Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma.

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).

Successful Non-operative Management of Metacarpophalangeal Collateral Ligament and Sagittal Band Rupture of the Long Finger: A Case Report.

The metacarpophalangeal (MCP) joint is surrounded by various structures critical to its stability and function. Though the ligamentous injury to the digits is common, rupture of the metacarpophalangeal collateral ligament and a sagittal band of the same finger is not well represented in the literature. We report a chronic case of a concurrent metacarpophalangeal collateral ligament and sagittal band injury. Though surgery would have been the most appropriate treatment soon after the injury, restrictions on elective procedures due to the COVID-19 pandemic precluded surgical treatment. The patient was alternatively treated with buddy tape, and a close follow-up was done. This is the first reported case of a concurrent metacarpophalangeal collateral ligament, and sagittal band injury successfully treated using nonoperative management.

Impact of Hypomethylating Agent Use on Hospital and Emergency Room Visits, and Predictors of Early Discontinuation in Patients With Higher-Risk Myelodysplastic Syndromes.

BACKGROUND: Previous analyses using the SEER-Medicare database have reported substantial underutilization of hypomethylating agents (HMAs) among patients with higher-risk myelodysplastic syndromes (MDS), and an association between poor HMA persistence and high economic burden. We aimed to compare rates of hospitalizations and emergency room (ER) visits among patients with higher-risk MDS according to use or non-use of HMA therapy, and to explore factors associated with early discontinuation of HMA therapy. PATIENTS AND METHODS: We used the 2010-2016 SEER-Medicare database to identify patients aged ≥66 years with a new diagnosis of refractory anemia with excess blasts (RAEB; a surrogate for higher-risk MDS) between 2011 and 2015. New hospitalizations and ER visits during the 12 months following MDS diagnosis were determined. Treatment discontinuation was defined as stopping HMA therapy before 4 cycles. RESULTS: Overall, 664 (55.8%) patients were HMA users and 526 (44.2%) non-users. Non-users had more hospitalizations (mean 0.47 vs. 0.30, P < .001) and ER visits (mean 0.69 vs. 0.41, P = .005) per month than HMA users. Among HMA users, 193 (29.1%) discontinued HMA therapy before 4 cycles, and 91 (47.2%) of these after 1 cycle. Older age and poor performance status were associated with higher risk of HMA discontinuation. CONCLUSION: An increased rate of hospitalizations and ER visits occurred in HMA non-users vs. HMA users. Approximately one-third of patients discontinued HMA therapy early. Predictors of discontinuation included older age and poor performance status. Novel approaches are needed to improve utilization and persistence with HMA therapy and associated outcomes, particularly among these higher-risk groups.

Treatment patterns and burden of myelosuppression for patients with small cell lung cancer: A SEER-medicare study.

PURPOSE: To depict the treatment journey for patients with small cell lung cancer (SCLC) and evaluate health care resource utilization (HCRU) associated with myelosuppression, a complication induced by chemotherapy or chemotherapy plus radiation therapy. PATIENTS AND METHODS: This was a descriptive, retrospective study of patients with SCLC aged ≥65 years, identified from linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data curated between January 2012 and December 2015. Treatment types (chemotherapy, radiation therapy, surgery) were classified as first, second, or third line, depending on the temporal sequence in which regimens were prescribed. For each year, the proportions of patients completing 4- or 6-cycle chemotherapy regimens, with hospital admissions associated with myelosuppression, or who used granulocyte colony-stimulating factors (G-CSFs), blood/platelet transfusions, or erythropoiesis-stimulating agents (ESAs), were calculated. RESULTS: Chemotherapy was administered as initial treatment in 7,807/11,907 (65.6%) patients whose treatment journey was recorded. Approximately one-third (n = 3,985) subsequently received radiation therapy. In total, 5,791 (57.8%) patients completed the guideline-recommended 4-6 cycles of chemotherapy. Among all chemotherapy-treated patients, 10,370 (74.3%) experienced ≥1 inpatient admission associated with myelosuppression (anemia, 7,366 [52.8%]; neutropenia, 4,642 [33.3%]; thrombocytopenia, 2,375 [17.0%]; pancytopenia, 1,983 [14.2%]). Supportive care interventions included G-CSF (6,756 [48.4%] patients), ESAs (1,534 [11.0%]), and transfusions (3,674 [26.3%]). CONCLUSION: Chemotherapy remains a cornerstone of care for patients with SCLC. Slightly over half of patients completed the recommended number of cycles, underscoring the frailty of patients and aggressiveness of SCLC. HCRU associated with myelosuppression was prominent, suggesting a substantial burden on older patients with SCLC.

Assessing the transition from intravenous to subcutaneous delivery of rituximab: Benefits for payers, health care professionals, and patients with lymphoma.

Subcutaneous (SC) administration of rituximab provides an opportunity for reduced patient treatment burden and increased healthcare efficiencies as an alternative to intravenous (IV) rituximab. There is minimal evidence comparing costs associated with SC and IV rituximab in a US setting. This research assessed the impact of transitioning patients from IV to SC rituximab for treatment of non-Hodgkin's lymphoma (NHL) from the US payer, provider, and patient perspective. We developed a model to estimate cost differences for transitioning 20% of a patient cohort from IV to SC rituximab. We included patients with incident diffuse large B-cell lymphoma, incident and recurrent follicular lymphoma, and incident and recurrent chronic lymphocytic leukemia. In the model, each patient received the same number of doses and that there was no difference in discontinuation between cohorts due to non-inferior efficacy and a similar safety profile. Model inputs were collected from published literature and publicly available data. Scenario analyses tested the impact of availability of low-cost biosimilars. In the base case (1,000,000 covered lives), we estimated a total of 157 patients, with 769 total drug administrations. A transition of 20% of patients from IV to SC was projected to generate $153,000 in payer savings, increase provider capacity by 270 hours, and free 470 hours of patient time. Scenario analyses suggest SC administration will be cost saving for payers even with a market where biosimilars approach 50% market share. A 20% transition to SC rituximab in a single cohort of patients has the potential to generate significant US health system value in the form of payer savings, increased practice capacity, and patient time.

Real-world burden of chemotherapy-induced myelosuppression in patients with small cell lung cancer: a retrospective analysis of electronic medical data from community cancer care providers.

AIMS: Chemotherapy-induced myelosuppression, which commonly exhibits as neutropenia, anemia, or thrombocytopenia, represents a substantial burden for patients with cancer that affects health-related quality of life and increases healthcare resource utilization (HCRU). We evaluated the burden of myelosuppression among chemotherapy-treated patients with small cell lung cancer (SCLC) using real-world data from community cancer care providers in the Western United States. MATERIALS AND METHODS: This was a retrospective, observational analysis of electronic medical records (EMRs) from Providence St. Joseph Health hospital-associated oncology clinics between January 2016 and December 2019. Patient demographics were assessed from the date of first SCLC diagnosis in adult patients with chemotherapy-induced grade ≥3 myelosuppression in first-line (1L) or second-line-and-beyond (2L+) treatment settings. Myelosuppressive adverse events (AEs), treatment patterns, and HCRU were assessed from the date of chemotherapy initiation (index date) until 12 months, date of the last visit, date of death, or study end, whichever occurred earliest. RESULTS: Of 347 eligible patients with SCLC who had received chemotherapy (mean age 66; 49% female), all had received at least 1L treatment, and 103 (29.7%) had a 2L + treatment recorded within the EMR during the study period. Of 338 evaluable patients with longitudinal laboratory data, 206 (60.9%) experienced grade ≥3 myelosuppressive AEs, most commonly neutropenia, anemia, and thrombocytopenia (44.9, 41.1, and 25.4 per 100 patients, respectively). Rates of granulocyte colony-stimulating factor use and red blood cell transfusions were 47.0 and 41.7 per 100 patients, respectively. There was a trend toward increasing the use of supportive care interventions and visits to inpatient and outpatient facilities in patients with myelosuppressive AEs in more than one cell lineage. CONCLUSIONS: Chemotherapy-induced myelosuppression places a substantial real-world burden on patients with SCLC in the community cancer care setting. Innovations to protect bone marrow from chemotherapy-induced damage have the potential to reduce this burden.

PLAIN LANGUAGE SUMMARYThis study looked at the medical records of people with a particular type of lung cancer known as small cell lung cancer. When treated with chemotherapy, people with this cancer may develop a condition called myelosuppression. This causes people to have fewer blood cells, which can lead to tiredness, or increase the risk of infection or bleeding. The study looked at what types of chemotherapy people with small cell lung cancer were given, what the side effects of myelosuppression were, how often the side effects were reported, and what treatments were given to manage these side effects. The study also looked at whether people with side effects from myelosuppression needed more visits to the doctor or hospital. Around 3 out of 5 people in the study experienced serious side effects resulting in reduced numbers of white blood cells (which fight infection), red blood cells (which carry oxygen), or platelets (which help the blood to clot), and many needed drugs or blood transfusions to treat these side effects. On average, people with side effects from myelosuppression had more visits to healthcare facilities than those people without these side effects. The findings suggest that myelosuppression places a large burden on people with small cell lung cancer who are treated with chemotherapy.

Real-world use and outcomes of hypomethylating agent therapy in higher-risk myelodysplastic syndromes: why are we not achieving the promise of clinical trials?

Myelodysplastic syndromes are hematological malignancies characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Hypomethylating agents (HMAs), azacitidine and decitabine, are standard of care therapy for higher-risk myelodysplastic syndromes. However, outcomes reported for real-world studies fall short of those achieved in clinical trials. We conducted a targeted literature review exploring real-world utilization, persistence and outcomes with intravenous and subcutaneous HMA therapies to better understand barriers to achieving optimal outcomes in clinical practice. The potential benefits of oral HMA therapy were also explored. Underutilization and poor persistence with HMA therapy are associated with suboptimal outcomes, highlighting the need for approaches to improve utilization and persistence, so that patients achieve the optimum benefit from HMA therapy.

Lay abstract Myelodysplastic syndromes (MDS) are bone marrow disorders affecting the production of blood cells. In some patients, MDS can progress to acute myeloid leukemia (AML), an aggressive blood cancer with poor prognosis. Patients with higher-risk MDS are often treated with a type of chemotherapy called hypomethylating agents (HMAs). Studies conducted in real-world clinical practice have shown HMAs to be less effective than has been found in clinical trials. We reviewed available studies exploring real-world utilization, persistence and outcomes with current HMA therapies to better understand any barriers to patients achieving the best outcomes. Two important factors were found to be the underuse of HMAs and poor persistence with HMA therapy, highlighting the need for approaches to improve HMA utilization and persistence.

How SARS-CoV-2 and Comparable Pathogens Can Be Defeated in a Single Day: Description and Mathematical Model of the Carrier Separation Plan (CSP).

A simple, common-sense, three-component procedure-the Carrier Separation Plan (CSP)-can immediately halt the transmission of SARS-CoV-2 or a comparable pathogen, allow the safe reopening of an entire economy without the need for social distancing, and quickly eradicate the pathogen from the population (assuming the pathogen can be killed by the immune systems of the carriers). The three components are (a) nearly simultaneous self-testing for the pathogen by an entire population, followed rapidly by (b) nearly simultaneous self-isolation of carriers, and (c) secondary screening at entrances to facilities where people congregate. After a period of preparation lasting roughly 5-10 weeks, these steps could and probably should be taken in a single day. The power of this methodology has already been demonstrated in varying degrees with groups ranging in size from 1,000 to 11 million. Although this plan might seem daunting, its costs are minimal compared to the losses we have incurred by relying on half measures, and the US and other countries have the technological, logistical, and industrial capacities to implement this plan in a matter of weeks. With proper messaging during the weeks leading up to the testing, compliance in such a program is likely to be high given the potential benefits, and because participation is voluntary and testing is noninvasive, the legal and ethical issues associated with such a program are minimal - trivial, in fact, compared to those associated with imposing a months-long lockdown on an entire population. A SIRD/CSP model suggests that the single-day testing and separation procedure will substantially lower the number of infections, even if compliance with the procedure is modest. Modeling also suggests that when long-term secondary screening is added to the 1-day procedure, over time, the pathogen is eradicated from the population. This can occur even when compliance with secondary screening is itself relatively low.

Cancer Patients' Perspectives and Experiences of Chemotherapy-Induced Myelosuppression and Its Impact on Daily Life.

PURPOSE: To evaluate which side effects of chemotherapy are considered most burdensome by patients with cancer, identify which health care professionals pay most attention to symptoms associated with chemotherapy-induced myelosuppression (CIM) from the patient perspective, and capture the "patient voice" describing how CIM impacts their daily lives. PARTICIPANTS AND METHODS: Online survey of participants with breast, lung, or colorectal cancer who had received chemotherapy within the past 12 months and experienced ≥1 episode of CIM in the past year. Participants were asked to answer close-ended questions and provide qualitative responses to: "In your own words, please describe how side effects from myelosuppression have impacted your life." RESULTS: Among 301 survey participants, fatigue was the most frequently reported side effect of chemotherapy; 55% of participants rated fatigue as highly bothersome (9 or 10 on a 1-10 scale of "bothersomeness"). Participants rated symptoms associated with CIM, including fatigue, weakened immune system (infections), bleeding and/or bruising, and shortness of breath, as being as bothersome as other side effects of chemotherapy, including alopecia, neuropathy, and nausea/vomiting. Overall, 24-43% of participants thought that CIM and its symptoms had a negative impact on their daily lives, including their ability to complete tasks at home and work, and to socialize. Qualitative responses supported these findings; participants highlighted that CIM-related symptoms, particularly fatigue and fear of infections, affected their ability to be physically active, complete work, or continue meaningful relationships with friends and family. CONCLUSION: Participants described a real-world impact of CIM that often isolates them from family and friends, and means that they are unable to work or perform tasks of daily living. Using measures that help patients to recognize and communicate the signs and symptoms of CIM might increase the likelihood of maintaining daily lives as close to normal as possible, during and after chemotherapy treatment.

Compaction of very thin corneas from ultraviolet A riboflavin-vitamin E transepithelial cross-linking.

The purpose of the study was to determine the decrease in pachymetry of very thin corneas with advanced keratoconus due to corneal compaction from the ultraviolet-A (UV-A) irradiation phase of transepithelial (epi-on) cross-linking. Twenty removed corneal buttons were obtained from patients who underwent penetrating keratoplasty for advanced keratoconus. Removed corneal buttons selected from among the post-surgical specimens for this study had intact epithelium, no scarring or surgical cautery, endothelial cell density >2500 cells/mm2, and average pachymetry over the measured points of below 400 µm. Corneas were mounted in a Franz chamber. Each epithelial surface was soaked in isotonic riboflavin and D-alpha-tocopheryl polyethylene glycol 1000 succinate (Ribocross® IROMED Group, Italy) for 15 min. Pachymetry was measured at three points over both the shielded and unshielded corneal halves for each corneal button. Surfaces were then washed in saline to remove the Ribocross®. Shields from UV-A irradiation over half of each cornea were then fixed to stand 5 mm above the test corneas. UV-A irradiation using the custom fast cross-linking (CF-CXL) protocol was then performed for the typical 10 ± 1.5 min, for a total energy of 1.08 ± 0.6 J/cm2 after which pachymetry was re-measured. The average percent change in pachymetry was -0.43% ± 0.38% (maximum -1.06%) in the shielded half. Pachymetry change was -6.2% ± 2.2% (maximum 12%) in the cross-linked halves. In conclusion, we estimate that the change in corneal thickness from corneal compaction due to the cross-linking reaction itself was -5.8% ± 2.2%. Scanning electron microscopy of cross-linked corneal segments showed stromal fiber contraction.

Patient Burden and Real-World Management of Chemotherapy-Induced Myelosuppression: Results from an Online Survey of Patients with Solid Tumors.

INTRODUCTION: Chemotherapy-induced myelosuppression (CIM) is one of the most common dose-limiting complications of cancer treatment, and is associated with a range of debilitating symptoms that can significantly impact patients' quality of life. The purpose of this study was to understand patients' perspectives on how the side effects of CIM are managed in routine clinical practice. METHODS: An online survey was conducted of participants with breast, lung, or colorectal cancer who had received chemotherapy treatment within the past 12 months, and had experienced at least one episode of myelosuppression in the past year. The survey was administered with predominantly close-ended questions, and lay definitions of key terms were provided to aid response selection. RESULTS: Of 301 participants who completed the online survey, 153 (51%) had breast cancer, 100 (33%) had lung cancer, and 48 (16%) had colorectal cancer. Anemia, neutropenia, lymphopenia, and thrombocytopenia were reported by 61%, 59%, 37%, and 34% of participants, respectively. Most participants (79%) reported having received treatment for CIM, and 64% of participants recalled chemotherapy dose modifications as a result of CIM. Although most participants believed their oncologist was aware of the side effects of CIM, and treated them quickly, 30% of participants felt their oncologists did not understand how uncomfortable they were due to the side effects of CIM. Overall, 88% of participants considered CIM to have a moderate or major impact on their lives. CONCLUSION: The data highlight that despite the various methods used to address CIM, and the patient-focused approach of oncologists, the real-world impact of CIM on patients is substantial. Improving communication between patients and health care providers may help improve patients' understanding of CIM, and foster shared decision-making in terms of treatment. Additional insights from patients should be obtained to further elucidate the totality of life burden associated with CIM.

This study looked at people with cancer who received chemotherapy and developed a condition where their bone marrow activity was reduced, called myelosuppression. This meant they had fewer red blood cells that carry oxygen around the body, white blood cells that help fight infections, and platelets that help the blood to clot. The researchers wanted to understand how chemotherapy-induced myelosuppression affects peoples' lives and their cancer treatment, and people's experiences of treatment for myelosuppression. Overall, 301 people in the USA with breast, lung, or large bowel (colorectal) cancer completed an online survey. They had all received chemotherapy in the last year, and had myelosuppression at least once during their treatment. The survey showed that around 8 in 10 people (79%) had to be treated for myelosuppression, and around 7 in 10 people (73%) felt they received treatment for myelosuppression quickly. Chemotherapy was delayed, reduced, or stopped because of myelosuppression in around 6 in 10 people (64%). Around 3 in 10 people (30%) felt their oncologist did not understand the discomfort that myelosuppression caused them, and around 9 in 10 people (88%) felt that myelosuppression made their quality of life worse. The researchers concluded that because myelosuppression impacts peoples' lives and their ability to keep receiving chemotherapy to treat their cancer, effective prevention and treatment for this condition are important. Better communication between people and their health care teams could help them to understand how people experience myelosuppression and make plans for treatment together.

Topography and Pachymetry Guided, Rapid Epi-on Corneal Cross-Linking for Keratoconus: 7-year Study Results.

PURPOSE: To evaluate custom fast cross-linking (cfCXL) treatment of keratoconus. METHODS: "Custom fast cross-linking" or "cfCXL" is a keratoconus treatment algorithm featuring no epithelial disruption, 15 minutes of corneal presoaking with a riboflavin-vitamin E TPGS solution, and a 370-nm ultraviolet A radiation beam centered on the most highly curved corneal region. Ultraviolet A radiation beam fluence, total energy, and exposure time are significantly less than those in the Dresden protocol. In this study, refraction, spectacle-corrected distance visual acuity, Kmax, and corneal hysteresis were monitored in 81 eyes of 81 patients for 7 years with 100% follow-up. Pretreatment Kmax and patient age averaged 53.01 ± 4.87 D and 25.9 ± 4.7 years, respectively. RESULTS: Average refractive cylinder magnitude was reduced by 26.1% at 1 month postoperatively and by 44.2% at 7 years postoperatively. Logarithm of the minimum angle of resolution average spectacle-corrected distance visual acuity (best spectacle-corrected distance visual acuity) improved from +0.26 ± 0.34 (20/36.4) to +0.15 ± 0.23 (20/28.25), +0.05 ± 0.20 (20/22.4), and +0.06 ± 0.20 (20/22.96) at 1 month, 1 year, and 7 years postoperatively, respectively. Best spectacle-corrected distance visual acuity improved in 54.3%, 74.1%, 84.0%, 87.7%, 84.0%, 84.0%, and 82.7% of patients at postoperative months 1, 3, 6, 12, 24, 48, and 84, respectively. Kmax did not increase in 96.3% of patients at 1 month, 97.5% at 1 year, and 98.8% at 7 years postoperatively, with average corneal apex flattening at 1 month and 7 years of -2.79 ± 1.70 D and -4.00 ± 2.40 D, respectively. CONCLUSIONS: Custom fast cross-linking, epi-on, rapid, narrowed beam apex-centered treatment of keratoconus with riboflavin-vitamin E TPGS produced a significant, rapid, and lasting cone progression stoppage, astigmatism reduction, and visual acuity improvement.

Practice Patterns and Treatment Challenges in Acute Postoperative Pain Management: A Survey of Practicing Physicians.

INTRODUCTION: The management of acute postoperative pain remains a significant challenge for physicians. Poorly controlled postoperative pain is associated with poorer overall outcomes. METHODS: Between April and May 2017, physicians from an online database who regularly prescribe intravenous (IV) medications for acute postoperative pain completed a 47-question survey on topics such as patient demographics, IV analgesia preferences, factors that influence prescribing decisions, and the challenges and unmet needs for the treatment of acute postoperative pain. RESULTS: Of 501 surveyed physicians, 55% practiced in community hospitals, 60% had been in practice for > 10 years, and 60% were surgeons. The three categories of IV pain medications most likely to be prescribed to patients with moderate-to-severe pain immediately after surgery were morphine, hydromorphone, or fentanyl (95.8% of respondents); COX-2 inhibitors or nonsteroidal anti-inflammatory drugs (73.7%); and acetaminophen (60.5%). Past clinical experience (81.6%), surgery type (78.2%), and onset of analgesia (67.1%) were practice-related factors that most determined their medication choice. Key patient-related risk factors, such as avoidance of medication-related adverse events (AEs), each influenced prescription decisions in > 75.0% of physicians. Nausea and vomiting were among the most common challenges associated with postoperative pain management (76.2 and 60.3%, respectively), and avoidance of analgesic medication-related AEs was among the three most influential patient-related factors that determined prescribing decision (75%). Physicians reported the top unmet need for acute pain management in patients experiencing moderate-to-severe postoperative pain was more medications with fewer side effects (i.e., nausea, vomiting, and respiratory depression; 80.7%). CONCLUSIONS: Opioids remain an integral component of multimodal acute analgesic therapy for acute postoperative pain in hospitalized patients. The use of all IV analgesic medications is limited by concerns over AEs, particularly with opioids and in high-risk patients. There remains a key unmet need for effective analgesic medications that are associated with a lower risk of AEs. FUNDING: Trevena, Inc.

Customized Corneal Cross-Linking-A Mathematical Model.

PURPOSE: To improve the safety, reproducibility, and depth of effect of corneal cross-linking with the ultraviolet A (UV-A) exposure time and fluence customized according to the corneal thickness. METHODS: Twelve human corneas were used for the experimental protocol. They were soaked using a transepithelial (EPI-ON) technique using riboflavin with the permeation enhancer vitamin E-tocopheryl polyethylene glycol succinate. The corneas were then placed on microscope slides and irradiated at 3 mW/cm for 30 minutes. The UV-A output parameters were measured to build a new equation describing the time-dependent loss of endothelial protection induced by riboflavin during cross-linking, as well as a pachymetry-dependent and exposure time-dependent prescription for input UV-A fluence. The proposed equation was used to establish graphs prescribing the maximum UV-A fluence input versus exposure time that always maintains corneal endothelium exposure below toxicity limits. RESULTS: Analysis modifying the Lambert-Beer law for riboflavin oxidation leads to graphs of the maximum safe level of UV-A radiation fluence versus the time applied and thickness of the treated cornea. These graphs prescribe UV-A fluence levels below 1.8 mW/cm for corneas of thickness 540 µm down to 1.2 mW/cm for corneas of thickness 350 µm. Irradiation times are typically below 15 minutes. CONCLUSIONS: The experimental and mathematical analyses establish the basis for graphs that prescribe maximum safe fluence and UV-A exposure time for corneas of different thicknesses. Because this clinically tested protocol specifies a corneal surface clear of shielding riboflavin on the corneal surface during UV-A irradiation, it allows for shorter UV-A irradiation time and lower fluence than in the Dresden protocol.

Pharmacoepidemiology of Clinically Relevant Hypothyroidism and Hypertension from Sunitinib and Sorafenib.

BACKGROUND: Thyroid dysfunction and hypertension (HTN) have been sporadically reported with sunitinib (SUN) and sorafenib (SOR). Determination of the side effect incidence will enhance monitoring and management recommendations. METHODS: An observational cohort study was performed using deidentified pharmacy claims data from a 3-year period to evaluate patients prescribed SUN, SOR, or capecitabine (CAP; comparison group). The primary outcome was time to first prescription for thyroid replacement or HTN treatment. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by Cox proportional hazards models. RESULTS: A total of 20,061 patients were eligible for evaluation of thyroid replacement therapy, which was initiated in 11.6% of those receiving SUN (HR, 16.77; 95% CI, 13.54-20.76), 2.6% of those receiving SOR (HR, 3.47; 95% CI, 2.46-4.98), and 1% of those receiving CAP, with median time to initiation of 4 months (range, 1-35 months). A total of 14,468 patients were eligible for evaluation of HTN therapy, which was initiated in 21% of SUN recipients (HR, 4.91; 95% CI, 4.19-5.74), 14% of SOR recipients (HR, 3.25; 95% CI, 2.69-3.91), and 5% of CAP recipients, with median time to initiation of 1 month (range, 1-18 months) for SOR and 2 months (range, 1-25 months) for SUN. CONCLUSION: SUN and SOR significantly increased the risk for clinically relevant hypothyroidism; the risk was at least 4 times greater with SUN than with SOR. Patients receiving SUN and SOR had a similar elevated risk for clinically relevant HTN. These data provide robust measures of the incidence and time to onset of these clinically actionable adverse events. The Oncologist 2017;22:208-212Implications for Practice: The side effect profiles for novel therapies are typically used to create monitoring and management recommendations using clinical trial data from patient populations that may not represent those seen in standard clinical practice. This analysis using a large pharmacy claims database better reflects typical patients treated with sorafenib or sunitinib outside of a clinical trial. The findings of increased need for thyroid replacement in patients receiving sunitinib compared with sorafenib and a similar increase in need for hypertension therapy with both agents can be used to form clinically relevant monitoring recommendations for these agents.

Transepithelial Corneal Cross-Linking With Vitamin E-Enhanced Riboflavin Solution and Abbreviated, Low-Dose UV-A: 24-Month Clinical Outcomes.

PURPOSE: To report the clinical outcomes with 24-month follow-up of transepithelial cross-linking using a combination of a D-alpha-tocopheryl polyethylene-glycol 1000 succinate (vitamin E-TPGS)-enhanced riboflavin solution and abbreviated low fluence UV-A treatment. METHODS: In a nonrandomized clinical trial, 25 corneas of 19 patients with topographically proven, progressive, mild to moderate keratoconus over the previous 6 months were cross-linked, and all patients were examined at 1, 3, 6, 12, and 24 months. The treatments were performed using a patented solution of riboflavin and vitamin E-TPGS, topically applied for 15 minutes, followed by two 5-minute UV-A treatments with separate doses both at fluence below 3 mW/cm(2) that were based on preoperative central pachymetry. RESULTS: During the 6-month pretreatment observation, the average Kmax increased by +1.99 ± 0.29 D (diopter). Postoperatively, the average Kmax decreased, changing by -0.55 ± 0.94 D, by -0.88 ± 1.02 D and by -1.01 ± 1.22 D at 6, 12, and 24 months. Postoperatively, Kmax decreased in 19, 20, and 20 of the 25 eyes at 6 months, 12 months, and 24 months, respectively. Refractive cylinder was decreased by 3 months postoperatively and afterward, changing by -1.35 ± 0.69 D at 24 months. Best spectacle-corrected visual acuity (BSCVA) improved at 6, 12, and 24 months, including an improvement of -0.19 ± 0.13 logarithm of the minimum angle of resolution units at 24 months. There was no reduction in endothelial cell count. No corneal abrasions occurred, and no bandage contact lenses or prescription analgesics were used during postoperative recovery. CONCLUSIONS: Transepithelial cross-linking using the riboflavin-vitamin E solution and brief, low-dose, pachymetry-dependent UV-A treatment safely stopped keratoconus progression.

The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplantation for Patients with Acute Leukemia.

Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI, n = 948; TBICy, n = 821) recipients of related or unrelated hematopoietic cell transplantation who received TBI (1200 to 1500 cGY) for acute leukemia from 2003 to 2010. The 2 cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Philadelphia chromosome-positive acute lymphoblastic leukemia, HLA-matched siblings, stem cell source, antithymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect transplantation-related mortality (24% versus 23% at 3 years, P = .67; relative risk, 1.01; P = .91), leukemia relapse (27% versus 29% at 3 years, P = .34; relative risk, .89, P = .18), leukemia-free survival (49% versus 48% at 3 years, P = .27; relative risk, .93; P = .29), chronic GVHD (45% versus 47% at 1 year, P = .39; relative risk, .9; P = .11), or overall survival (53% versus 52% at 3 years, P = .62; relative risk, .96; P = .57) for CyTBI and TBICy, respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (P = .08), respectively. This study demonstrates that the sequence of Cy and TBI does not impact transplantation outcomes and complications in patients with acute leukemia undergoing hematopoietic cell transplantation with myeloablative conditioning.

Pentacam HR criteria for curvature change in keratoconus and postoperative LASIK ectasia.

PURPOSE: To determine criteria for keratoconus or postoperative LASIK ectasia progression or improvement based on Pentacam HR (Oculus Optikgeräte GmbH) measured steepest corneal curvature. METHODS: Sixty-one eyes from 41 patients with keratoconus or postoperative LASIK ectasia were evaluated. Each eye was measured 5 times with the Pentacam HR during the same clinic visit and the random measurement variations of Rmin(back) and maximal keratometry (Kmax; mathematically linked to Rmin[front]) were statistically analyzed. Confidence levels for diagnosing true curvature change were determined for 3 typical clinical situations differing by the number of available Pentacam measurements. RESULTS: With a single past and single present Pentacam HR measurement available (situation 1+1), the 95% confidence levels of true change for ΔKmax, ΔRmin(front), and ΔRmin(back) were 1.51 diopters (D), 0.162 mm, and 0.290 mm, respectively. With one prior and the average of five present Pentacam measurements (situation 5+1), the 95% confidence levels of true change for ΔKmax, ΔRmin(front), and ΔRmin(back) were 1.17 D, 0.126 mm, and 0.225 mm, respectively. With the average of five past and five present measurements (situation 5+5), the 95% confidence levels of true change for ΔKmax, ΔRmin(front), and ΔRmin(back) were 0.68 D, 0.072 mm, and 0.130 mm, respectively. CONCLUSIONS: Steepest corneal curvature changed with 95% confidence if the difference between single past and present Kmax exceeded 1.51 D. With the advantage of five past and five present measurements, 95% confidence of real Kmax change occurs at a 0.68-D difference.

[18F]fluorothymidine PET imaging in the diagnosis of leptomeningeal involvement with diffuse large B-cell lymphoma.

The diagnosis of leptomeningeal carcinomatosis remains difficult despite improvement in central nervous system (CNS) imaging and cytologic examination of the cerebral spinal fluid. False-negative results are common, providing obstacles in assessing both prophylactic and therapeutic efforts. As a result of increased survival of patients with a variety of systemic neoplasms it is likely that central nervous involvement will need to be addressed more often. This article presents a patient with a diffuse large B-cell lymphoma with polymorphic features. Imaging using 18F-labeled fluorodeoxythymidine (FLT) proved useful in demonstrating both parenchymal and leptomeningeal CNS involvement. The potential for FLT to identify proliferative tissue may make it uniquely suitable for detection of CNS malignant disease.