Management of newly diagnosed glioblastoma multiforme: current state of the art and emerging therapeutic approaches.

Glioblastoma multiforme represent > 50% of primary gliomas and have five year survival rates of ~ 5%. Maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide remains the standard treatment since published by Stupp et al. (in N Engl J Med 352:987-996, 2005), with additional benefit for patients with MGMT-methylated tumors. We review the current treatment landscape and ongoing efforts to improve these outcomes. An extensive literature search of Pubmed and Google Scholar involving the search terms "glioblastoma," "glioblastoma multiforme," or "GBM" for papers published to July 2021 was conducted and papers evaluated for relevance. As well as current data that informs clinical practice, we review ongoing clinical research in both newly diagnosed and recurrent settings that provides hope for a breakthrough. The Stupp protocol remains standard of care in 2021. Addition of tumor treating fields improved mOS modestly, with benefit seen in MGMT-methylated and unmethylated cohorts and also improved time to cognitive decline but has not been widely adopted. The addition of lomustine to temozolomide, in MGMT-methylated patients, also showed a mOS benefit but further investigation is required. Other promising therapeutic strategies including anti-angiogenic therapy, targeted therapy, and immunotherapy have yet to show a survival advantage. Improvements in the multidisciplinary management, surgical techniques and equipment, early palliative care, carrier support, and psychological support may be responsible for improving survival over time. Despite promising preclinical rationale, immunotherapy and targeted therapy are struggling to impact survival. A number of ongoing clinical trials provide hope for a breakthrough.

Radium-223 in the Treatment of Metastatic Castrate-Resistant Prostate Cancer.

Background Radium 223 (Ra-223) has been successfully utilised for the treatment of men with metastatic castrate resistant prostate cancer (mCRPC). To date, no real world outcomes from its use in the Irish population have been described. Methods All men referred to our institution for Ra-223 from September 2016 to March 2019 were included. Patient demographics, treatments received, toxicities and outcomes were recorded. Overall survival (OS) and progression free survival (PFS) were analysed using the Kaplan-Meier method. Results Complete data was available for 54 men. Median age was 75 years (range 61-86 years). The median number of prior systemic treatments for mCRPC was 2 (range 0-4). Median ECOG performance status was 1 at the start of treatment and 2 at completion. The median number of Ra-223 cycles received was 4 with 37%(n=20) completing all 6 planned cycles. The most common treatment-related toxicity was fatigue seen in 52% of patients ( n=28). Improved pain scores were documented in 76% of men requiring opioid analgesia at the start of treatment. The median OS was 7 months. A good ECOG performance status, fewer than 6 bone metastases, normal alkaline phosphatase level at start of treatment and chemotherapy naivety were associated with improved OS. Conclusions Ra-223 is a moderately well tolerated palliative treatment amongst Irish men with mCRPC.

Immune Checkpoint Inhibitors and Palliative Care at the End of Life: An Irish Multicentre Retrospective Study.

Background and Objectives: Immune checkpoint inhibitors (ICIs) have less toxicity than standard chemotherapy and are now standard of care for many patients with advanced cancer. A manageable side effect profile and potential for durable responses may lead to aggressive care of the palliative patient. We sought to evaluate palliative care input and ICI use at the end of life at two Irish cancer centres. Methods: We identified deceased patients who received at least one dose of an ICI between first of January 2013 to 31st of December 2018. A retrospective electronic chart review was performed. Results: The electronic records of 102 patients were analysed. Fifty eight percent were male and the median age of diagnosis of advanced disease was 60 years (range 17-78). Median time from last dose of ICI to death was 57 days (range 8-574) and 20% of patients died within 30 days of last dose of ICI. Most patients, 92%, were referred to palliative care. The median time from palliative care referral to death was 64 days (range 1- 1010). In the last 30 days of life, 39% of patients attended the emergency department (ED) and 46% had at least one hospital admission. Late palliative care referrals, ≤3 months before death, were associated with hospitalisations in the last month of life (64% vs. 36%, P = .02). Timing of palliative care referral did not affect ICI prescribing at the end of life (P = 0.38). ICI use in the last 30 days of life was not associated with increased ED presentations or hospitalisations at the end of life. Patients who received ICI in the last month had a higher likelihood of in-hospital death (43% vs. 16%, P = 0.02). Conclusions: ICI within 30 days of death was associated with dying in hospital but did not lead to more hospitalisations and emergency department presentations. Early palliative care did not affect ICI use but reduced hospitalisations at the end of life.

Commentary on "DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma."

PURPOSE: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. EXPERIMENTAL DESIGN: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features. RESULTS: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rank P = 0.007) and overall survival (23.7 vs. 13.0 months, log-rank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable effect on clinical outcomes. CONCLUSIONS: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment.

A regional analysis of epidermal growth factor receptor (EGFR) mutated lung cancer for HSE South.

BACKGROUND: EGFR mutated lung cancer represents a subgroup with distinct clinical presentations, prognosis, and management requirements. We investigated the survival, prognostic factors, and real-world treatment of NSCLC patients with EGFR mutation in clinical practice. METHODS: A retrospective review of all specimens sent for EGFR analysis from December 2009 to September 2015 was performed. Patient demographics, specimen type, EGFR mutation status/type, stage at diagnosis, treatment, response rate, and survival data were recorded. RESULTS: 27/334 (8%) patient specimens sent for EGFR testing tested positive for a sensitising EGFR mutation. The median age was 65 years (40-85 years). Exon 19 deletion represented the most commonly detected alteration, accounting for 39% (n = 11). First-line treatment for those with Exon 18, 19, or 21 alterations (n = 24) was with an EGFR tyrosine kinase inhibitor (TKI) in 79% (n = 19). Objective response rate among these patients was 74% and median duration of response was 13 months (range 7-35 months). CONCLUSION: The incidence of EGFR mutation in our cohort of NSCLC is 9% which is consistent with mutation incidence reported in other countries. The rate of EGFR mutation in our population is slightly below that reported internationally, but treatment outcomes are consistent with published data. Real-world patient data have important contributions to make with regard to quality measurement, incorporating patient experience into guidelines and identifying safety signals.

Empathy and the wounded healer: a mixed-method study of patients and doctors views on empathy.

Empathy is increasingly being recognized as a crucial component for an effective doctor-patient relationship. Using a mixed method approach, we surveyed 125 patients and 361 medical practitioners (doctors and medical students) views of the doctor-patient relationship. We qualitatively assessed patients' views of what constituted a good doctor and qualitatively measured empathy using a validated scale in medical practitioners. Patients desire a doctor that is both clinically proficient 66 (55%) and caring 32 (27%). Doctors who have a personal experience of illness have a statistically higher empathy score. These doctors may be well placed to help develop and foster empathy in our profession.

Enzalutamide: Development from bench to bedside.

Prostate tissue, whether benign or malignant, is heavily dependent on androgen receptor (AR) signaling for growth and proliferation. Androgen deprivation therapy has been standard of care for management of metastatic prostate cancer for the past 70 years. AR antagonists were developed to further abrogate signaling through this pathway by competitive inhibition of the receptor. First-generation compounds such as bicalutamide had modest efficacy, and in the setting of AR overexpression or specific mutations in the AR ligand-binding domain, these early compounds had partial agonist properties that could stimulate tumor growth. Enzalutamide was developed to overcome these deficiencies, and here, we present the story of its preclinical discovery, clinical development, and ultimate approval as a standard-of-care therapy for castration-resistant prostate cancer. Also discussed are ongoing efforts to elucidate mechanisms of resistance to this agent as well as studies that are investigating its role in other prostate cancer disease states and other cancer types.

The association of pre-treatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme.

Neutrophil-lymphocyte ratio (NLR) is a marker of systemic inflammatory response and its elevation has recently been shown to be a poor prognostic factor in many malignancies including colon, prostate and bladder cancer. The primary aim of this study was to assess the prognostic impact of NLR in a clinically annotated cohort of patients with glioblastoma multiforme (GBM). We hypothesised that elevated NLR would be associated with worse prognosis. Between 2004 and 2009, 137 patients had surgery for GBM and were assessed for consideration of adjuvant therapy at our institution. Of these, 84 patients with an evaluable pre-corticosteroid full blood count result were identified and included in the final analysis. Median overall survival was 9.3 months (range 0.7-82.1). On univariate analysis, age >65 years, gender, ECOG performance status ≥2, frontal tumour, extent of surgical resection, completion of adjuvant chemoradiation protocol and NLR > 4 were significantly correlated with overall survival. Patients with NLR > 4, had a worse median overall survival at 7.5 months versus 11.2 months in patients with NLR ≤ 4 (hazard ratio 1.6, 95 % CI 1.00-2.52, p = 0.048). On multivariate analysis NLR > 4 remained an independent prognostic indicator for poor outcome. These data are an important reminder of the potential relevance of host immunity in GBM. In our cohort, NLR > 4 conferred a worse prognosis independent of other well established prognostic factors. If validated in other cohorts NLR may prove to be a useful addition in predicting prognosis in GBM patients. The demonstration that host immunity plays a role in GBM biology suggests that investigation of emerging therapies which modulate host immune response are warranted in this disease.

Primary cardiac lymphoma: diagnostic tools and treatment challenges.

Primary cardiac lymphoma (PCL) is a rare malignancy and the optimal treatment strategy remains uncertain. It appears to respond much better to systemic chemotherapy than to surgery and it should be considered in the differential diagnosis of all cardiac tumours before definitive management is undertaken. We report a case of this rare disorder treated successfully with a combination of rituximab and cyclophosphamide, adriamycin, vincristine and prednisolone. The patient developed recurrent unstable ventricular tachycardia (VT) post-chemotherapy secondary to extensive scarring at the tumour site. The tumour as well as the post-treatment scarring is well illustrated by cardiac magnetic resonance imaging highlighting its usefulness in this setting. An implantable cardioverter defibrillator (ICD) was placed. This is only the second case in the literature of PCL to have an ICD placed for recurrent VT. A brief literature review is included.

Mesoionic pyridazine ribonucleosides. A novel biologically active nucleoside metabolite.

4-Cyano-3-oxido-1-beta-D-ribofuranosylpyridazinium (10a) has been prepared from 4-cyano-3(2H)-pyridazinone (4) by using a low-temperature, kinetically controlled, silyl Hilbert-Johnson reaction followed by deblocking of the resulting triacetate derivative, 8a, with NaHCO3 in methanol. 10a is apparently the first example of a mesoionic analogue of a pyrimidine nucleoside. It was discovered as a urine metabolite of 4-cyano-3(2H)-pyridazinone (4) in mice. 10a possesses Gram-negative antibacterial activity in vivo against a systemic Escherichia coli infection in mice with an ED50 of 25-50 mg/kg. A series of 4-substituted 3-oxidopyridazinium ribonucleosides, 11a-h, were synthesized as analogues of 10a. 4-Chloro-3-oxido-1-beta-D-ribofuranosylpyridazinium (11a) was found to be several times more active than 10a against E. coli in vitro although it showed no in vivo activity.

Synthesis of 4-substituted aminoquinoline-3-carboxylates as potential antimicrobial agents.

A series of 4-substituted aminoquinoline-3-carboxylates was prepared and evaluated for antimicrobial activity. Four of the compounds (VIII, XIII, XV, and XXIII) exhibited low activity against Staphylococcus aureus.

beta-lactam antibiotics derived from nitrogen heterocyclic acetic acids. 2. Cephalosporin derivatives.

Three cephalosporin derivatives were prepared from 1,4-dihydro-4-oxypyridine-1-acetic acid. These were the 7-aminocephalosporanic acid (7-ACA) derivative and the compounds with 5-methyl-1,3,4-thiadiazol-2-thiol and 1-methyl-1,2,3,4-tetrazole-5-thiol at C-3 of the cephalosporin nucleus. The antibacterial activity of the 7-ACA derivative was comparable to cephalothin, and that of the other two derivatives was comparable to cefazolin. The 7-ACA derivative, compared to cephalothin, was significantly less metabolized, was less protein bound, and had a longer half life.

Orally active cephalosporins and penicillins.

A number of orally active cephalosporins and penicillins with interesting biological activity were synthesized. Two of these, 7-[[[3,4-(methylenedioxy)phenyl]glycyl]amino]deacetoxycephalosporanic acid and 7-[[2-(2,3-dihydro-5-benzofuranyl)glycyl]amino]deacetoxycephalosporanic acid were considerably more active than cephalexin both in vitro and in vivo against staphylococcal and streptococcal infections.

Nitrones. 7. alpha-Quinoxalinyl-N-substituted nitrone 1,4-dioxides.

A series of alpha-quinoxalinyl-N-substitute nitrone 1,4-dioxides has been synthesize and evaluated as antibacterial and antiprotozoal agents. Structure-activity relationships are discussed. Of the compounds tested, alpha-(3-methyl-2-quinoxalinyl)-N-methylnitrone 1,4-dioxide (2) was the most active agent in vivo against the gram-negative and the gram-positive organisms.

Beta-lactam antibiotics with N-oxide side chains. 1. Quinoxaline N-oxides.

A series of penicillin derivatives of quinoxaline di-N-oxide carboxylic acids was prepared. These compounds were prepared from the acid chlorides and mixed anhydrides of the quinoxaline di-N-oxides. The compounds prepared exhibited minimal antibacterial activity against gram-negative organisms.

3-Substituted 2-formylquinoxaline 1,4-dioxides.

The methylnitrone of 3-methyl-1,4-dioxidoquinoxaline-2-carboxaldehyde (1) has been exceptional antibacterial activity in vivo. Derivatives of 3-hydroxymethyl-1,4-dioxidoquinoxaline-2-carboxaldehyde and 3-acetoxymethyl-1,4-dioxidoquinoxaline-2-carboxaldehyde were prepared. Several of these compounds were found to be antibacterial agents of the same order of activity as I.