, and advice on thumb and fingertip repair. The basic requirements and methods of thumb and fingertip repair are first outlined, followed by descriptions of the methods favored by individual units or surgeons. More recent innovative methods and modifications are described and challenging topics are discussed. This review ends by illustrating and discussing a few exploratory treatments that hold promise of greatly changing future perspectives of this common clinical problem.

Surgical management of painful peripheral nerves.

This article deals with the classification, assessment, and management of painful nerves of the distal upper limb. The author's preferred surgical and rehabilitation techniques in managing these conditions are discussed in detail and include (1) relocation of end-neuromas to specific sites, (2) division and relocation of painful nerves in continuity (neuromas-in-continuity and scar-tethered nerves) involving small nerves to the same sites, and (3) fascial wrapping of painful nerves in continuity involving larger nerves such as the median and ulnar nerves. The results of these treatments are presented as justification for current use of these techniques.

IFSSH Flexor Tendon Committee report 2014: from the IFSSH Flexor Tendon Committee (Chairman: Jin Bo Tang).

Hand surgeons continue to search for the best surgical flexor tendon repair and treatment of the tendon sheaths and pulleys, and they are attempting to establish postoperative regimens that fit diverse clinical needs. It is the purpose of this report to present the current views, methods, and suggestions of six senior hand surgeons from six different countries - all experienced in tendon repair and reconstruction. Although certainly there is common ground, the report presents provocative views and approaches. The report reflects an update in the views of the committee. We hope that it is helpful to surgeons and therapists in treating flexor tendon injuries.