The Ineffectiveness of Osimertinib in Epidermal Growth Factor Receptor (EGFR)-Mutated Stage IV Lung Adenocarcinoma With Bone Metastasis: A Case Report.

This case report examines the effectiveness of osimertinib in a 64-year-old non-smoking female diagnosed with stage IV lung adenocarcinoma and an epidermal growth factor receptor (EGFR) exon 19 mutation, focusing on the treatment's impact on bone metastasis. Despite initial responsiveness to osimertinib, the patient's bone lesions remained largely unresponsive, prompting a comprehensive exploration of alternative treatments and clinical trials. This report highlights the patient's clinical journey, from diagnosis through various treatment phases, culminating in palliative care, and underscores the need for further research into targeted treatments for bone metastasis in lung cancer.

Re-operation within 30 days of radical cystectomy: Identifying high-risk patients and complications using American College of Surgeons National Surgical Quality Improvement Program database.

INTRODUCTION: Radical cystectomy (RC) is a highly morbid procedure, with 30-day complication rates approaching 31%. Our objective was to determine risk factors for re-operation within 30 days following a RC for non-metastatic bladder cancer. METHODS: We included all patients who underwent a RC for non-metastatic bladder cancer using The American College of Surgeons National Surgical Quality Improvement Program database between January 1, 2007 and December 31, 2014. Logistic regression analyses were used to evaluate predictors of re-operation. RESULTS: A total of 2608 patients were included; 5.8% of patients underwent re-operation within 30 days. On multivariable analysis, increasing body mass index (BMI) (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.01-1.07), African American race (vs. Caucasian OR 2.29, 95% CI 1.21-4.34), and history of chronic obstructive pulmonary disease (COPD) (OR 2.33, 95% CI 1.45-3.74) were significant predictors of re-operation within 30 days of RC. Urinary diversion type (ileal conduit vs. continent) and history of chemotherapy or radiotherapy within 30 days prior to RC were not. Patients who underwent re-operation within this timeframe had a significantly higher mortality rate (4.0% vs. 1.6%) and were more likely to experience cardiac (7.2% vs. 1.9%), pulmonary (23.0% vs. 3.0%), neurological (2.0% vs. 0.49%), and venous thromboembolic events (10.5% vs. 5.4%), as well as infectious complications (64.5% vs. 24.1%), with a significantly longer hospital length of stay (16.5 vs. 7.0 days). CONCLUSIONS: Recognizing increasing BMI, COPD, and African American race as risk factors for re-operation within 30 days of RC will allow urologists to preoperatively identify such high-risk patients and prompt them to adopt more aggressive approaches to minimize postoperative surgical complications.

The association between patient body mass index and perioperative outcomes following radical cystectomy: An analysis using the American College of Surgeons National Surgical Quality Improvement Program database.

INTRODUCTION: Radical cystectomy is a highly morbid procedure, with 30-day perioperative complication rates approaching 50%. Our objective was to determine the effect of patients' body mass index (BMI) on perioperative outcomes following radical cystectomy for bladder cancer. METHODS: We identified 3930 eligible patients who underwent radical cystectomy for non-metastatic bladder cancer using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. The primary exposure was preoperative BMI, categorically operationalized in four strata according to the World Health Organization criteria: <18.5 kg/m2, 18.5-25 kg/m2, 25-30 kg/m2, and >30 kg/m2. Our primary outcome was major perioperative complication comprising mortality, reoperation, cardiac event, or neurological event. RESULTS: BMI was significantly associated with rates of major complications (p=0.003): major complications were experienced by 17.0% of patients with BMI <18.5 kg/m2, 7.8% of patients with BMI 18.5-25 kg/m2, 7.9% of patients with BMI 25-30 kg/m2, and 10.8% of patient with BMI >30 kg/m2. Following multivariable adjustment for relevant demographic, comorbidity, and treatment factors, compared to patients with BMI 18.5-25 kg/m2, patients with BMI <18.5 kg/m2 (odds ratio [OR] 2.28, 95% confidence interval [CI] 1.07-4.78) and BMI >30 kg/m2 (OR 1.59, 95% CI 1.17-2.16) were significantly more likely to experience a major complication in the 30 days following cystectomy. Among the secondary outcomes, significant differences were identified in rates of pulmonary complications (p=0.003), infectious complications (p<0.001), bleeding requiring transfusion (p=0.01), and length of stay (p=0.001). CONCLUSIONS: Patients who are outside of a normal BMI range are more likely to experience major complications following radical cystectomy for bladder cancer.

Epidemiology and treatment modalities for the management of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is one of the most common conditions affecting men. BPH can lead to a number of symptoms for patients commonly referred to as lower urinary tract symptoms (LUTS). Over the last decade, increased modifiable risk factors, such as metabolic disease and obesity, have resulted in an increased incidence of BPH. This increasing incidence has brought about a multitude of treatment modalities in the last two decades. With so many treatment modalities available, physicians are tasked with selecting the optimal therapy for their patients. Current therapies can first be divided into medical or surgical intervention. Medical therapy for BPH includes 5-alpha-reductase inhibitors and alpha-blockers, or a combination of both. Surgical interventions include a conventional transurethral resection of the prostate (TURP), as well as newer modalities such as bipolar TURP, holmium laser enucleation of the prostate (HoLEP), Greenlight and thulium laser, and prostatic urethral lift (PUL). Emerging therapies in this field must also be further investigated for safety and efficacy. This narrative review attempts to consolidate current and emerging treatment options for BPH and highlights the need for additional investigation on optimizing treatment selection.

The influence of salinity and water chemistry on acute toxicity of cadmium to two euryhaline fish species.

The euryhaline killifishes, Fundulus heteroclitus and Kryptolebias marmoratus inhabit estuaries that rapidly change salinity. Although cadmium (Cd) toxicity has been well characterized in fish inhabiting freshwaters, fewer studies have examined the toxic effects of Cd in estuarine and saltwater environments. Additionally, current environmental regulations do not account for organism physiology in different salinity waters even though metal sensitivity is likely to change in these environments. In this study, we investigated effects of changing salinity on acute Cd toxicity to larval (7-9 d old) F. heteroclitus and K. marmoratus. Median 96-h lethal concentrations (LC50) for Cd were calculated for both fish species at six different salinities. As salinity increased, metal toxicity decreased in both fish species up to 18 ppt salinity; and F. heteroclitus were more sensitive than K. marmoratus at salinities above 12 ppt. To determine which components of saltwater were protective against Cd toxicity, we investigated the influence of CaSO4 (100 and 200 mg/L), CaCl2 (200 mg/L), and MgSO4 (300 mg/L) on Cd toxicity to K. marmoratus. The results demonstrated that both competition with calcium and complexation with chloride reduced the toxic effects of Cd to K. marmoratus. These findings could be used to improve marine/estuarine biotic ligand models for the determination of site-specific water quality criteria for Cd.

Synthesis, characterization and in vitro and in vivo anticancer activity of Pt(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)].

This report describes the synthesis, characterization and biological activity of a series of platinum(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] (Pt56MeSS) with non-bioactive, lipophilic and bioactive axial ligands. In an attempt to explore the anticancer activity potential of the Pt(iv) derivatives, 2D and 3D cytotoxic screening and a preliminary in vivo study were performed. The average IC50 values of the platinum(iv) derivatives ranged from 1.26 to 5.39 µM, compared with 1.24 µM for Pt56MeSS, suggesting that the axial ligands have a relatively minor effect on the potency of the compounds. Preliminary in vivo studies indicate that the platinum(iv) derivatives of Pt56MeSS are active in vivo and can reduce the tumor to a similar extent to cisplatin.

Probing the Interactions of Cytotoxic [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] and Its PtIV Derivatives with Human Serum.

The discrepancy between the in vitro cytotoxic results and the in vivo performance of Pt56MeSS prompted us to look into its interactions and those of its PtIV derivatives with human serum (HS), human serum albumin (HSA), lipoproteins, and serum-supplemented cell culture media. The PtII complex, Pt56MeSS, binds noncovalently and reversibly to slow-tumbling proteins in HS and in cell culture media and interacts through the phenanthroline group with HSA, with a Kd value of ∼1.5×10-6 m. All PtIV complexes were found to be stable toward reduction in HS, but those with axial carboxylate ligands, cct-[Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenantroline)(acetato)2 ](TFA)2 (Pt56MeSS(OAc)2 ) and cct-[Pt(1S,2S-DACH)(5,6-dimehtyl-1,10-phenantroline)(phenylbutyrato)2 ](TFA)2 (Pt56MeSS(PhB)2 ), were spontaneously reduced at pH 7 or higher in phosphate buffer, but not in Tris buffer (pH 8). HS also decreased the rate of reduction by ascorbate of the PtIV complexes relative to the reduction rates in phosphate buffer, suggesting that for this compound class, phosphate buffer is not a good model for HS.

Probing the interaction of bisintercalating (2,2':6',2″-terpyridine)platinum(II) complexes with glutathione and rabbit plasma.

Platinum(II) complexes have demonstrated considerable success in the treatment of cancer, but severe toxic side effects drive the search for new complexes with increased tumour selectivity and better efficacy. A critical concept that has to be considered in the context of designing novel Pt complexes is their interactions with biomolecules other than DNA. To this end, here the interactions of 16 previously reported bisintercalating (2,2':6',2″-terpyridine)platinum(II) complexes, [{Pt(terpy)}2µ-(X)]n+ (where X is a linker) with glutathione (GSH) by means of 1H and 195Pt NMR spectroscopy were investigated. The GSH half-life (GSH t1/2) was determined following the incubation of each [{Pt(terpy)}2µ-(X)]n+ complex with GSH (8mM). It was observed that complexes 1-7, 11, 12 and 14-16 reacted more rapidly than cisplatin, whereas complexes 8-10, 13 and 17 reacted more slowly (≥200min). There was no apparent correlation between linker length and the GSH t1/2. In order to understand these interactions, two complexes: 1 (t1/2<1min) and a previously studied 17 [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)] (56MESS) (GSH t1/2=4080min) were incubated with rabbit plasma. A "metallomics" approach was used to analyse plasma for all platinum species at the 5 and the 60min time point and provided results that were congruent with the reaction of the selected Pt complexes with GSH. Our studies demonstrate that the combined application of NMR spectroscopy, cytotoxicity studies and a metallomics approach can contribute to better understand the interaction of [{Pt(terpy)}2µ-(X)]n+ complexes with biomolecules to better assess which compounds may be advanced to in vivo studies.

The Impact of Radical Cystectomy and Urinary Diversion on Suicidal Death in Patients With Bladder Cancer.

PURPOSE: Compared to the general population, suicide is more common in the elderly and in patients with cancer. We sought to examine the incidence of suicide in patients with bladder cancer and evaluate the impact of radical cystectomy in this high-risk population. METHODS: Patients diagnosed with urothelial carcinoma from 1988 to 2010 were identified in the Survey, Epidemiology, and End Results (SEER) database. Contingency tables of suicide rates and standardized mortality ratios (SMRs) and 95% confidence intervals were calculated. Multivariable logistic regression models were performed to generate odds ratios (ORs) for the identification of factors associated with suicide in this population. RESULTS: There were 439 suicides among patients with bladder cancer observed for 1,178,000 person-years (Standard Morbidity Ratio [SMR] = 2.71). All demographic variables analyzed had a higher SMR for suicide compared to the general population, in particular age ≥80 years (SMR = 3.12), unmarried status (SMR = 3.41), and white race (SMR = 2.60). The incidence of suicide was higher in the general population for patients who underwent radical cystectomy compared to those who did not (SMR = 3.54 vs SMR = 2.66). On multivariate analysis, the strongest predictors of suicide were male gender (vs female; OR = 6.63) and distant disease (vs localized; OR = 5.43). CONCLUSIONS: Clinicians should be aware of risk factors for suicide in patients diagnosed with bladder cancer, particularly older, white, unmarried patients with distant disease, and/or those who have undergone radical cystectomy. A multidisciplinary team-based approach, including wound ostomy care trained nursing staff and mental health care providers, may be essential to provide care required to decrease suicide rates in this at-risk population.

Quadruplex DNA-Stabilising Dinuclear Platinum(II) Terpyridine Complexes with Flexible Linkers.

Four dinuclear terpyridineplatinum(II) (Pt-terpy) complexes were investigated for interactions with G-quadruplex DNA (QDNA) and duplex DNA (dsDNA) by synchrotron radiation circular dichroism (SRCD), fluorescent intercalator displacement (FID) assays and fluorescence resonance energy transfer (FRET) melting studies. Additionally, computational docking studies were undertaken to provide insight into potential binding modes for these complexes. The complexes demonstrated the ability to increase the melting temperature of various QDNA motifs by up to 17 °C and maintain this in up to a 600-fold excess of dsDNA. This study demonstrates that dinuclear Pt-terpy complexes stabilise QDNA and have a high degree of selectivity for QDNA over dsDNA.

Intracompartmental Pressure Monitoring Using a Handheld Pressure Monitoring System.

INTRODUCTION: We describe the correct technique for measuring compartment pressure with a handheld device to diagnose compartment syndrome. STEP 1 DEVICE PREPARATION: Proper preparation of the handheld pressure monitoring device (Stryker Surgical, Kalamazoo, Michigan) is critical to ensure that the device performs appropriately. STEP 2 IDENTIFICATION OF THE COMPARTMENT OF INTEREST: The needle must be placed in the proper location to appropriately measure a compartment's pressure. STEP 3 INJECTION: Inject saline solution from the pressure monitoring device to clear any soft tissue from the side port on the needle that could result in inaccurate pressure measurements. STEP 4 STABILIZATION AND PRESSURE READING: The pressure must reach a stable state before it is recorded; different pressure thresholds for decompression have been recommended in the literature. STEP 5 REPEAT MEASUREMENTS: As mistakes can be made with any single measurement, accuracy may be improved by repeating steps 1 through 4 and averaging the results. STEP 6 ADDITIONAL COMPARTMENTS: After the reading is obtained, move on to any additional compartment(s) that need to be evaluated, repeating the steps listed above. RESULTS: The handheld intracompartmental monitoring device with a side-ported needle has been shown to be extremely accurate in the laboratory.IndicationsContraindicationsPitfalls & Challenges.

The synthesis, characterisation and cytotoxicity of bisintercalating (2,2':6',2''-terpyridine)platinum(II) complexes.

Dinuclear (2,2':6',2''-terpyridine)platinum(II) (PtTerpy) complexes were synthesised by tethering either thiol or pyridine based linkers. All intermediates and resulting complexes were characterised using a combination of (1)H and (195)Pt NMR, two-dimensional (1)H correlation spectroscopy (NOSY/COSY), two-dimensional (1)H/(195)Pt heteronuclear multiple bond correlation spectroscopy (HMQC), elemental analysis and electrospray ionisation mass spectrometry (ESI-MS). The cytotoxicity of the complexes was determined against human A2780 ovarian carcinoma cells and its cisplatin-resistant sub-line A2780cis, as well as L1210 murine leukemia cells.

Combination studies of platinum(II)-based metallointercalators with buthionine-S,R-sulfoximine, 3-bromopyruvate, cisplatin or carboplatin.

With current chemotherapeutic treatment regimes often limited by adverse side effects, the synergistic combination of complexes with anticancer activity appears to offer a promising strategy for effective cancer treatment. This work investigates the anti-proliferative activity using a combination therapy approach where metallointercalators of the type [Pt(IL)(AL)](2+) (where IL is the intercalating ligand and AL is the ancillary ligand) are used in combination with currently approved anticancer drugs cisplatin and carboplatin and organic molecules buthionine-S,R-sulfoximine and 3-bromopyruvate. Synergistic relationships were observed, indicating a potential to decrease dose-dependent toxicity and improve therapeutic efficacy.

The effects of 56MESS on mitochondrial and cytoskeletal proteins and the cell cycle in MDCK cells.

BACKGROUND: 56MESS has been shown to be cytotoxic but the mode of this action is unclear. In order to probe the mechanism of action for 56MESS, MDCK cells were utilised to investigate the effect on treated cells. RESULTS: IC50 values for 56MESS and cisplatin in the MDCK cell line, determined by a SRB assay, were 0.25 ± 0.03 and 18 ± 1.2 µM respectively. In a preliminary study, cells treated with 56MESS displayed no caspase-3/7 activity, suggesting that the mechanism of action is caspase independent. Protein expression studies revealed an increase the expression in the MTC02 protein associated with mitochondria in cells treated with 56MESS and cisplatin. Non-synchronised 56MESS-treated cells caused an arrest in the G2/M phase of the cell cycle, in comparison to the S phase arrest of cisplatin. In G0/G1 synchronised cells, both 56MESS and cisplatin both appeared to arrest within the S phase. CONCLUSIONS: these results suggest that 56MESS is capable of causing cell-cycle arrest, and that mitochondrial and cell cycle proteins may be involved in the mode of action of cytotoxicity of 56MESS.

Comparison of cemented and uncemented fixation in total knee arthroplasty.

EDUCATIONAL OBJECTIVES: As a result of reading this article, physicians should be able to :1. Understand the rationale behind using uncemented fixation in total knee arthroplasty.2.Discuss the current literature comparing cemented and uncemented total knee arthroplasty3. Describe the value of radiostereographic analysis in assessing implant stability.4. Appreciate the limitations in the available literature advocating 1 mode of fixation in total knee arthroplasty. Total knee arthroplasty performed worldwide uses either cemented, cementless, or hybrid (cementless femur with a cemented tibia) fixation of the components. No recent literature review concerning the outcomes of cemented vs noncemented components has been performed. Noncemented components offer the potential advantage of a biologic interface between the bone and implants, which could demonstrate the greatest advantage in long-term durable fixation in the follow-up of young patients undergoing arthroplasty. Several advances have been made in the backing of the tibial components that have not been available long enough to yield long-term comparative follow-up studies. Short-term radiostereographic analysis studies have yielded differing results. Although long-term, high-quality studies are still needed, material advances in biologic fixation surfaces, such as trabecular metal and hydroxyapatite, may offer promising results for young and active patients undergoing total knee arthroplasty when compared with traditional cemented options.