New-onset diabetes is a predictive risk factor for pancreatic lesions in high-risk individuals: An observational cohort study.

Background and Objectives: Pancreatic cancer (PC) is the third cause of cancer-related deaths. Early detection and interception of premalignant pancreatic lesions represent a promising strategy to improve outcomes. We evaluated risk factors of focal pancreatic lesions (FPLs) in asymptomatic individuals at hereditary high risk for PC. Methods: This is an observational single-institution cohort study conducted over a period of 5 years. Surveillance was performed through imaging studies (EUS or magnetic resonance imaging/magnetic resonance cholangiopancreatography) and serum biomarkers. We collected demographic characteristics and used univariate and multivariate logistic regression models to evaluate associations between potential risk factors and odd ratios (ORs) for FPL development. Results: A total of 205 patients completed baseline screening. Patients were followed up to 53 months. We detected FPL in 37 patients (18%) at baseline; 2 patients had lesions progression during follow-up period, 1 of them to PC. Furthermore, 13 patients developed new FPLs during the follow-up period. Univariate and multivariate analyses revealed that new-onset diabetes (NOD) is strongly associated with the presence of FPL (OR, 10.94 [95% confidence interval, 3.01-51.79; P < 0.001]; OR, 9.98 [95% confidence interval, 2.15-46.33; P = 0.003]). Follow-up data analysis revealed that NOD is also predictive of lesions progression or development of new lesions during screening (26.7% vs. 2.6%; P = 0.005). Conclusions: In a PC high-risk cohort, NOD is significantly associated with presence of FPL at baseline and predictive of lesions progression or new lesions during surveillance.

Germline Testing Identifies Pathogenic/Likely Pathogenic Variants in Patients with Pancreatic Neuroendocrine Tumors.

Ten percent of pancreatic neuroendocrine tumors (pNET) are related to inherited syndromes (MEN1, MEN4, VHL, NF1, and TSC). Growing evidence suggests that clinically sporadic pNETs can also harbor germline pathogenic variants. In this study, we report the prevalence of pathologic/likely pathologic (P/LP) germline variants in a high-risk cohort and an unselected cohort. We collected clinical data of patients with pNETs seen at MD Anderson Cancer Center and Johns Hopkins Hospital. The high-risk cohort included (n = 132) patients seen at MD Anderson Cancer Center who underwent germline testing for high-risk criteria (early onset, personal or family history of cancer, and syndromic features) between 2013 and 2019. The unselected cohort included (n = 106) patients seen at Johns Hopkins Hospital who underwent germline testing following their diagnosis of pNETs between 2020 and 2022. In the high-risk cohort (n = 132), 33% (n = 44) had P/LP variants. The majority of the patients had P/LP variants in MEN1 56% (n = 25), followed by DNA repair pathways 18% (n = 8), and 7% (n = 3) in MSH2 (Lynch syndrome). Patients with P/LP were younger (45 vs. 50 years; P = 0.002). In the unselected cohort (n = 106), 21% (n = 22) had P/LP. The majority were noted in DNA repair pathways 40% (n = 9) and MEN1 36% (n = 8). Multifocal tumors correlated with the presence of P/LP (P = 0.0035). MEN1 germline P/LP variants correlated with younger age (40 vs. 56 years; P = 0.0012), presence of multifocal tumors (P < 0.0001), and World Health Organization grade 1 histology (P = 0.0078). P/LP variants are prevalent in patients with clinically sporadic pNET irrespective of high-risk features. The findings support upfront universal germline testing in all patients with pNET. Prevention Relevance: Here, we present germline data from the largest reported cohort of patients with pNET (n = 238), comprising both a high-risk cohort and an unselected cohort. In both cohorts, we identify a high number of P/LPs, including those in the DNA repair pathway. Our findings support universal germline testing in patients with pNET.

Impact of high neutrophil-to-lymphocyte ratio on survival in hospitalized cancer patients with COVID-19.

Neutrophil-to-lymphocyte ratio (NLR) has been studied as a prognostic factor for mortality in COVID-19 patients. Our study aimed to evaluate the association between NLR at COVID-19 diagnosis and survival during the following 90 days in hospitalized patients with solid cancer. Between May 2020 and June 2021, 120 patients were included in a retrospective cohort study. Univariable analysis showed patients with an NLR > 8.3 were associated with an increased risk of death (HR: 4.34; 95% CI: 1.74-10.84) compared to patients with NLR < 3.82 and with NLR ≥3.82 and ≤8.30 (HR: 2.89; 95% CI: 1.32-6.36). Furthermore, on multivariable analysis, NLR > 8.30 independently correlated with increased mortality. In patients with solid malignancies with COVID-19, an NLR > 8.3 is associated with an increased risk of death.

The Evolving Paradigm of Germline Testing in Pancreatic Ductal Adenocarcinoma and Implications for Clinical Practice.

Identification of deleterious germline mutations in pancreatic ductal adenocarcinoma (PDAC) patients can have therapeutic implications for the patients and result in cascade testing and prevention in their relatives. Universal testing for germline mutations is now considered standard of care in patients with PDAC, regardless of family history, personal history, or age. Here, we highlight the commonly identified germline mutations in PDAC patients as well as the impact of multigene panel testing. We further discuss therapeutic implications of germline testing on the index cases, and the impact of cascade testing on cancer early detection and prevention in relatives.

Genetics of Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (pNETs) represent a relatively rare disease; however, the incidence has been increasing during the last 2 decades. Next generation sequencing has greatly increased our understanding of driver mutations in pNETs. Sporadic pNETs have consistently presented with mutations in MEN1, DAXX/ATRX, and genes related to the mammalian target of rapamycin pathway. Inherited pNETs have traditionally been associated with multiple endocrine neoplasia type 1, von Hippel-Lindau syndrome, neurofibromatosis type 1, and tuberous sclerosis complex. The current review expands on the existing knowledge and the relevant updates on the genetics of pNETs.

Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer.

Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα+ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.

Mechanisms of Antitumor Immunity and Immunosurveillance.

The immune system has a well-defined role in all stages of carcinogenesis. The current chapter presents a discussion of various constituents of immunity involved in tumorigenesis along with their mechanisms, forming the basis for immunoprevention and immunotherapy.

Targets and Strategies for Cancer Immunoprevention.

The immune system plays a key role in cancer prevention, initiation, and progression. Antitumoral immune responses can be boosted by harnessing antitumorigenic immune activators and/or blocking tumorigenic proinflammatory factors. Here we define these targets as well as the strategies that could be developed for effective cancer immunoprevention.

Antibiotic use influences outcomes in advanced pancreatic adenocarcinoma patients.

Recent studies defined a potentially important role of the microbiome in modulating pancreatic ductal adenocarcinoma (PDAC) and responses to therapies. We hypothesized that antibiotic usage may predict outcomes in patients with PDAC. We retrospectively analyzed clinical data of patients with resectable or metastatic PDAC seen at MD Anderson Cancer from 2003 to 2017. Demographic, chemotherapy regimen and antibiotic use, duration, type, and reason for indication were recorded. A total of 580 patients with PDAC were studied, 342 resected and 238 metastatic patients, selected retrospectively from our database. Antibiotic use, for longer than 48 hrs, was detected in 209 resected patients (61%) and 195 metastatic ones (62%). On resectable patients, we did not find differences in overall survival (OS) or progression-free survival (PFS), based on antibiotic intake. However, in the metastatic cohort, antibiotic consumption was associated with a significantly longer OS (13.3 months vs. 9.0 months, HR 0.48, 95% CI 0.34-0.7, p = 0.0001) and PFS (4.4 months vs. 2 months, HR 0.48, 95% CI 0.34-0.68, p = <0.0001). In multivariate analysis, the impact of ATB remained significant for PFS (HR 0.59, p = 0.005) and borderline statistically significant for OS (HR 0.69, p = 0.06). When we analyzed by chemotherapy regimen, we found that patients who received gemcitabine-based chemotherapy as first-line therapy (n = 118) had significantly prolonged OS (HR 0.4, p 0.0013) and PFS (HR 0.55, p 0.02) if they received antibiotics, while those receiving 5FU-based chemotherapy (n = 98) had only prolonged PFS (HR 0.54, p = 0.03). Antibiotics-associated modulation of the microbiome is associated with better outcomes in patients with metastatic PDAC.

Autoimmune Hemolytic Anemia as Presenting Symptom of Hodgkin Lymphoma.

Autoimmune hemolytic anemia (AIHA) is related to an underlying condition in an estimated 50 to 60%, while the remaining is idiopathic, as a result of a combination of immune activation, deficiency, or dysregulation. AIHA is associated with viral infections, autoimmune disorders, immunodeficiencies, lymphoproliferative disorders, and pregnancy. AIHA has predictive properties and may be a harbinger of future lymphoproliferative disorders in up to 20% of AIHA cases. Autoimmune hemolytic anemia (AIHA) has been associated with lymphoproliferative disorders particularly chronic lymphocytic leukemia and non-Hodgkin lymphoma. Rarely is it seen in Hodgkin disease. In the following report, we describe the presentation of AIHA, ultimately resulting in the diagnosis of nodular sclerosis Hodgkin lymphoma (stage III). From the limited reports and reviews available, it is understood that advanced Hodgkin (stage III or IV) of nodular sclerosis (NS) or mixed cellularity (MC) types portend a stronger affiliation to AIHA. The majority of AIHA-associated Hodgkin lymphoma presents as stage III or IV disease with the hemolysis being the presenting symptom, as in this case. The mainstay of AIHA therapy has been corticosteroids; however, this first-line regimen appears to be less effective when treating AIHA in the setting of HL. The exact mechanism of AIHA related to HL is unclear, and it may be thought to be that tumor cell produced autoantibodies. Other hypotheses include paraneoplastic phenomena or more, perhaps immunity to tumor cells may cross-react with antigens on the red cells. Although these mechanisms require further investigation, the relationship of the AIHA and HL represents a piece to a larger puzzle between autoimmune disorders and lymphoproliferative conditions.

Modified gemcitabine plus nab-paclitaxel regimen in advanced pancreatic ductal adenocarcinoma.

BACKGROUND: Gemcitabine (GEM) plus nab-paclitaxel (NabP) (GEM 1000 mg/m2 IV over 30 minutes + NabP 125 mg/m2 IV given days 1, 8, and 15 every 28 days) is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC). Our cancer center has utilized GEM-NabP given every two-weeks due to tolerability and patient convenience. Here, we review the safety and efficacy of this modified regimen. METHODS: Metastatic PDAC patients (pts) who initiated front-line or second-line GEM-NabP during 2013-2017 were retrospectively reviewed. Primary objective was overall survival. Secondary objectives were disease control rate, progression-free survival, and the incidence of dose delays and/or adjustments. RESULTS: From a total of 235 patients, 140 pts received GEM-NabP front-line while 95 pts received GEM-NabP second-line. Median dosing was 600 mg/m2 at fixed-dose rate for GEM and 125 mg/m2 for NabP given predominantly (~90%) every two-weeks. Eastern Cooperative Group performance status of 0 and 1 pts had front-line OS of 12.7 and 9.6 months and when given second-line had OS of 8 months and 7.3 months, respectively. ECOG 0 and 1 pts had front-line progression-free survival (PFS) of 5.3 months and 2.8 months and second-line PFS was 3.5 months and 2.4 months, respectively. Treatment was well tolerated with limited dose modifications. CONCLUSION: Our analysis revealed safety with every two-week low dose GEM-NabP while maintaining efficacy. Patient schedule convenience should factor into metastatic incurable malignancies. We suggest the use of every two-week GEM-NabP particularly in patients desiring a modified schedule.

Current Imaging Modalities for assessing Ocular Blood Flow in Glaucoma.

Glaucoma may be caused by an interplay of elevated intraocular pressure (IOP), vascular, genetic, anatomical, brain, and immune factors. The direct assessment of ocular hemodynam-ics offers promise for glaucoma detection, differentiation, and possibly new treatment modalities. All the methods currently in use to measure ocular blood flow have inherent limitations and measure different aspects of ocular blood flow. This review article attempts to provide detailed information on ocular perfu-sion pressure as well as an overview of the newly developed imaging technologies used to investigate ocular blood flow in glaucoma patients. HOW TO CITE THIS ARTICLE: Mohindroo C, Ichhpujani P, Kumar S. Current Imaging Modalities for assessing Ocular Blood Flow in Glaucoma. J Curr Glaucoma Pract 2016;10(3):104-112.

Aqueous Angiography with Fluorescein and Indocyanine Green in Bovine Eyes.

PURPOSE: We characterize aqueous angiography as a real-time aqueous humor outflow imaging (AHO) modality in cow eyes with two tracers of different molecular characteristics. METHODS: Cow enucleated eyes (n = 31) were obtained and perfused with balanced salt solution via a Lewicky AC maintainer through a 1-mm side-port. Fluorescein (2.5%) or indocyanine green (ICG; 0.4%) were introduced intracamerally at 10 mm Hg individually or sequentially. With an angiographer, infrared and fluorescent images were acquired. Concurrent anterior segment optical coherence tomography (OCT) was performed, and fixable fluorescent dextrans were introduced into the eye for histologic analysis of angiographically positive and negative areas. RESULTS: Aqueous angiography in cow eyes with fluorescein and ICG yielded high-quality images with segmental patterns. Over time, ICG maintained a better intraluminal presence. Angiographically positive, but not negative, areas demonstrated intrascleral lumens with anterior segment OCT. Aqueous angiography with fluorescent dextrans led to their trapping in AHO pathways. Sequential aqueous angiography with ICG followed by fluorescein in cow eyes demonstrated similar patterns. CONCLUSIONS: Aqueous angiography in model cow eyes demonstrated segmental angiographic outflow patterns with either fluorescein or ICG as a tracer. TRANSLATIONAL RELEVANCE: Further characterization of segmental AHO with aqueous angiography may allow for intelligent placement of trabecular bypass minimally invasive glaucoma surgeries for improved surgical results.

Aqueous Humor Outflow Structure and Function Imaging At the Bench and Bedside: A Review.

Anterior segment glaucoma clinical care and research has recently gained new focus because of novel imaging modalities and the advent of angle-based surgical treatments. Traditional investigation drawn to the trabecular meshwork now emphasizes the entire conventional aqueous humor outflow (AHO) pathway from the anterior chamber to the episcleral vein. AHO investigation can be divided into structural and functional assessments using different methods. The historical basis for studying the anterior segment of the eye and AHO in glaucoma is discussed. Structural studies of AHO are reviewed and include traditional pathological approaches to modern tools such as multi-model two-photon microscopy and optical coherence tomography. Functional assessment focuses on visualizing AHO itself through a variety of non-real-time and real-time techniques such as aqueous angiography. Implications of distal outflow resistance and segmental AHO are discussed with an emphasis on melding bench-side research to viable clinical applications. Through the development of an improved structure: function relationship for AHO in the anterior segment of the normal and diseased eye, a better understanding of the eye with improved therapeutics may be developed.

Aqueous Angiography-Mediated Guidance of Trabecular Bypass Improves Angiographic Outflow in Human Enucleated Eyes.

PURPOSE: To assess the ability of trabecular micro-bypass stents to improve aqueous humor outflow (AHO) in regions initially devoid of AHO as assessed by aqueous angiography. METHODS: Enucleated human eyes (14 total from 7 males and 3 females [ages 52-84]) were obtained from an eye bank within 48 hours of death. Eyes were oriented by inferior oblique insertion, and aqueous angiography was performed with indocyanine green (ICG; 0.4%) or fluorescein (2.5%) at 10 mm Hg. With an angiographer, infrared and fluorescent images were acquired. Concurrent anterior segment optical coherence tomography (OCT) was performed, and fixable fluorescent dextrans were introduced into the eye for histologic analysis of angiographically positive and negative areas. Experimentally, some eyes (n = 11) first received ICG aqueous angiography to determine angiographic patterns. These eyes then underwent trabecular micro-bypass sham or stent placement in regions initially devoid of angiographic signal. This was followed by fluorescein aqueous angiography to query the effects. RESULTS: Aqueous angiography in human eyes yielded high-quality images with segmental patterns. Distally, angiographically positive but not negative areas demonstrated intrascleral lumens on OCT images. Aqueous angiography with fluorescent dextrans led to their trapping in AHO pathways. Trabecular bypass but not sham in regions initially devoid of ICG aqueous angiography led to increased aqueous angiography as assessed by fluorescein (P = 0.043). CONCLUSIONS: Using sequential aqueous angiography in an enucleated human eye model system, regions initially without angiographic flow or signal could be recruited for AHO using a trabecular bypass stent.

How 'Drug Aware' are our Glaucoma Patients?

BACKGROUND: Poor knowledge, attitude and self-care practices (KAP) as regards medication compliance is a major concern in the management of glaucoma. This study aims to evaluate the knowledge, attitude regarding eyedrop instillation and self-care practices pertaining to eyedrops in diagnosed glaucoma patients. METHODS: In this cross-sectional, open-ended questionnaire-based study, 101 consecutive glaucoma patients on medication were recruited from an urban tertiary care hospital of North India. A self-designed 10-point KAP questionnaire that addressed patient-, medication-, environment- and physicians related factors was used. For each desirable answer, the participant gives a score of 1 was given and for each undesirable answer a score of '0' was given for each question. The total scores for each domain were calculated separately along with the total score. The association between the individual domain scores, the total score and various sociodemographic parameters were compared using unpaired t-test. Analysis of variance (ANOVA) test was used to compare the means, where the exposure variable had more than two categories. RESULTS: Out of 101 participants, 98% knew the reason why they were instilling the medicine. Only 61.4% subjects knew that the eyedrops should be stored in cool and dry place. Nearly 30% participants believed that two eyedrops could be instilled back to back. Half of the participants (55.4%) did not consider missing a dose of medicine to be significant. Majority (89.1%) of the participants asked the doctor about the drug dosage and timings and 71.3% of them did not use the eyedrops beyond 40 days after opening the vial. 37.6% participants believed that the medicine could be discontinued without asking the doctor, once the symptoms are relieved. Eighty percent patients checked the vial for correct drug name and expiry date before buying. 57.4% of the participants washed their hands before instilling the eyedrops. Only 23.8% patients asked their doctor for alternate medication name, in case they do not get the primary medication. There were no statistically significant differences in the mean domain and total scores between males and females and between urban and rural patients. There were no statistically significant differences in knowledge (p = 0.059) and attitude (p = 0.809) scores in people with different educational qualification. But education had a statistically significant relation with the practice scores (p = 0.004) and total scores (p = 0.047). CONCLUSION(S): There exists marked variation in the reported practices, even in the very basic prerequisites of instilling eye-drops like washing of hands, checking the expiry date before the usage of eyedrops. The findings in our study suggest a need to better educate our patients by providing them detailed information about eyedrop and its administration. This would help to reduce patients' frustration, improve compliance and increase the efficacy of anti-glaucoma therapy. How to cite this article: Mohindroo C, Ichhpujani P, Kumar S. How 'Drug Aware' are our Glaucoma Patients? J Curr Glaucoma Pract 2015;9(2):33-37.