Current State and Future Directions of Radiation Therapy for Pancreas Adenocarcinoma.

Studies suggest select patients from across the pancreatic adenocarcinoma (PDAC) disease spectrum may benefit from adding radiation therapy (RT) to multi-modality care. In resectable PDAC, there is an evolving role for neoadjuvant RT with adjuvant RT reserved for patients with increased recurrence risk. In borderline resectable PDAC, neoadjuvant chemoradiation likely improves R0 resection rates and in unresectable PDAC, definitive RT may prolong survival for some patients. Recent developments in RT delivery are promising but additional studies are needed to determine the benefit of these technologies and to optimize the role of RT in multi-modality care.

Addition of Postoperative Radiation Therapy After Preoperative Chemotherapy and Surgery in Patients With Locally Advanced Endometrial Cancer Is Associated With Improved Outcomes.

Purpose: Our purpose was to examine outcomes of patients with locally advanced endometrial cancer who undergo neoadjuvant chemotherapy followed by surgery (PreCT) with/without postoperative adjuvant radiation therapy. A secondary analysis of down staging and margin clearance was made with reference to those receiving upfront surgery and then adjuvant chemotherapy (PostCT). Methods and Materials: The National Cancer Database was queried for FIGO (The International Federation of Gynecology and Obstetrics) stage III/IV locally advanced endometrial cancer cases who underwent definitive surgery from 2010 to 2016 and received chemotherapy as part of their treatment. Cases were classified into 2 cohorts: preoperative chemotherapy +/- postoperative chemotherapy cohort (PreCT) and postoperative chemotherapy cohort (PostCT) for reference for margin assessment. Cases who received preoperative radiation therapy were excluded while those who received postoperative radiation were included in the analysis. Primary endpoints were overall survival (OS), surgical margin status, rate of downstaging, and effect of adjuvant radiation therapy on OS among the PreCT cohort. Univariable (UVA) and multivariable (MVA) Cox regression analyses were performed. Results: A total of 13,369 cases were identified with 1059 in PreCT and 12,310 in PostCT cohorts. PreCT had lower OS than PostCT (UVA: hazard ratio [HR], 2.18; P < .001; MVA: HR, 1.873; P < .001). PreCT cases with negative margins, who presumably had unresectable tumors initially, also had worse OS compared with PostCT with negative margins (UVA: HR, 2.20; P < .001; MVA: HR, 1.84; P < .001); however, PreCT with negative margins had similar survival to PostCT with positive margins (UVA: HR, 0.825; P < .001; MVA: P = .885). The addition of radiation after surgery in the PreCT cohort was associated with improved survival (5-year OS 20.5% compared with 50%, respectively; UVA: HR, 0.450; P < .001; MVA: HR, 0.337; P < .001). Although fewer cases in PreCT had negative margins compared with PostCT (72% compared with 84%, P < .001), approximately 19% of cases in PreCT had lower pathologic T-stage compared with clinical T-stage and 11% had lower N-stage. Conclusions: Neoadjuvant chemotherapy was given in cases with worse oncologic prognostic factors, many of whom were likely unresectable at outset, compared with those who received postoperative chemotherapy. Although neoadjuvant chemotherapy is associated with tumor downstaging, survival is lower than with primary surgery probably because of these baseline differences. The addition of adjuvant radiation after surgery in cases who received preoperative chemotherapy is associated with improved survival.

Radiotherapy for Pancreatic Adenocarcinoma: Recent Developments and Advances on the Horizon.

Current indications for radiotherapy in pancreatic cancer vary by surgical resectability status of the tumor. Radiation is generally not used pre-operatively for resectable tumors, but may be given adjuvantly particularly in settings of a close or positive surgical margin. For borderline resectable tumors, pre-operative radiation has been shown to improve surgical parameters including lowering nodal positivity and positive margin rates. For locally advanced unresectable tumors, radiation can improve local control, give patients an interval off of chemotherapy and provide symptomatic relief. Multidisciplinary discussion is critical for choosing the best modality and sequencing of care for patients with pancreatic cancer. Prospective trials with appropriately chosen endpoints and meticulous radiotherapy quality assurance are needed to best define populations with pancreatic cancer most likely to benefit from radiotherapy.

SABR for High-Risk Prostate Cancer: A Prospective Multilevel MRI-Based Dose Escalation Trial.

PURPOSE: Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa. METHODS AND MATERIALS: This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate <33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events. RESULTS: Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively. CONCLUSIONS: SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity.

Inter-Fraction Tumor Volume Response during Lung Stereotactic Body Radiation Therapy Correlated to Patient Variables.

PURPOSE: Analyze inter-fraction volumetric changes of lung tumors treated with stereotactic body radiation therapy (SBRT) and determine if the volume changes during treatment can be predicted and thus considered in treatment planning. METHODS AND MATERIALS: Kilo-voltage cone-beam CT (kV-CBCT) images obtained immediately prior to each fraction were used to monitor inter-fraction volumetric changes of 15 consecutive patients (18 lung nodules) treated with lung SBRT at our institution (45-54 Gy in 3-5 fractions) in the year of 2011-2012. Spearman's (ρ) correlation and Spearman's partial correlation analysis was performed with respect to patient/tumor and treatment characteristics. Multiple hypothesis correction was performed using False Discovery Rate (FDR) and q-values were reported. RESULTS: All tumors studied experienced volume change during treatment. Tumor increased in volume by an average of 15% and regressed by an average of 11%. The overall volume increase during treatment is contained within the planning target volume (PTV) for all tumors. Larger tumors increased in volume more than smaller tumors during treatment (q = 0.0029). The volume increase on CBCT was correlated to the treatment planning gross target volume (GTV) as well as internal target volumes (ITV) (q = 0.0085 and q = 0.0039 respectively) and could be predicted for tumors with a GTV less than 22 mL. The volume increase was correlated to the integral dose (ID) in the ITV at every fraction (q = 0.0049). The peak inter-fraction volume occurred at an earlier fraction in younger patients (q = 0.0122). CONCLUSIONS: We introduced a new analysis method to follow inter-fraction tumor volume changes and determined that the observed changes during lung SBRT treatment are correlated to the initial tumor volume, integral dose (ID), and patient age. Furthermore, the volume increase during treatment of tumors less than 22mL can be predicted during treatment planning. The volume increase remained significantly less than the overall PTV expansion, and radiation re-planning was therefore not required for the purpose of tumor control. The presence of the studied correlations suggests that the observed volumetric changes may reflect some underlying biologic process rather than random fluctuations.

Membrane disruption and early events in the aggregation of the diabetes related peptide IAPP from a molecular perspective.

The aggregation of proteins is tightly controlled in living systems, and misfolded proteins are normally removed before aggregation of the misfolded protein can occur. But for reasons not clearly understood, in some individuals this degradation process breaks down, and misfolded proteins accumulate in insoluble protein aggregates (amyloid deposits) over time. Of the many proteins expressed in humans, a small but growing number have been found to form the long, highly ordered ß-sheet protein fibers that comprise amyloid deposits. Despite a lack of obvious sequence similarity, the amyloid forms of diverse proteins are strikingly similar, consisting of long, highly ordered insoluble fibers with a characteristic crossed ß-sheet pattern. Amyloidogenesis has been the focus of intense basic and clinical research, because a high proportion of amyloidogenic proteins have been linked to common degenerative diseases, including Alzheimer's disease, type II diabetes, and Parkinson's disease. The apparent link between amyloidogenic proteins and disease was initially attributed to the amyloid form of the protein; however, increasing evidence suggests that the toxicity is due to intermediates generated during the assembly of amyloid fibers. These intermediates have been proposed to attack cells in a variety of ways, such as by generating inflammation, creating reactive oxygen species, and overloading the misfolded protein response pathway. One common, well-studied mechanism is the disruption of the plasma and organelle membranes. In this Account, we examine the early molecular-level events in the aggregation of the islet amyloid polypeptide (IAPP, also called amylin) and its ensuing disruption of membranes. IAPP is a 37-residue peptide secreted in conjunction with insulin; it is highly amyloidogenic and often found in amyloid deposits in type II diabetics. IAPP aggregates are highly toxic to the ß-cells that produce insulin, and thus IAPP is believed to be one of the factors involved in the transition from early to later stages of type II diabetes. Using variants of IAPP that are combinations of toxic or non-toxic and amyloidogenic or nonamyloidogenic forms, we have shown that formation of amyloid fibers is a sufficient but not necessary condition for the disruption of ß-cells. Instead, the ability to induce membrane disruption in model membranes appears to be related to the peptide's ability to stabilize curvature in the membrane, which in turn is related to the depth of penetration in the membrane. Although many similarities exist between IAPP and other amyloidogenic proteins, one important difference appears to be the role of small oligomers in the assembly process of amyloid fibers. In many amyloidogenic proteins, small oligomers form a distinct metastable intermediate that is frequently the most toxic species; however, in IAPP, small oligomers appear to be transient and are rapidly converted to amyloid fibers. Moreover, the aggregation and toxicity of IAPP is controlled by other cofactors present in the secretory granule from which it is released, such as zinc and insulin, in a control mechanism that is somehow unbalanced in type II diabetics. Investigations into this process are likely to give clues to the mysterious origins of type II diabetes at the molecular level.

Misfolded proteins in Alzheimer's disease and type II diabetes.

This tutorial review presents descriptions of two amyloidogenic proteins, amyloid-ß (Aß) peptides and islet amyloid polypeptide (IAPP), whose misfolding propensities are implicated in Alzheimer's disease (AD) and type II diabetes, respectively. Protein misfolding diseases share similarities, as well as some unique protein-specific traits, that could contribute to the initiation and/or development of their associated conditions. Aß and IAPP are representative amyloidoses and are used to highlight some of the primary considerations for studying misfolded proteins associated with human diseases in this review. Among these factors, their physiological formation, aggregation, interactions with metal ions and other protein partners, and toxicity are presented. Small molecules that target and modulate the metal-Aß interaction and neurotoxicity are included to illustrate one of the current approaches for uncovering the complexities of protein misfolding at the molecular level.

A two-site mechanism for the inhibition of IAPP amyloidogenesis by zinc.

Human islet amyloid polypeptide (hIAPP) is a highly amyloidogenic protein co-secreted with insulin in response to glucose levels. The formation of hIAPP amyloid plaques near islet cells has been linked to the death of insulin-secreting ß-cells in humans and the progression of type II diabetes. Since both healthy individuals and those with type II diabetes produce and secrete hIAPP, it is reasonable to look for factors involved in storing hIAPP and preventing amyloidosis. We have previously shown that zinc inhibits the formation of insoluble amyloid plaques of hIAPP; however, there remains significant ambiguity in the underlying mechanisms. In this study, we show that zinc binds unaggregated hIAPP at micromolar concentrations similar to those found in the extracellular environment. By contrast, the fibrillar amyloid form of hIAPP has low affinity for zinc. The binding stoichiometry obtained from isothermal titration calorimetry experiments indicates that zinc favors the formation of hIAPP hexamers. High-resolution NMR structures of hIAPP bound to zinc reveal changes in the electron environment along residues that would be located along one face of the amphipathic hIAPP α-helix proposed as an intermediate for amyloid formation. Results from electrospray ionization mass spectroscopy investigations showed that a single zinc atom is predominantly bound to hIAPP and revealed that zinc inhibits the formation of the dimer. At higher concentrations of zinc, a second zinc atom binds to hIAPP, suggesting the presence of a low-affinity secondary binding site. Combined, these results suggest that zinc promotes the formation of oligomers while creating an energetic barrier for the formation of amyloid fibers.