Polypoid Large Intestinal Involvement of Metastatic Castrate-Resistant Prostate Cancer: A Case Report.

Introduction: Prostate cancer most commonly metastasizes to the bone and lymph nodes. Gastrointestinal metastasis has been noted in the literature but appears to be an exceedingly uncommon phenomenon. Large intestinal involvement in particular has been reported on only a few occasions, and never concomitantly with small intestinal metastatic involvement. Case Report: We report the case of a 69-year-old gentleman with metastatic castrate-resistant prostate cancer with development of gastrointestinal symptomatology with extensive investigation eventually revealing small and large intestinal polyps subsequently confirmed to be representative of metastatic prostate cancer. Conclusion: This case demonstrates the importance of maintaining a wide differential diagnosis in the context of gastrointestinal symptomatology in malignancy. Thorough endoscopic evaluation may be necessary in such cases in order to identify potential metastatic malignancy in otherwise relatively unremarkable appearing polyps.

Pathological and clinical outcomes following neoadjuvant dual HER2 therapy for early-stage breast cancer: An Australian institutional real-world experience.

AIM: There has been significant progress made in developing novel targeted therapies in the neoadjuvant setting for non-metastatic HER2-positive breast cancer, which may be used in combination with conventional chemotherapy to optimise pathological responses at surgery. However, these therapies, particularly the chemotherapeutic components, may portend significant and long-lasting toxicity. Hence, de-escalation of treatment intensity has been an area of interest and was evaluated in the phase II NeoSphere study. Herein, we report the real-world pathological and survival outcomes from neoadjuvant taxane and dual HER2 blockade recorded at our centre. METHODS: This was a retrospective cohort study of patients receiving neoadjuvant pertuzumab, trastuzumab and taxane chemotherapy for non-metastatic HER2-positive breast cancer at a single centre in Sydney, Australia. We collected data pertaining to baseline demographic characteristics, pathological response rates, post-surgical prescribing patterns and also undertook survival analyses for invasive disease-free survival (iDFS) as well as exploratory analyses for correlations between pre-specified clinicopathologic factors and pathological response at surgery. RESULTS: Our population was largely similar at baseline to the NeoSphere study. 71 patients were included in the final analysis. 61% achieved a pathological complete response (pCR). Three patients received conventional chemotherapy in the adjuvant setting. 92% of included patients were alive and disease-free at 3 years of follow-up. Only 3 events of recurrence or death were recorded at a median follow-up of 32 months. No significant difference in iDFS was noted between patients achieving pCR and those with residual disease at surgery. CONCLUSION: This study demonstrates that de-escalated adjuvant treatment for HER2-positive early breast cancer achieved favourable pathological and long-term outcomes comparable to large trials, some utilising more intensive chemotherapeutic components.

Therapeutic drug monitoring of osimertinib in EGFR mutant non-small cell lung cancer by dried blood spot and plasma collection: A pilot study.

AIMS: Therapeutic drug monitoring (TDM) has led to significant improvements in individualized medical care, although its implementation in oncology has been limited to date. Tyrosine kinase inhibitors (TKIs) are a group of therapies for which TDM has been suggested. Osimertinib is one such therapy used in the treatment of epidermal growth factor receptor (EGFR) mutation-driven lung cancer. Herein, we describe a prospective pilot study involving 21 patients on osimertinib primarily as a preliminary evaluation of drug levels in a real-world setting. METHODS: Concentrations of the drug and its primary metabolites were measured with a validated liquid chromatography-mass spectrometry (LC-MS) assay across serial timepoints. As part of this study, inter-individual variability by dose and ethnicity as well as intra-individual variability across timepoints are explored. Furthermore, we attempted to validate dried blood spot (DBS)-based quantitation as an accurate alternative to plasma quantitation. RESULTS: Successful quantitation of osimertinib and primary metabolites was achieved for our subjects. Compound plasma levels were highly correlated to DBS levels. There was no significant difference in concentrations with ethnicity or dosing or intra-individual variability across timepoints. CONCLUSIONS: As such, we demonstrate that TDM for osimertinib is practical for future trials. We also validated the use of DBS as an alternative to conventional quantitation for exploration of TDM for osimertinib in larger trials and for other targeted therapies.

A Validated Assay to Quantify Osimertinib and Its Metabolites, AZ5104 and AZ7550, from Microsampled Dried Blood Spots and Plasma.

BACKGROUND: Osimertinib is an oral small-molecule tyrosine kinase receptor inhibitor used to treat non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor mutation. Patients may experience drug toxicity and require dose deescalation. The study aimed to quantitate osimertinib and its 2 active metabolites, AZ5104 and AZ7550, in microsampled dried blood spots (DBS) collected from patients with NSCLC using a hemaPEN device and compare them with plasma drug levels. METHODS: A 6-min ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed and validated using plasma and DBS. The accuracy, selectivity, matrix effect, recovery, and stability were assessed using bioanalytical validation criteria. The hematocrit effect was investigated in DBS. Drug levels were measured in 15 patients with NSCLC, and the Bland-Altman method was used to compare measurements between plasma and DBS. RESULTS: The validated assay determined accurate and precise quantities, respectively, for osimertinib in both plasma (93.2%-99.3%; 0.2%-2.3%) and DBS (96.7%-99.6%; 0.5%-10.3%) over a concentration of 1-729 ng/mL. The osimertinib metabolites, AZ5104 and AZ7550, were similarly validated in accordance with bioanalytical guidelines. For 30%-60% patient hematocrit, no hematocrit bias was observed with DBS for all analytes. The Bland-Altman method showed high concordance between plasma and DBS analyte levels. Stability experiments revealed that osimertinib and its metabolites were poorly stable in plasma at room temperature, whereas all analytes were stable in DBS for 10 days at room temperature. CONCLUSIONS: The measurement of osimertinib, AZ5104, and AZ7550 from hemaPEN microsampled DBS is a convenient and reliable approach for therapeutic drug monitoring that produces measurements consistent with plasma drug levels.

Rare immune-related adverse events in patients with melanoma: incidence, spectrum, and clinical presentations.

Immune-related adverse events (irAEs) are side effects of immune checkpoint inhibitor therapy (ICI). While common irAEs have been well characterized, there are more limited data on rare immune related adverse events (RirAEs) due to low incidence. Lack of characterization of these entities has led to difficulties in accurate diagnosis and management. Here, we conducted a multi-institution analysis of all patients with stage III/IV melanoma who developed RirAEs after being treated with ICIs (anti-PD-1/L1, anti-CTLA-4, and combination PD-1/CTLA-4 blockade) at three institutions (Vanderbilt University Medical Center, Massachusetts General Hospital, and Melanoma Institute of Australia). RirAEs were defined as those occurring in approximately <1% of patients treated with anti-PD-1 or <2% with combination. Of 2834 patients who received ICIs, 82 developed RirAEs and were more common with combination PD-1/CTLA-4 blockade (4.6%) vs. anti-PD-1/L1 agents (2.8%). Overall median time from ICI start to RirAE was 86 days (interquartile range 42-235 days) with significantly earlier onset in combination therapy (p < 0.001). The spectrum of RirAEs spanned across several organ systems. Most RirAEs were grade 2 (57 [41.3%]) and grade 3 (40 [29.0%]) with relatively few grade 4 (11 [8.0%]) or 5 (5 [3.6%]) events. Steroid re-escalation (21.4%) or additional immunosuppression (13.8%) were commonly required. RirAE recurrence occurred in 22.6% with ICI rechallenge; 37.1% had new irAEs with rechallenge. In conclusion, RirAEs associated with ICIs in melanoma patients occurred, in aggregate, in 2-5% of patients treated with anti-PD-1-based therapy. Steroid re-escalation and alternative immunosuppression use were frequently required but fatal irAEs were fairly uncommon.

Technical and Medium-Term Clinical Outcomes of Transjugular Intrahepatic Portosystemic Shunt with Fluoroscopy and Additional Trans-abdominal Ultrasound Guidance.

Background and Objective The aim of the study is to evaluate the technical and clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) performed with additional transabdominal ultrasound guidance. Material and Methods Patients who underwent TIPS between January 2004 to January 2020 in our center were studied. Technical, hemodynamic, angiographic, and clinical outcome were recorded up to 1 year of follow-up. Results TIPS was attempted in 162 patients (median [range] age 37[3-69] years; 105 were males and 57 were females; Etiology: Budd-Chiari syndrome [BCS] 91, cirrhosis 65, symptomatic acute portal venous thrombosis [PVT] 3, veno-occlusive disease [VOD] 2, congenital portosystemic shunt [CPSS] 1) during the study period. Indication for TIPS was refractory ascites in 135 patients (BCS 86, cirrhosis 49) and variceal bleed in 21 patients (BCS 5, cirrhosis 16). Technical success was seen in 161 of the 162 (99.4%) patients. The tract was created from hepatic vein in 55 patients and inferior vena cava (IVC) in 106 patients. Complications within 1 week post TIPS were seen in 29 of the 162 (18%) patients, of whom one developed unexplained arrhythmia and hypotension and died. Of the patients with available follow-up, clinical success was noted in 120 (81%), while 14 (9%) patients had partial nonresponse and six (4%) had complete nonresponse. Eight (5%) patients died during the follow-up period. Conclusion The technical success of TIPS creation with additional transabdominal ultrasound guidance is very high with low peri-procedural complication rate. It has enabled the inclusion of a wider spectrum of cases like acute PVT and obliterated hepatic veins which were otherwise considered contraindications.

Hirayama disease: imaging profile of three cases emphasizing the role of flexion MRI.

We report three cases of Hirayama disease, cervical flexion myelopathy presenting as unilateral or bilateral asymmetric muscular atrophy of forearm and hand involving C7 - T1 myotomes in young males. MRI revealed asymmetric cord atrophy, altered signal intensity of cord, posterior dural detachment and enlarged posterior epidural space with multiple flow voids. This article emphasizes the role of Flexion MRI in diagnosing Hirayama disease.

Left-sided Poland's syndrome in a girl with rare associations like spina bifida and diaphragmatic hernia.

Poland's syndrome is a rare congenital anomaly characterised by partial or complete absence of sternocostal head of pectoralis major muscle and anomalies of ipsilateral hand and digits. Other associated anomalies involving anterior thoracic wall, breast, diaphragm and vertebrae have also been reported in various cases. We report a case of a 10-year-old girl, with features of left-sided Poland's syndrome associated with spina bifida, dextroposition of the heart and left-sided diaphragmatic hernia. These are rare associations of Poland's syndrome. She was investigated with chest X-ray, contrast-enhanced CT of the thorax, ultrasonography of abdomen and echocardiography which helped in arriving at an accurate diagnosis and assessing all the associated abnormalities.

Identification of novel small molecule TGF-ß antagonists using structure-based drug design.

Aberrant transforming growth factor-ß (TGF-ß) signalling has been associated with a number of disease pathologies, such as the development of fibrosis in the heart, lung and liver, cardiovascular disease and cancer, hence the TGF-ß pathway represents a promising target for a variety of diseases. However, highly specific ways to inhibit TGF-ß signalling need to be developed to prevent cross-talk with related receptors and minimise unwanted side effects. We have used used virtual screening and molecular docking to identify small molecule inhibitors of TGF-ß binding to TßRII. The crystal structure of TGF-ß3 in complex with the extracellular domain of the type II TGF-ß receptor was taken as a starting point for molecular docking and we developed a structure-based pharmacophore model to identify compounds that competitively inhibit the binding of TGF-ß to TßRII and antogonize TGF-ß signalling. We have experimentally tested 67 molecules suggested by in silico screening and similarity searching for their ability to inhibit TGF-ß signalling in TGF-ß-dependent luciferase assays in vitro and the molecule with the strongest inhibition had an IC50 of 18 µM. These compounds were selected to bind to the SS1 subsite (composed of F30, C31, D32, I50, T51 S52, I53, C54 and E55) of TßRII and all share the general property of being aromatic and fairly flat. Molecular dynamics simulations confirmed that this was the most likely binding mode. The computational methods used and the hits identified in this study provide an excellent guide to medicinal chemistry efforts to design tighter binding molecules to disrupt the TGF-ß/TßRII interaction.