Precision Oncology Clinical Trials: A Systematic Review of Phase II Clinical Trials with Biomarker-Driven, Adaptive Design.

Purpose: Novel clinical trial designs are conducted in the precision medicine era. This study aimed to evaluate biomarker-driven, adaptive phase II trials in precision oncology, focusing on infrastructure, efficacy, and safety. Materials and Methods: We systematically reviewed and analyzed the target studies. EMBASE and PubMed searches from 2015 to 2023 generated 29 eligible trials. Data extraction included infrastructure, biomarker screening methodologies, efficacy, and safety profiles. Results: Government agencies, cancer hospitals, and academic societies with accumulated experiences led investigator-initiated precision oncology clinical trials (IIPOCTs), which later guided sponsor-initiated precision oncology clinical trials (SIPOCTs). Most SIPOCTs were international studies with basket design. IIPOCTs primarily used the central laboratory for biomarker screening, but SIPOCTs used both central and local laboratories. Most of the studies adapted next-generation sequencing and/or immunohistochemistry for biomarker screening. Fifteen studies included an independent central review committee for outcome investigation. Efficacy assessments predominantly featured objective response rate as the primary endpoint, with varying results. Nine eligible studies contributed to the United States Food and Drug Administration's marketing authorization. Safety monitoring was rigorous, but reporting formats lacked uniformity. Health-related quality of life and patient-reported outcomes were described in some protocols but rarely reported. Conclusion: Our results reveal that precision oncology trials with adaptive design rapidly and efficiently evaluate anticancer drugs' efficacy and safety, particularly in specified biomarker-driven cohorts. The evolution from IIPOCT to SIPOCT has facilitated fast regulatory approval, providing valuable insights into the precision oncology landscape.

Preoperative planning of unilateral breast reconstruction with pedicled transverse rectus abdominis myocutaneous (TRAM) flaps: a pilot study of perforator mapping.

Background: Pedicled transverse rectus abdominis myocutaneous (TRAM) flaps are well-established autologous reconstructive options for breast reconstruction. Preoperative computed tomographic angiography (CTA) has since become part of the routine workup in breast reconstruction with deep inferior epigastric artery perforator (DIEP) flaps. CTA provides an improved understanding of perforator anatomy which can facilitate optimal choice of hemiabdominal wall, and guide sheath harvest. Despite this knowledge, the role of preoperative CTA for breast reconstruction with the pedicled TRAM flap has not yet been established. Methods: A consecutive cohort of patients undergoing breast reconstruction with pedicled TRAM flaps without preoperative imaging were compared to a similar cohort of consecutive patients undergoing the same procedure with the use of preoperative CTA. Both flap and donor outcomes were assessed. Results: Thirty-four consecutive patients undergoing ipsilateral breast reconstruction with pedicled TRAM flaps were included. There was no statistical difference in the operative times or outcomes between the two groups. There were no complete flap losses in either group. Conclusions: The use of preoperative CTA may help to guide surgical technique and provide the surgeon with greater confidence intraoperatively, however, this study did not show significant change in operative outcomes. Further study and risk/benefit analysis may better highlight the role of CTA in pedicled TRAM flap planning.

Identification of an Oxidosqualene Cyclase Gene Involved in Steroidal Triterpenoid Biosynthesis in Cordyceps farinosa.

Various fungi including Cordyceps farinosa, an entomopathogenic fungus, can produce steroidal triterpenoids. Protostadienol (protosta-17(20)Z,24-dien-3ß-ol) is a precursor of steroidal triterpenoid compounds. To identify oxidosqualene cyclase (OSC) gene candidates involved in triterpenoid biosynthesis, genome mining was performed using Illumina sequencing platform. In the sequence database, two OSC genes, CfaOSC1 and CfaOSC2, in the genome of C. farinosa were identified. Predicted amino-acid sequences of CfaOSC2 shared 66% similarities with protostadienol synthase (OSPC) of Aspergillus fumigatus. Phylogenetic analysis showed a clear grouping of CfaOSC2 in the OSPC clade. Function of CfaOSC2 was examined using a yeast INVSc1 heterologous expression system to endogenously synthesize 2,3-oxidosqualene. GC-MS analysis indicated that CfaOSC2 produced protosta-13(17),24-dien-3ß-ol and protostadienol at a 5:95 ratio. Our results demonstrate that CfaOSC2 is a multifunctional triterpene synthase yielding a predominant protostadienol together with a minor triterpenoid. These results will facilitate a greater understanding of biosynthetic mechanisms underlying steroidal triterpenoid biosynthesis in C. farinosa and other fungi.

Distraction ligamentotaxis for complex proximal interphalangeal joint fracture dislocations: a clinical study and the modified pins rubber band traction system revisited.

BACKGROUND: The purpose of this study is to present our experience with the modified pins and rubber band traction system, discuss problems encountered, and make recommendations to optimize outcomes. METHODS: Data was collected prospectively from November 2013 to March 2017 at a tertiary referral hospital in Melbourne, Australia. Patients with closed complex proximal interphalangeal joint fracture dislocations that were considered unsuitable for other surgical options were included in the study. Patients underwent dynamic skeletal distraction using the modified (Deshmukh) pins rubber band traction system. Outcomes were measured using the Nominal Rating Scale for pain; Disabilities of the Arm, Shoulder, and Hand (DASH) score; active and passive range of motion; patient rating scale; and complications. RESULTS: Twenty patients underwent the procedure, and 19 were included in analyses. At the final follow-up assessment, an average of 62° and 77° was achieved for proximal interphalangeal joint active and passive range of motion, respectively. Pain levels were low (median score of 0 at rest and 1 ranging, out of 10). Four patients suffered minor pin site infections. CONCLUSION: Distraction ligamentotaxis is a useful part of the armamentarium, especially in the absence of more suitable procedures. It is important to select appropriate patients, educate, and ensure adherence to postoperative therapy. Employing the Deshmukh frame modification streamlines the theatre processes, and removal of wires at approximately 4 weeks minimizes risk of pin site infection.

Effects of Panax ginseng on Obesity in Animal Models: A Systematic Review and Meta-Analysis.

OBJECTIVE: To determine the antiobesity effects of Panax ginseng in animals. METHODS: We conducted a systematic search for all controlled trials (up to March 2017) that assessed the antiobesity effects of P. ginseng in animal obesity models in the PubMed, EMBASE, Cochrane library, Web of Science, and Scopus databases. The primary outcome was final body weight measured at the longest follow-up time after administration of the intervention. The secondary outcome was the lipid profile. We assessed methodological quality using the SYRCLE risk of bias tool, and RevMan 5.3 was used to perform a meta-analysis. Finally, a subgroup analysis of parameters including intervention duration, animal models, and type of ginseng was performed. RESULT: We identified 16 studies that met the inclusion criteria. Data from the meta-analysis indicated that the intervention group had a significantly lower body weight than the control group (SMD: -1.50, 95% CI: -1.90 to -1.11, χ2: 78.14, P < 0.0001, I2 = 58%). Final body weight was lower in an animal obesity model induced by high-fat diet than in genetic models. Also the intervention group had a significantly higher serum HDL level and lower serum LDL, TG, and TC level than the control group. CONCLUSION: Our meta-analysis indicated that oral administration of P. ginseng significantly inhibits weight gain and improves serum lipid profiles in animal obesity models. However, causes of obesity and type of ginseng may affect treatment effects.

Early pathogenic colonisers of acute burn wounds: A retrospective review.

BACKGROUND: Early excision of burns reduces the incidence of local and systemic infections caused by colonising microorganisms, and reduces mortality and length of hospital stay. Appropriate antibiotic prophylaxis can reduce the risk of postoperative wound infections and skin graft loss. Antibiotic selection should be based on likely pathogens. However, there are few studies that have investigated the early pathogenic colonisers of acute burn wounds. AIM: To describe pathogenic microorganisms found in acute burns and to make further recommendations on the use of early perioperative prophylactic antibiotics. METHODS: All burns patients admitted at the tertiary adult burns centre in Victoria over a 2-year period, who had surface swabs or tissue samples obtained from wounds within 24h of injury were included in this retrospective cohort study. Pathogenic organisms were examined with respect to patient characteristics, burn characteristics, treatment provided and immediate exposure to environmental contaminants. RESULTS: Nearly one third of burns patients had wounds colonised with pathogenic microorganisms. Gram-negative bacteria were isolated from 52% of these. Staphylococcus aureus was the most common isolate. Pseudomonas and Enterobacter species were the most common gram-negatives. The only independent risk factor associated with early colonisation with gram-negative bacteria was per cent TBSA burn. CONCLUSION: Increased colonisation of acute burn wounds with pathogenic gram-negative bacteria was associated with increased size of burn.

An Application of Keystone Perforator Island Flap for Closure of Lumbosacral Myelomeningocele Defects.

Myelomeningocele, also known as spina bifida, is the commonest form of neural tube defect in which both meninges and spinal cord herniate through a large vertebral defect. It may be located at any spinal level; however; lumbosacral involvement is most common. After birth, the closure of spinal lesion is preferably undertaken in the first 48 hours to minimize the risk of injury and central nervous system infection. Relatively small skin defects overlying the dural repair may be directly closed. However, larger defects require reconstructive closure. Numerous methods of reconstruction have been described, such as split skin graft, local flaps or lumbosacral fasciocutaneous flaps, muscle flaps using latissimus dorsi, gluteal or paraspinous muscles, and perforator flaps namely superior gluteal artery perforators, and dorsal intercostal artery perforator flaps. At Monash Health, Victoria, we have used the keystone perforator island flaps to reconstruct lumbosacral myelomeningocele defects on 5 newborns between January 2008 and January 2014. This article evaluates the short-term and long-term outcomes of these patients who were followed up for 10 to 66 months.

A rare case of primary thymic adenocarcinoma mimicking small cell lung cancer.

Primary thymic adenocarcinoma is a very rare malignancy of the anterior mediastinum with no standardized treatment. A 36-year-old male patient presented with hoarseness over the past 3 months. A chest computed tomography (CT) scan showed an infiltrative mass to the proximal vessels and aortic arch in left upper mediastinum (4.1×3.1×5.4 cm). Brain magnetic resonance imaging (MRI) showed focal lesions, suggesting metastasis in the left frontal lobe. A thoracoscopic biopsy of the mediastinal mass confirmed a primary thymic adenocarcinoma forming a glandular structure with atypia of tumor cells. The patient received four cycles of systemic chemotherapy, consisting of etoposide and cisplatin, with concurrent radiotherapy (6,000 cGy/30 fractions) to the mediastinal lesion and the metastatic brain lesion (4,200 cGy/12 fractions). A follow-up chest CT scan and brain MRI showed a decrease in the size of the left upper mediastinal mass and brain lesion. We report a rare case of the primary thymic adenocarcinoma with a literature review.

Thoracic sympathetic nerve reconstruction for compensatory hyperhidrosis: the Melbourne technique.

BACKGROUND: Compensatory hyperhidrosis (CH) is a potential complication following endoscopic thoracic sympathectomy (ETS) in the management of primary hyperhidrosis. CH is considered a permanent condition with significant psychosocial impacts but with few treatment options. Various reversal surgical techniques, aimed at reconstituting sympathetic pathways, have been developed but results have been inconsistent. OBJECTIVE: We present two case reports of a novel technique of reversal surgery, the Melbourne technique, which was employed to treat severe CH that developed within 3-5 months following ETS. Both patients were followed-up to 8 years. METHODS: The Melbourne technique employs an endoscopic approach to expose previously sympathectomized or sympathotomized thoracic sympathetic chains. In these two cases it was performed on the right side only. Instead of an interpositional nerve graft, an autogenous vein graft was simultaneously harvested and used as a nerve conduit to bridge the secondary nerve defect after neuroma excision. Long-term outcomes were assessed using the dermatology life quality index (DLQI) and the quality of life (QoL) questionnaires, which are validated for hyperhidrosis. RESULTS: In both cases, patients reported postoperative improvements in QoL scores. However, the improvement was more marked in one case compared with the other. There were no significant immediate and long-term postoperative complications. CONCLUSIONS: The Melbourne technique shows promise as an alternative to interpositional nerve grafts or nerve transfers employed in other endoscopic reversal surgeries for CH.

Natural inhibitors of carcinogenesis.

Previous collaborative work by our group has led to the discovery of several plant isolates and derivatives with activities in in vivo models of cancer chemoprevention, including deguelin, resveratrol, bruceantin, brassinin, 4'-bromoflavone, and oxomate. Using a panel of in vitro bioassays to monitor chromatographic fractionation, a diverse group of plant secondary metabolites has been identified as potential cancer chemopreventive agents from mainly edible plants. Nearly 50 new compounds have been isolated as bioactive principles in one or more in vitro bioassays in work performed over the last five years. Included among these new active compounds are alkaloids, flavonoids, stilbenoids, and withanolides, as well as a novel stilbenolignan and the first representatives of the norwithanolides, which have a 27-carbon atom skeleton. In addition, over 100 active compounds of previously known structure have been obtained. Based on this large pool of potential cancer chemopreventive compounds, structure-activity relationships are discussed in terms of the quinone reductase induction ability of flavonoids and withanolides and the cyclooxygenase-1 and -2 inhibitory activities of flavanones, flavones and stilbenoids. Several of the bioactive compounds were found to be active when evaluated in a mouse mammary organ culture assay, when used as a secondary discriminator in our work. The compounds (2 S)-abyssinone II, (2 S)-2',4'-dihydroxy-2"-(1-hydroxy-1-methylethyl)dihydrofuro[2,3- h]-flavanone, 3'-[gamma-hydroxymethyl-( E)-gamma-methylallyl]-2,4,2',4'-tetrahydroxychalcone 11'- O-coumarate, isolicoflavonol, isoliquiritigenin, and ixocarpalactone A are regarded as promising leads as potential cancer chemopreventive agents.