Futility, the Multiorganization Policy Statement, and the Schneiderman Response.

This essay offers a brief history of futility, in both sociocultural and medical contexts, with some personal reflection on the disappearance and reappearance of medical futility during the author's 40-plus years in medicine. It discusses the creation of the Texas Advance Directives Act (TADA), which, even with its flaws, creates the only legal safe harbor for physicians engaged in futility disputes. It also offers reflection on the commendable Multiorganization Policy Statement on "potentially inappropriate treatment" yet comes to the same conclusion as Schneiderman. The words recommended for use in futility disputes are not helpful in facing these disputes. Medical futility appropriately understood transcends pure physiologic, quantitative, or qualitative concepts. Those who seek to help resolve futility disputes must take into account not only these concepts, but also emotional, social, and spiritual factors as well. If we are to collectively face the challenge of medical futility, we must cultivate a more covenantal and communitarian ethical framework, develop processes similar to TADA in other state laws, and teach that the acceptance of finitude does not reduce the sacred value of life.

Neoadjuvant gemcitabine, docetaxel, and capecitabine followed by gemcitabine and capecitabine/radiation therapy and surgery in locally advanced, unresectable pancreatic adenocarcinoma.

BACKGROUND: This prospective study was undertaken to assess toxicity, resectability, and survival in pancreatic adenocarcinoma patients presenting with locally advanced, unresectable disease treated with neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX) and gemcitabine and capecitabine (GX)/radiation therapy (RT). METHODS: All patients presenting to the Pancreas Center were evaluated for eligibility. Forty-five patients (mean age, 64 years; range, 44-83 years)-34 patients deemed unresectable because of arterial involvement and 11 patients deemed unresectable because of extensive venous involvement-were treated with 6 cycles of GTX. Those with arterial involvement were treated with GX/RT after chemotherapy. RESULTS: The GTX and GX/RT treatments were tolerated with the expected drug-related toxicities. There were no bowel perforations, cases of pancreatitis, or delayed strictures. Among those with arterial involvement, 29 underwent subsequent resection, with 20 (69%) achieving R0 resections. All 11 patients with venous-only involvement underwent resection, with 8 achieving R0 resections and 3 achieving complete pathologic responses. For the arterial arm, the 1-year survival rate was 71% (24 of 34 patients), and the median survival was 29 months (95% confidence interval, 21-38 months). Thirteen patients (38%) have not relapsed (range, 5-49+ months). For the venous arm, the median survival has not been reached at more than 42 months. Six patients (55%) in the venous arm did not experience recurrence (range, 6.2-42+ months). CONCLUSIONS: GTX plus GX/RT is an effective neoadjuvant regimen that can be safely administered to patients up to at least the age of 83 years. It is associated with a high response rate, a high rate of R0 resections, and prolonged overall survival.

Treatment of multiple endocrine neoplasia 1/2 tumors: case report and review of the literature.

BACKGROUND: Neuroendocrine tumors are uncommon tumors that are histopathologically and biologically heterogeneous and include the multiple endocrine neoplasia (MEN) 1 and 2 syndromes. The morbidity of MEN-1 and MEN-2 is often due to the symptomatology of the endocrine hormones produced, and the mortality mainly occurs from hepatic dysfunction incurred by liver metastases. At present, there is essentially no effective cure once the tumor has metastasized to the liver. PATIENT: We present a patient with progressive, metastatic MEN-1 with the classic '3 P's' triad of neuroendocrine tumor of the pancreas, parathyroid adenoma and a pituitary adenoma. RESULTS: After progression on high-dose Sandostatin LAR (60 mg/month) and multiple surgeries, the patient had a partial response (40% decrease) to a novel regimen of capecitabine and temozolomide (CAPTEM) and progression-free survival of 18 months. He had minor grade 1 toxicities and no grade 2, 3 or 4 toxicities. DISCUSSION: The history and treatment options for MEN-1/2 cancers are reviewed, as well as the data behind our novel regimen, CAPTEM. CONCLUSION: The CAPTEM regimen is a tolerable, safe, easy to administer oral regimen with possible efficacy for MEN-1 tumors.

The intensity and frequency of moral distress among different healthcare disciplines.

INTRODUCTION: The objectives of this study are to assess and compare differences in the intensity, frequency, and overall severity of moral distress among a diverse group of healthcare professionals. METHODS: Participants from within Baylor Health Care System completed an online seven-point Likert scale (range, 0 to 6) moral distress survey containing nine core clinical scenarios and additional scenarios specific to each participant's discipline. Higher scores reflected greater intensity and/or frequency of moral distress. RESULTS: More than 2,700 healthcare professionals responded to the survey (response rate 18.14 percent); survey respondents represented multiple healthcare disciplines across a variety of settings in a single healthcare system. Intensity of moral distress was high in all disciplines, although the causes of highest intensity varied by discipline. Mean moral distress intensity for the nine core scenarios was higher among physicians than nurses, but the mean moral distress frequency was higher among nurses. Taking into account both intensity and frequency, the difference in mean moral distress score was statistically significant among the various disciplines. Using post hoc analysis, differences were greatest between nurses and therapists. CONCLUSIONS: Moral distress has previously been described as a phenomenon predominantly among nursing professionals.This first-of-its-kind multidisciplinary study of moral distress suggests the phenomenon is significant across multiple professional healthcare disciplines. Healthcare professionals should be sensitive to situations that create moral distress for colleagues from other disciplines. Policy makers and administrators should explore options to lessen moral distress and professional burnout that frequently accompanies it.

Food as Love: Ethical and Moral Dilemmas in Withdrawal of Artificial Nutrition and Hydration in the Minimally Conscious State.

Supportive Palliative Care and Hospice professionals frequently attend to Minimally Conscious State (MCS) patients near the end of life and in so doing, face decisions over maintenance or withdrawal of artificial nutrition and hydration. Although both withholding and withdrawal of artificial nutrition and hydration (ANH) in such circumstances are considered by experts in ethics and law to be acceptable, not all families nor health care professionals agree. This paper will explore basic aspects of serious brain injuries, especially MCS, the psychological role of food in interpersonal relationships, and lessons from clinical ethics that can help in goals of care discussions about withdrawal of ANH.

Gene Therapy with p14/tBID Induces Selective and Synergistic Apoptosis in Mutant Ras and Mutant p53 Cancer Cells In Vitro and In Vivo.

Any gene therapy for cancer will be predicated upon its selectivity against cancer cells and non-toxicity to normal cells. Therefore, safeguards are needed to prevent its activation in normal cells. We designed a minimal p14ARF promoter with upstream Ap1 and E2F enhancer elements and a downstream MDR1 inhibitory element, TATA box, and a transcription initiation site (hereafter p14ARFmin). The modified p14ARFmin promoter was linked to bicistronic P14 and truncated BID (tBID) genes, which led to synergistic apoptosis via the intrinsic and extrinsic pathways of apoptosis when expressed. The promoter was designed to be preferentially activated by mutant Ras and completely inhibited by wild-type p53 so that only cells with both mutant Ras and mutant p53 would activate the construct. In comparison to most p53 gene therapies, this construct has selective advantages: (1) p53-based gene therapies with a constitutive CMV promoter cannot differentiate between normal cells and cancer cells, and can be toxic to normal cells; (2) our construct does not induce p21WAF/CIPI in contrast to other p53-based gene therapies, which can induce cell cycle arrest leading to increased chemotherapy resistance; (3) the modified construct (p14ARFmin-p14-tBID) demonstrates bidirectional control of its promoter, which is completely repressed by wild-type p53 and activated only in cells with both RAS and P53 mutations; and (4) a novel combination of genes (p14 and tBID) can synergistically induce potent intrinsic and extrinsic apoptosis in cancer cells.

C-Terminal p53 Palindromic Tetrapeptide Restores Full Apoptotic Function to Mutant p53 Cancer Cells In Vitro and In Vivo.

We previously demonstrated that a synthetic monomer peptide derived from the C-terminus of p53 (aa 361−382) induced preferential apoptosis in mutant p53 malignant cells, but not normal cells. The major problem with the peptide was its short half-life (half-life < 10 min.) due to a random coil topology found in 3D proton NMR spectroscopy studies. To induce secondary/tertiary structures to produce more stability, we developed a peptide modelled after the tetrameric structure of p53 essential for activation of target genes. Starting with the above monomer peptide (aa 361−382), we added the nuclear localization sequence of p53 (aa 353−360) and the end of the C-terminal sequence (aa 383−393), resulting in a monomer spanning aa 353−393. Four monomers were linked by glycine to maximize flexibility and in a palindromic order that mimics p53 tetramer formation with four orthogonal alpha helices, which is required for p53 transactivation of target genes. This is now known as the 4 repeat-palindromic-p53 peptide or (4R-Pal-p53p). We explored two methods for testing the activity of the palindromic tetrapeptide: (1) exogenous peptide with a truncated antennapedia carrier (Ant) and (2) a doxycycline (Dox) inducer for endogenous expression. The exogenous peptide, 4R-Pal-p53p-Ant, contained a His tag at the N-terminal and a truncated 17aa Ant at the C-terminal. Exposure of human breast cancer MB-468 cells and human skin squamous cell cancer cells (both with mutant p53, 273 Arg->His) with purified peptide at 7 µM and 15 µM produced 52% and 75%, cell death, respectively. Comparatively, the monomeric p53 C-terminal peptide-Ant (aa 361−382, termed p53p-Ant), at 15 µM and 30 µM induced 15% and 24% cell death, respectively. Compared to the p53p-Ant, the exogenous 4R-pal-p53p-Ant was over five-fold more potent for inducing apoptosis at an equimolar concentration (15 µM). Endogenous 4R-Pal-p53p expression (without Ant), induced by Dox, resulted in 43% cell death in an engineered MB468 breast cancer stable cell line, while endogenous p53 C-terminal monomeric peptide expression produced no cell death due to rapid peptide degradation. The mechanism of apoptosis from 4R-Pal-p53p involved the extrinsic and intrinsic pathways (FAS, caspase-8, Bax, PUMA) for apoptosis, as well as increasing reactive oxygen species (ROS). All three death pathways were induced from transcriptional/translational activation of pro-apoptotic genes. Additionally, mRNA of p53 target genes (Bax and Fas) increased 14-fold and 18-fold, respectively, implying that the 4R-Pal-p53p restored full apoptotic potential to mutant p53. Monomeric p53p only increased Fas expression without a transcriptional or translational increase in Fas, and other genes and human marrow stem cell studies revealed no toxicity to normal stem cells for granulocytes, erythrocytes, monocytes, and macrophages (CFU-GEMM). Additionally, the peptide specifically targeted pre-malignant and malignant cells with mutant p53 and was not toxic to normal cells with basal levels of WT p53.

The feasibility of real-time in vivo optical detection of blood-brain barrier disruption with indocyanine green.

Osmotic disruption of the blood-brain barrier (BBB) by intraarterial mannitol injection is sometimes required for the delivery of chemotherapeutic drugs to brain tissue. Osmotic disruption is affected by a number of factors, and there is a significant variability in the degree and distribution of BBB disruption in clinical and experimental settings. Brain tissue concentrations of indocyanine green (ICG) can be measured by optical techniques. The aim of this experiment was to determine whether the disruption of the BBB significantly altered the regional pharmacokinetics of ICG. We were able to track in vivo brain tissue concentrations of ICG in 13 New Zealand white rabbits by employing a novel optical approach. Evan's blue was used to assess the distribution of BBB disruption on post mortem examination. BBB disruption by intraarterial mannitol injection was found to be highly variable, and only five of the 13 animals demonstrated the disruption at the site of optical measurements. In these animals, we observed a ninefold increase in ICG concentrations and fourfold increase in the area under the concentration-time curve, compared to those without BBB disruption at the site of measurement. This study shows the feasibility of optical monitoring of BBB disruption with intravenous (IV) ICG injections. Virtual real-time optical monitoring of the BBB disruption could help improve intraarterial delivery of chemotherapeutic drugs.

Temozolomide (Temodar®) and capecitabine (Xeloda®) treatment of an aggressive corticotroph pituitary tumor.

Only rarely do corticotroph pituitary tumors become invasive leading to symptoms caused by compression of cranial nerves and other local structures. When aggressive pituitary neuroendocrine tumors do develop, conventional treatment options are of limited success. A 50-year-old man developed a giant invasive corticotroph pituitary tumor 2 years after initial presentation. His tumor and symptoms failed to respond to maximal surgical, radio-surgical, radiation and medical therapy and a bilateral adrenalectomy was done. He subsequently developed rapid growth of his tumor leading to multiple cranial nerve deficits. He was administered salvage chemotherapy with capecitabine and temozolomide (CAPTEM), a novel oral chemotherapy regimen developed at our institution for treatment of neuroendocrine tumors. After two cycles of CAPTEM, his tumor markedly decreased in size and ACTH levels fell by almost 90%. Despite further decreases in ACTH levels, his tumor recurred after 5 months with increased avidity on PET scan suggesting a transformation to a more aggressive phenotype. Temozolomide had been reported to be effective against other pituitary tumors and this case adds to this literature demonstrating its use along with capecitabine (CAPTEM) against a corticotroph tumor. Further evaluation of the CAPTEM regimen in patients with pituitary neuroendocrine tumors which fail to respond to classic treatments is warranted.

Economic Analysis of Hospital Palliative Care: Investigating Heterogeneity by Noncancer Diagnoses.

Background. Single-disease-focused treatment and hospital-centric care are poorly suited to meet complex needs in an era of multimorbidity. Understanding variation in palliative care's association with treatment choices is essential to optimizing interdisciplinary decision making in care of complex patients. Aim. To estimate the association between palliative care and hospital costs by primary diagnosis and multimorbidity for adults with one of six life-limiting conditions: heart failure, chronic obstructive pulmonary disease (COPD), liver failure, kidney failure, neurodegenerative conditions including dementia, and HIV/AIDS. Methods. Data from four studies (2002-2015) were pooled to provide an analytic dataset of 73,304 participants with mean costs $10,483, of whom 5,348 (7%) received palliative care. We estimated average effect of palliative care on direct hospital costs among the treated, using propensity scores to control for observed confounding. Results. Palliative care was associated with a statistically significant reduction in total direct costs for heart failure (estimated treatment effect: -$2666; 95% confidence interval [CI]: -$3440 to -$1892), neurodegenerative conditions (-$3523; -$4394 to -$2651), COPD (-$1613; -$2217 to -$1009), kidney failure (-$3589; -$5132 to -$2045), and liver failure (-$7574; -$9232 to -$5916). The association for liver failure patients was statistically significantly larger than for any other disease group. Cost-saving associations were also statistically larger for patients with multimorbidity than single disease for two of the six groups: neurodegenerative and liver failure. Conclusions. Heterogeneity in treatment effect estimates was observable in assessing association between palliative care and hospital costs for adults with serious life-limiting illnesses other than cancer. The results illustrate the importance of careful definition of palliative care populations in research and practice, and raise further questions about the role of interdisciplinary decision making in treatment of complex medical illness.