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We developed a laboratory based regimen called GTX which induces synergistic apoptosis in human pancreatic cancer cells. This retrospective review summarizes our clinical experience with GTX in an initial group of 35 patients; 66% untreated and 34% failed prior therapies. All patients treated with GTX for metastatic pancreatic cancer, prior to initiation of a prospective phase II trial of GTX were assessed and followed until death. GTX consisted of capecitabine (X), 750 mg/m2 p.o. BID on days 1–14, gemcitabine (G) (750 mg/m2) over 75 min and docetaxel (T) (30 mg/m2) on days 4 and 11. Thus one cycle of GTX was 14 days with 7 days off for a 21 day cycle. Tumor assessments were repeated every 3 cycles. All 35 patients had metastatic pancreatic cancer (94% liver, 6% lung sites). Grade 3–4 hematological toxicities were: leukopenia and thrombocytopenia—both 14%, and anemia 9%, respectively. The overall response rate of all 35 patients treated with GTX (from 0.5 cycles onward) was 29% (CR/PR) by WHO criteria, and 31% had a minor response or stable disease (MR, SD). At the metastatic sites for the 35 patients, there were 9% complete (CR) and 31% partial (PR) responses (total 40%). For the 31 patients who had their primary tumor (4 patients had a prior Whipple resection), there were 13% CR and 19% PR for a response rate of 32% at the primary tumor site. Overall median progression free survival of responders was 6.3 months (95% C.I. 4.4–10.4 months) and median survival was 11.2 months (95% C.I. 8.1–15.1 months). Survival after initiation of GTX at 12, 18, 24 and 30 months was 43, 29, 20, and 11%, respectively. Our retrospective review suggests that GTX has potential as a regimen for untreated and treated metastatic pancreatic cancer. [ABSTRACT FROM AUTHOR]

Effective pain relief, especially at the end of life, is a primary ethical obligation based upon the principles of beneficence, nonmaleficence, patient autonomy, and particularly the concept of double effect. The pragmatic foundation of pain management begins with a complete assessment, which incorporates 'WILDA' (words, intensity, location, duration, aggravating/alleviating factors) and considers the components of total pain: physical, emotional, social, and spiritual pain. Opioids are the pharmacologic sine qua non of pain management in life-limiting illness and should be prescribed based on the severity of pain, considering the functional and psychological significance of that severity. Numerous misunderstandings present a barrier to effective pain management. These misconceptions include the idea that opioids are highly addictive, that dependence or tolerance are forms of addiction, that respiratory depression is common with opioids, that opioids have a narrow therapeutic range, and that opioids are ineffective by mouth and cause too much nausea. In reality, opioids are the safest and most effective pain medicine for most moderate to severe pain in most patients. Aspects of basic opioid pharmacology, such as dosage, route of administration, rotation of drugs, and the avoidance of toxicity and complications, should be considered when initiating and maintaining therapy. Failure to pay attention to the basic rules can lead to errors in opioid management. [ABSTRACT FROM AUTHOR]

Thromboembolic disease is a common complication of pancreatic cancer and is causally associated with the generation of an intrinsic hypercoagulable state. Pancreatic-cancer cells activate platelets and express several procoagulant factors, including tissue factor and thrombin. The activation of coagulation is not simply an epiphenomenon, but might also be related to enhanced tumour growth and angiogenesis. Clinical manifestations of thromboembolic disease in pancreatic cancer include deep venous thrombosis, pulmonary embolism, disseminated intravascular coagulation, portal vein thrombosis, and arterial thromboembolism. Reported incidences of disease range from 17% to 57%. Treatment options include warfarin and low-molecular-weight heparins. Studies over the past decade suggest that long-term use of these heparins in both primary and secondary prevention of venous thromboembolic disease improves outcomes in comparison with warfarin. Further research is needed to understand better the morbidity and mortality associated with this disease in pancreatic cancer and to optimise strategies of prevention and treatment. [ABSTRACT FROM AUTHOR]

Ru-MACHO®-BH is an effective catalyst for controlled depolymerization of polybutylene succinate. Under low pressure hydrogen the catalyst produces gamma -butyrolactone via a novel transfer hydrogenation wherein dehydrogenation and hydrogenation deconstruct the polymer chain. Simply increasing the hydrogen pressure selectively generates 1,4-butanediol.

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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 p14 ARF promoter with upstream Ap1 and E2F enhancer elements and a downstream MDR1 inhibitory element, TATA box, and a transcription initiation site (hereafter p14 ARF min). The modified p14 ARF min 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 p21 WAF/CIPI in contrast to other p53-based gene therapies, which can induce cell cycle arrest leading to increased chemotherapy resistance; (3) the modified construct (p14 ARF min-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.

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.

Purpose: To evaluate the recent Otolaryngology-Head and Neck Surgery (OTO-HNS) applicant characteristics, to identify which applicant characteristics are associated with successful match into OTO-HNS, and to compare OTO-HNS applicant trends and characteristics to that of peer surgical specialties (PS)., Materials and Methods: Data were obtained from official reports by the National Residency Matching Program (NRMP) for OTO-HNS, plastic and reconstructive surgery, orthopedic surgery, neurosurgery, and dermatology from 2006 to 2019. Alpha Omega Alpha (AOA) membership, United States Medical Licensing Examination (USMLE) scores, research productivity, graduation from a top-40 NIH-funded U.S. medical school, and additional graduate degree were recorded. Odds ratios (OR) were calculated to evaluate the relationship between applicant qualifications and match success., Results: From 2014 to 2018, the OTO-HNS applicant pool shrunk from 443 to 333, representing the largest drop of all PS. Furthermore, OTO-HNS reported the most unfilled positions and highest match rates in 2017 (n = 14; 92.1%) and 2018 (n = 12; 94.6%) among any PS. Despite recent trends, 2019 NRMP data revealed a 38.74% increase in OTO-HNS applicant numbers compared to 2018. AOA membership (OR, 7.3; P  = .030), USMLE Step 2 scores between 241 and 260 (OR, 6.5; P  = .009), and research productivity (OR, 5.6; P  = .005) significantly increased the odds of matching into OTO-HNS., Conclusions: Despite recent fluctuations in application trends, OTO-HNS continues to successfully match highly qualified applicants, including applicants with AOA membership, high Step 2 scores, and high research productivity. An understanding of the qualifications used to evaluate residency applicants may be helpful to both applicants and residency programs of OTO-HNS.

Over the last decade, the interplay between the gut microbiota, the consortium of intestinal microbes that colonizes intestinal mucosal barriers, and its host immune system has been increasingly better understood. Disruption of the delicate balance between beneficial and pathogenic commensals, known as dysbiosis, contributes to a variety of chronic immunologic and metabolic diseases. Complicating this paradigm are bacterial strains that can operate paradoxically both as instigators and attenuators of inflammatory responses, depending on host background. Here, we review the role of several strains in the genus Lactobacillus within the context of autoimmune and other chronic disorders with a predominant focus on L. reuteri. While strains within this species have been shown to provide immune health benefits, they have also been demonstrated to act as a pathobiont in autoimmune-prone hosts. Beneficial functions in healthy hosts include competing with pathogenic microbes, promoting regulatory T cell development, and protecting the integrity of the gut barrier. On the other hand, certain strains can also break through a dysfunctional gut barrier, colonize internal tissues such as the spleen or liver and promote inflammatory responses in host tissues that lead to autoimmune disease. This review summarizes the manifold roles that these commensals play in the context of health and disease., (© 2020 Elsevier Inc. All rights reserved.)

Humans and other mammalian hosts have evolved mechanisms to control the bacteria colonizing their mucosal barriers to prevent invasion. While the breach of barriers by bacteria typically leads to overt infection, increasing evidence supports a role for translocation of commensal bacteria across an impaired gut barrier to extraintestinal sites in the pathogenesis of autoimmune and other chronic, non-infectious diseases. Whether gut commensal translocation is a cause or consequence of the disease is incompletely defined. Here we discuss factors that lead to translocation of live bacteria across the gut barrier. We expand upon our recently published demonstration that translocation of the gut pathobiont Enterococcus gallinarum can induce autoimmunity in susceptible hosts and postulate on the role of Enterococcus species as instigators of chronic, non-infectious diseases.

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., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Western lifestyle is linked to autoimmune and metabolic diseases, driven by changes in diet and gut microbiota composition. Using Toll-like receptor 7 (TLR7)-dependent mouse models of systemic lupus erythematosus (SLE), we dissect dietary effects on the gut microbiota and find that Lactobacillus reuteri can drive autoimmunity but is ameliorated by dietary resistant starch (RS). Culture of internal organs and 16S rDNA sequencing revealed TLR7-dependent translocation of L. reuteri in mice and fecal enrichment of Lactobacillus in a subset of SLE patients. L. reuteri colonization worsened autoimmune manifestations under specific-pathogen-free and gnotobiotic conditions, notably increasing plasmacytoid dendritic cells (pDCs) and interferon signaling. However, RS suppressed the abundance and translocation of L. reuteri via short-chain fatty acids, which inhibited its growth. Additionally, RS decreased pDCs, interferon pathways, organ involvement, and mortality. Thus, RS exerts beneficial effects in lupus-prone hosts through suppressing a pathobiont that promotes interferon pathways implicated in the pathogenesis of human autoimmunity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: Economics of care for adults with serious illness is a policy priority worldwide. Palliative care may lower costs for hospitalized adults, but the evidence has important limitations., Objective: To estimate the association of palliative care consultation (PCC) with direct hospital costs for adults with serious illness., Data Sources: Systematic searches of the Embase, PsycINFO, CENTRAL, PubMed, CINAHL, and EconLit databases were performed for English-language journal articles using keywords in the domains of palliative care (eg, palliative, terminal) and economics (eg, cost, utilization), with limiters for hospital and consultation. For Embase, PsycINFO, and CENTRAL, we searched without a time limitation. For PubMed, CINAHL, and EconLit, we searched for articles published after August 1, 2013. Data analysis was performed from April 8, 2017, to September 16, 2017., Study Selection: Economic evaluations of interdisciplinary PCC for hospitalized adults with at least 1 of 7 illnesses (cancer; heart, liver, or kidney failure; chronic obstructive pulmonary disease; AIDS/HIV; or selected neurodegenerative conditions) in the hospital inpatient setting vs usual care only, controlling for a minimum list of confounders., Data Extraction and Synthesis: Eight eligible studies were identified, all cohort studies, of which 6 provided sufficient information for inclusion. The study estimated the association of PCC within 3 days of admission with direct hospital costs for each sample and for subsamples defined by primary diagnoses and number of comorbidities at admission, controlling for confounding with an instrumental variable when available and otherwise propensity score weighting. Treatment effect estimates were pooled in the meta-analysis., Main Outcomes and Measures: Total direct hospital costs., Results: This study included 6 samples with a total 133 118 patients (range, 1020-82 273), of whom 93.2% were discharged alive (range, 89.0%-98.4%), 40.8% had a primary diagnosis of cancer (range, 15.7%-100.0%), and 3.6% received a PCC (range, 2.2%-22.3%). Mean Elixhauser index scores ranged from 2.2 to 3.5 among the studies. When patients were pooled irrespective of diagnosis, there was a statistically significant reduction in costs (-$3237; 95% CI, -$3581 to -$2893; P < .001). In the stratified analyses, there was a reduction in costs for the cancer (-$4251; 95% CI, -$4664 to -$3837; P < .001) and noncancer (-$2105; 95% CI, -$2698 to -$1511; P < .001) subsamples. The reduction in cost was greater in those with 4 or more comorbidities than for those with 2 or fewer., Conclusions and Relevance: The estimated association of early hospital PCC with hospital costs may vary according to baseline clinical factors. Estimates may be larger for primary diagnosis of cancer and more comorbidities compared with primary diagnosis of noncancer and fewer comorbidities. Increasing palliative care capacity to meet national guidelines may reduce costs for hospitalized adults with serious and complex illnesses.

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.

Background: Olaparib is an oral inhibitor of polyadenosine 5'-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC)., Patients and Methods: In this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m2 on days 1 and 8 and cisplatin 25 mg/m2 on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m2 on day 1 to this regimen (olaparib plus ICM)., Results: 18 patients with unresectable PDAC were enrolled. The MTD of olaparib plus IC was olaparib 100 mg twice-daily on days 1 and 8. The addition of mitomycin C to this dose level was not tolerated. Grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities included neutropenia (89%), lymphopenia (72%), and anemia (22%). Two patients (11%), both of whom had remained on study for more than 12 cycles, developed drug-related myelodysplastic syndrome (MDS). The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years, but died from complications of treatment-related MDS., Conclusions: Olaparib had substantial toxicity when combined with IC or ICM in patients with PDAC, and this treatment combination did not have an acceptable risk/benefit profile for further study. However, durable clinical responses were observed in a subset of patients and further clinical investigation of PARP inhibitors in PDAC is warranted., Trial Registration: This clinical trial was registered on ClinicalTrials.gov as NCT01296763.

Barriers to traditional advance care planning (ACP) and advance directive (AD) creation have limited the promise of ACP/AD for individuals and families, the healthcare team, and society. Our objectives were to determine the results of a digital ACP/AD through which consumers create, store, locate, and retrieve their ACP/AD at no charge and with minimal physician involvement, and the ACP/AD can be integrated into the electronic health record. The authors chose 900 users of MyDirectives, a digital ACP/AD tool, to achieve proportional representation of all 50 states by population size and then reviewed their responses. The 900 participants had an average age of 50.8 years (SD = 16.6); 84% of the men and 91% of the women were in self-reported good health when signing their ADs. Among the respondents, 94% wanted their physicians to consult a supportive and palliative care team if they were seriously ill; nearly 85% preferred cessation of life-sustaining treatments during their final days; 76% preferred to spend their final days at home or in a hospice; and 70% would accept attempted cardiopulmonary resuscitation in limited circumstances. Most respondents wanted an autopsy under certain conditions, and 62% wished to donate their organs. In conclusion, analysis of early experience with this ACP/AD platform demonstrates that individuals of different ages and conditions can engage in an interrogatory process about values, develop ADs that are more nuanced than traditional paper-based ADs in reflecting those values, and easily make changes to their ADs. Online ADs have the potential to remove barriers to ACP/AD and thus further improve patient-centered end-of-life care.

Purpose: GVAX pancreas, granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes-expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma., Patients and Methods: Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response., Results: A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm., Conclusion: Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity., (© 2015 by American Society of Clinical Oncology.)

Aims: While overexpression of TGFα has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGFα develop premalignant pancreatic acinar-to-ductal metaplasia (ADM) but not PDAC. TGF-β signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGFα and TGF-β signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation., Methods: The MT-TGFα mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4flox/flox;p48-Cre or S4) to generate Smad4flox/flox;MT-TGFα;p48-Cre (STP). After TGFα overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGFα, and S4 mice were examined for tumor development and fibrotic responses. PanIN lesions and number of ducts were counted, and proliferation was measured by Ki67 immunohistochemistry (IHC). Qualitative analysis of fibrosis was analyzed by Trichrome Masson and Sirius Red staining, while vimentin was used for quantification. Expression analyses of fibrosis, pancreatitis, or desmoplasia associated markers (α-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR., Results: Our STP mice exhibited advanced ADM, increased fibrosis, increased numbers of PanIN lesions, overexpression of chronic pancreatitis-related marker Muc6, and elevated expression of desmoplasia-associated marker Col1A1, compared to the MT-TGFα mice. The inactivation of Smad4 in the exocrine compartment was responsible for both the enhanced PanIN formation and fibrosis in the pancreas. The phenotype of the STP mice represents a transient state from ADMs to PanINs, closely mimicking the interface area seen in human chronic pancreatitis associated with PDAC., Conclusion: We have documented a novel mouse model, the STP mice, which displayed histologic presentations reminiscent to those of human chronic pancreatitis with signs of early tumorigenesis. The STP mice could be a suitable animal model for interrogating the transition of chronic pancreatitis to pancreatic cancer.

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., (© 2014 American Cancer Society.)

Objectives: To quantify the cost savings of palliative care (PC) and identify differences in savings according to team structure, patient diagnosis, and timing of consult., Data Sources: Hospital administrative records on all inpatient stays at five hospital campuses from January 2009 through June 2012., Study Design: The analysis matched PC patients to non-PC patients (separately by discharge status) using propensity score methods. Weighted generalized linear model regressions of hospital costs were estimated for the matched groups., Data Collection: Data were restricted to patients at least 18 years old with inpatient stays of between 7 and 30 days. Variables available included patient demographics, primary and secondary diagnoses, hospital costs incurred for the inpatient stay, and when/if the patient had a PC consult., Principal Findings: We found overall cost savings from PC of $3,426 per patient for those dying in the hospital. No significant cost savings were found for patients discharged alive; however, significant cost savings for patients discharged alive could be achieved for certain diagnoses, PC team structures, or if consults occurred within 10 days of admission., Conclusions: Appropriately selected and timed PC consults with physician and RN involvement can help ensure a financially viable PC program via cost savings to the hospital., (© Health Research and Educational Trust.)

Background and Importance: Rarely, corticotrophic pituitary tumors take on an aggressive form characterized by rapid growth, invasion into local structures, compression of cranial nerves, and possible spread to distant sites. When conventional surgery, radiation therapy, and hormones fail to control progression and symptoms, alternative therapies are needed. A novel chemotherapeutic regimen of capecitabine and temozolomide (CAPTEM), originally designed in our laboratory, demonstrated dramatic antineoplastic effects against corticotrophic pituitary tumors., Clinical Presentation: We present a case series of 4 patients with aggressive, adrenocorticotrophic hormone--producing pituitary tumors who had previously depleted all surgical, radiation, and hormonal therapies and were then treated with CAPTEM. Dramatic clinical improvements in neurological deficits and Cushing symptoms were evident in all patients after treatment was initiated. Confirmed by radiographic imaging, 2 of 4 patients demonstrated complete regression of disease, 1 patient had a 75% regression, and the fourth patient has ongoing stable disease for > 4.5 years at the time of this writing. Immunohistochemical analysis of patients' tumor samples showed low O-methyguanyl methyltransferase expression and adequate levels of mismatch repair enzymes (MLH-1, MSH-2, MSH-6, and PMS-2), which are important for the in vivo efficacy of CAPTEM., Conclusion: This is the first report of prolonged antitumor response to and radiographic complete remissions as a result of CAPTEM in patients with aggressive pituitary tumors who had exhausted all other therapies.

Pancreatic cancer cell lines with mutated ras underwent an alternative form of cell death (aponecrosis) when treated concomitantly with clinically achievable concentrations of arsenic trioxide, ascorbic acid, and disulfiram (Antabuse; AAA). AAA's major effects are mediated through generation of intracellular reactive oxygen species (ROS) and more than 50% decline in intracellular ATP. N-acetyl cysteine and a superoxide dismutase mimetic prevented aponecrosis and restored intracellular ATP levels. DIDS (4,4'-diisothiocyanatostilbene-2, 2' disulfonic acid), the pan- Voltage-Dependent Anion Channel (VDAC), -1, 2, 3 inhibitor and short hairpin RNA (shRNA) to VDAC-1 blocked cell death and ROS accumulation. In vivo exposure of AAA led to a 62% reduction in mean tumor size and eliminated tumors in 30% of nude mice with PANC-1 xenografts. We concluded that early caspase-independent apoptosis was shifted to VDAC-mediated "targeted" aponecrosis by the addition of disulfiram to arsenic trioxide and ascorbic acid. Conceptually, this work represents a paradigm shift where switching from apoptosis to aponecrosis death pathways, also known as targeted aponecrosis, could be utilized to selectively kill pancreatic cancer cells resistant to apoptosis., (©2013 AACR.)

Background: Pancreatic cancer is an aggressive disease which metastasizes readily. The presence of brain metastases from pancreatic cancer is rare and it carries a poor prognosis. Our approach to treating these lesions stresses extensive use of stereotactic radiosurgery (SRS), whereas other reports focus on surgical resection., Case Report: Information regarding the patient's clinical history was extracted from a retrospective review of the medical records and imaging studies. The patient survived seven years after his primary diagnosis of pancreatic cancer, and 36 months after diagnosis of metastatic disease to the brain. In addition to surgical resection and the use of multiple chemotherapeutic agents, the patient received six separate radiosurgery treatments., Conclusion: We present a case of brain metastasis from pancreatic cancer that is remarkable for an unusually long survivorship and discuss the utility of SRS along with a multimodality treatment approach for dealing with these cases.

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.

Purpose: We evaluated the efficacy and safety of capecitabine and temozolomide (CAPTEM) in patients with metastatic neuroendocrine tumors (NETs) to the liver. This regimen was based on our studies with carcinoid cell lines that showed synergistic cytotoxicity with sequence-specific dosing of 5-fluorouracil preceding temozolomide (TMZ)., Methods: A retrospective review was conducted of 18 patients with NETs metastatic to the liver who had failed 60 mg/month of Sandostatin LAR™ (100%), chemotherapy (61%), and hepatic chemoembolization (50%). Patients received capecitabine at 600 mg/m(2) orally twice daily on days 1-14 (maximum 1,000 mg orally twice daily) and TMZ 150-200 mg/m(2) divided into two doses daily on days 10-14 of a 28-day cycle. Imaging was performed every 2 cycles, and serum tumor markers were measured every cycle., Results: Using RECIST parameters, 1 patient (5.5%) with midgut carcinoid achieved a surgically proven complete pathological response (CR), 10 patients (55.5%) achieved a partial response (PR), and 4 patients (22.2%) had stable disease (SD). Total response rate was 61%, and clinical benefit (responders and SD) was 83.2%. Of four carcinoid cases treated with CAPTEM, there was 1 CR, 1 PR, 1 SD, and 1 progressive disease. Median progression-free survival was 14.0 months (11.3-18.0 months). Median overall survival from diagnosis of liver metastases was 83 months (28-140 months). The only grade 3 toxicity was thrombocytopenia (11%). There were no grade 4 toxicities, hospitalizations, opportunistic infections, febrile neutropenias, or deaths., Conclusions: CAPTEM is highly active, well tolerated and may prolong survival in patients with well-differentiated, metastatic NET who have progressed on previous therapies.

The use of fluorescent probes can be an easy and quick method to analyze whether or not reactive oxygen species (ROS) are involved in a particular cellular process or the result of a particular drug treatment. ROS activate a variety of cell signaling and death pathways including apoptosis and necrosis (Raha and Robinson. Am J Med Gen 106:62-70, 2001). Here we describe a number of different probes, their specificities, advantages and limitations, as well as useful techniques important for their use.

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., (Copyright © 2012 S. Karger AG, Basel.)

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.

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.

Background: Convection-enhanced delivery of chemotherapeutics for the treatment of malignant glioma is a technique that delivers drugs directly into a tumor and the surrounding interstitium through continuous, low-grade positive-pressure infusion. This allows high local concentrations of drug while overcoming the limitations imposed by toxicity and the blood-brain barrier in systemic therapies that prevent the use of many potentially effective drugs., Objective: To examine the safety profile of a conventional chemotherapeutic agent, topotecan, via convection-enhanced delivery in the treatment of recurrent malignant gliomas and secondarily to assess radiographic response and survival., Methods: We performed a prospective, dose-escalation phase Ib study of the topoisomerase-I inhibitor topotecan given by convection-enhanced delivery in patients with recurrent malignant gliomas., Results: Significant antitumor activity as described by radiographic changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated. A maximum tolerated dose was established for future phase II studies., Conclusion: Topotecan by convection-enhanced delivery has significant antitumor activity at concentrations that are nontoxic to normal brain. The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and III trials.

Background: Several human studies have demonstrated the feasibility of intra-arterial delivery of mitoxantrone in systemic malignancies. Computational models predict that an intra-arterial bolus injection of mitoxantrone during transient cerebral hypoperfusion will enhance brain tissue drug deposition in comparison with injections during normal blood flow., Objective: To assess whether transient reduction in cerebral blood flow would enhance the delivery of mitoxantrone. This is accomplished by obtaining real-time measurements of mitoxantrone concentrations in brain tissues by using a novel optical pharmacokinetics technique, based on reflectance spectroscopy., Methods: The blood-brain barrier of anesthetized rabbits was disrupted by intracarotid injection of mannitol (8 mL, 25% over 40 seconds). Thereafter, animals received 3 mg of mitoxantrone injection during normal perfusion (n = 5) or cerebral hypoperfusion that was induced by contralateral arterial occlusion and systemic hypotension (n = 8)., Results: Cerebral hypoperfusion significantly decreased the cerebral blood flow, allowing a longer exposure time of the drug. It was determined that therapeutic concentrations of mitoxantrone were achieved in both groups; however, hypoperfusion did not increase the tissue concentrations of mitoxantrone after 20 minutes., Conclusion: These results demonstrate the effective delivery of mitoxantrone by the intra-arterial route, after blood-brain-barrier disruption, but the predicted benefits of flow reduction for improving intra-arterial deposition of mitoxantrone was not evident.

Dendritic-cell (DC) targeted antigen delivery systems hold promise for enhancing vaccine efficacy and delivery of therapeutics. However, it is not known how the number and density of targeting ligands on such systems may affect DC function and subsequent T cell response. We modified the surface of biodegradable nanoparticles loaded with antigen with different densities of the mAb to the DC lectin DEC-205 receptor and assessed changes in the cytokine response of DCs and T cells. DEC-205 targeted nanoparticles unexpectedly induced a differential cytokine response that depended on the density of ligands on the surface. Strikingly, nanoparticle surface density of DEC-205 mAb increased the amount of anti-inflammatory, IL-10, produced by DCs and T cells. Boosting mice with DEC-205 targeted OVA-nanoparticles after immunization with an antigen in CFA induced a similar pattern of IL-10 response. The correlation between DC production of IL-10 as a function of the density of anti-DEC-205 is shown to be due to cross-linking of the DEC-205 receptor. Cross-linking also increased DC expression of the scavenger receptor CD36, and blockade of CD36 largely abrogated the IL-10 response. Our studies highlight the importance of target ligand density in the design of vaccine delivery systems., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Isothiocyanates (ITCs) derived from cruciferous vegetables induce apoptosis in cancer cells. We demonstrate that certain naturally occurring ITCs selectively deplete mutant p53 but not the wild-type and do so via a transcription-independent mechanism. Direct p53 binding followed by conformational changes appears to be a mechanism by which mutant p53 is depleted. Structure-activity relationship studies (SARs) using naturally occurring and synthetic ITCs show that depletion is influenced by the ITC side-chain moiety. Furthermore, we show that cells with p53 mutations are more sensitive to cytotoxicity induced by phenethyl isothiocyanate (PEITC) than those with the wild-type protein. 2,2-Diphenylethyl ITC, a synthetic ITC, is one of the most potent depletors of mutant p53 studies and induces apoptosis to the greatest extent in mutant p53 breast cancer cells. Collectively, this study shows that mutant p53 depletion may be an important novel target for cancer chemoprevention and therapy by natural and synthetic ITCs.

Background: Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In vitro data indicate that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines. The authors retrospectively evaluated the efficacy of capecitabine and temozolomide in 30 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS), and overall survival (OS)., Methods: Patients with metastatic, well, or moderately differentiated pancreatic endocrine carcinomas who had not received prior systemic chemotherapy were treated with capecitabine (750 mg/m² twice daily, days 1-14) and temozolomide (200 mg/m² once daily, days 10-14) every 28 days., Results: Among 30 patients treated, 21 (70%) patients achieved an objective radiographic response. Median progression-free survival was 18 months. The rate of survival at two years was 92%. Only 4 patients (12%) experienced grade 3 or 4 adverse events., Conclusions: The combination of capecitabine and temozolomide is associated with an exceptionally high and durable response rate in metastatic endocrine carcinomas of the pancreas. Clinical endpoints, including response rate, survival, and toxicity, are superior to those observed with streptozocin-based regimens., (Copyright © 2010 American Cancer Society.)

Purpose: Pancreatic cancer is a virtually uniformly fatal disease. We aimed to determine if screening to identify curable neoplasms is effective when offered to patients at high risk., Experimental Design: Patients at high risk of pancreatic cancer were prospectively enrolled into a screening program. Endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and genetic testing were offered by a multidisciplinary team according to each patient's risk., Results: Fifty-one patients in 43 families were enrolled, with mean age of 52 years, 35% of whom were male. Of these patients, 31 underwent EUS and 33 MRI. EUS revealed two patients with pancreatic cancer (one resectable, one metastatic), five with intraductal papillary mucinous neoplasms (IPMN), seven with cysts, and six with parenchymal changes. Five had pancreatic surgery (one total pancreatectomy for pancreatic cancer, three distal and one central pancreatectomy for pancreatic intraepithelial neoplasia 2 and IPMN). A total of 24 (47%) had genetic testing (19 for BRCA1/2 mutations, 4 for CDKN2A, 1 for MLH1/MSH2) and 7 were positive for BRCA1/2 mutations. Four extrapancreatic neoplasms were found: two ovarian cancers on prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy, one carcinoid, and one papillary thyroid carcinoma. Overall, 6 (12%) of the 51 patients had neoplastic lesions in the pancreas and 9 (18%) had neoplasms in any location. All were on the initial round of screening. All patients remain alive and without complications of screening., Conclusions: Pancreatic cancer screening for high-risk patients with a comprehensive strategy of imaging and genetics is effective and identifies curable neoplasms that can be resected. Ongoing study will better define who will benefit from screening and what screening strategy will be the most effective., (©2010 AACR.)

The practice of palliative care typically refers to the focus of treatment as the patient and family. Tending to the needs of both patients and their families is usually good, but what should clinicians do when they perceive the best interests, needs, or treatment preferences of the patient are in conflict with those of the family or other surrogate? Physicians may be able to suppress the inevitable moral cognitive dissonance of such circumstances, write orders, and walk away, but other health care professionals, especially nurses, may not have it so easy. This article suggests practical steps to obviate conflict in such circumstances before offering an ethical analysis focusing on notions of autonomy, beneficence, and true caring for patients, especially those near the end of life. The limitations of surrogate decision makers are considered and legal liability concerns are briefly explored, ultimately leading to the conclusion that keeping the patient at the center is sine qua non of patient- and family-centered care., (Copyright © 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

PURPOSE Conventional medicine has had little to offer patients with inoperable pancreatic adenocarcinoma; thus, many patients seek alternative treatments. The National Cancer Institute, in 1998, sponsored a randomized, phase III, controlled trial of proteolytic enzyme therapy versus chemotherapy. Because most eligible patients refused random assignment, the trial was changed in 2001 to a controlled, observational study. METHODS All patients were seen by one of the investigators at Columbia University, and patients who received enzyme therapy were seen by the participating alternative practitioner. Of 55 patients who had inoperable pancreatic cancer, 23 elected gemcitabine-based chemotherapy, and 32 elected enzyme treatment, which included pancreatic enzymes, nutritional supplements, detoxification, and an organic diet. Primary and secondary outcomes were overall survival and quality of life, respectively. Results At enrollment, the treatment groups had no statistically significant differences in patient characteristics, pathology, quality of life, or clinically meaningful laboratory values. Kaplan-Meier analysis found a 9.7-month difference in median survival between the chemotherapy group (median survival, 14 months) and enzyme treatment groups (median survival, 4.3 months) and found an adjusted-mortality hazard ratio of the enzyme group compared with the chemotherapy group of 6.96 (P < .001). At 1 year, 56% of chemotherapy-group patients were alive, and 16% of enzyme-therapy patients were alive. The quality of life ratings were better in the chemotherapy group than in the enzyme-treated group (P < .01). CONCLUSION Among patients who have pancreatic cancer, those who chose gemcitabine-based chemotherapy survived more than three times as long (14.0 v 4.3 months) and had better quality of life than those who chose proteolytic enzyme treatment.

Background: Germline mutations at the INK4a/p16 locus are implicated in several human cancer syndromes, including familial atypical multiple mole melanoma (FAMMM) syndrome, FAMMM-pancreatic cancer (FAMMM-PC) syndrome, and in familial head and neck cancer syndrome., Methods: We present an individual with a family history of melanoma and pancreatic cancer who had multiple dysplastic nevi, squamous cell carcinoma of the tongue at age 22, multiple melanomas, a second squamous cell cancer of the tongue at age 40, and ultimately a pancreatic cancer., Results: We demonstrate a germline mutation in INK4a and loss of heterozygosity at this locus in his HNSCC tissue., Conclusions: This report suggests that INK4a germline mutations associated with FAMMM/FAMMM-PC can also be associated with HNSCC. We conclude that HNSCC in young individuals should prompt clinicians to obtain a family history and consider that the patient may have a germline p16 defect that could predispose them to other cancers, including melanoma and pancreatic cancer., ((c) 2009 Wiley Periodicals, Inc. Head Neck, 2009.)