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PURPOSE Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4–blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy. PATIENTS AND METHODS In a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety. RESULTS A total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A ( P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B ( P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated. CONCLUSION Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients withIn a phase III trial, patients with treatment-naiveA total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rankCombination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

TPS818 Background: Albumin-bound ( nab)-sirolimus, a novel mTOR inhibitor (mTORi) that utilizes nanoparticle technology to preferentially target tumors, is approved in the US for the treatment of adults with malignant PEComa. In an exploratory analysis of the AMPECT registrational trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with TSC1 and TSC2 inactivating alterations, respectively, had confirmed response (Wagner, J Clin Oncol. 2021). Importantly, both TSC1 and TSC2 alterations have been observed in patients with various gastrointestinal cancers (Table). Overall, most treatment-related adverse events (TRAEs) in AMPECT were grade 1/2 and manageable for long-term treatment; no grade ≥4 TRAEs occurred. Methods: PRECISION I (NCT05103358) is a phase 2, open-label, multi-institutional basket trial evaluating efficacy and safety of nab-sirolimus in patients with alterations in TSC1 (Arm A) and TSC2 (Arm B). Patients ≥12 years old with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 (confirmed by central review of next generation sequencing reports) who have progressed on standard therapies and are mTORi-naïve are eligible. nab-Sirolimus 100 mg/m2 will be administered weekly as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate determined by independent review using RECIST v1.1; other endpoints include duration of response, disease control rate, time to response, progression-free survival by independent radiographic review, overall survival, patient-reported quality of life, and safety. Enrollment is ongoing. The most frequent tumor types expected in this tissue-agnostic trial are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric based on the prevalence of TSC1 or TSC2 alterations (Table). Clinical trial information: NCT05103358 . [Table: see text]

Introduced salmonids can impact aquatic ecosystems through direct predation and indirect effects. We explored the effects of introduced Cutthroat Trout (Onchoryncus clarki) on Boreal Toad (Anaxyrus boreas boreas) survival and habitat use during two aquatic life stages, the embryo and tadpole, at Boreal Toad breeding sites with and without Cutthroat Trout. We found no difference in embryo survival and higher tadpole survival at the site with Cutthroat Trout. Cutthroat Trout are unlikely to use the shallow areas where Boreal Toad eggs are deposited; however, during the tadpole stage, Cutthroat Trout and tadpoles overlap broadly in near-shore aquatic habitats. Frequency of tadpole habitat use is lower in Cutthroat Trout–used areas, but we observed no behavioral or temporal avoidance of Cutthroat Trout by tadpoles. Our results suggest that Cutthroat Trout do not have a negative effect on Boreal Toad embryo or tadpole survival in wild settings and that Cutthroat Trout presence does not preclude tadpoles from using habitats.

Objective To explore the role of clinical providers and mothers on young women's ability to have confidential, candid reproductive health conversations with their providers. Methods We conducted 14 focus groups with 48 women aged 15-28 years (n = 9), and 32 reproductive healthcare workers (n = 5). Focus groups were audio recorded and transcribed. Data were analyzed using inductive coding and thematic analyses. We examined findings through the lens of paternalism, a theory that illustrates adults' role in children's autonomy and wellbeing. Results Mothers have a substantial impact on young women's health values, knowledge, and empowerment. Young women reported bringing information from their mothers into patient-provider health discussions. Clinical best practices included intermingled components of office policies, state laws, and clinical guidelines, which supported health workers' actions to have confidential conversations. There were variations in how health workers engaged young women in a confidential conversation within the exam room. Conclusions Both young women and health workers benefit from situations in which health workers firmly ask the parent to leave the exam room for a private conversation with the patient. Young women reported this improves their comfort in asking the questions they need to make the best decision for themselves. Clinic leadership needs to ensure that confidentiality surrounding young women's reproductive health is uniform throughout their practice and integrated into patient flow.

Since around 2008, the shift from Gold (Au) bonding wire to Copper (Cu) bonding wire has been taking place, full scale, with the aim of reducing costs. When compared with Au, Cu wire presents challenges in reliability and repeatable bonding characteristics in terms of chemical stability, which is required in high reliability applications. Therefore Cu wire adoption in automotive and industrial semiconductors has been limited. Conventionally the market for Cu bonding wires has been divided into two types: bare Cu wires (high purity) and Palladium coated copper (PCC) bonding wires. These wires have yet to satisfy the required characteristics for high reliability products such as industrial and automotive electronics. A new breed of alternative bonding wires has been developed to offer performance advantages for high reliability applications compared to bare copper wire and PCC wire. Cu alloy wire and Ag alloy wires continue their market introduction for advanced bonding applications, where bare Cu and PCC wires have known limitations.

The use of large databases has provided advancements in the understanding of racial, ethnic, and socioeconomic disparities in the field of adult hematopoietic cell transplants (HCT). Disparities exist on individual, institutional, and systemic levels for both allogeneic and autologous HCT. We reviewed the most recent publications that utilized large databases to elucidate disparities in HCT and placed them into historical context of the other major studies in the field. Two emerging themes were identified. These themes are persistent inequalities in both allogeneic HCT and autologous HCT for myeloma and the importance of improving homogeneity of care in HCT. Minimization of inequalities can be achieved only with an understanding of the persistent barriers that exist in the field.

Purpose of review Benign prostatic obstruction (BPO) is a common cause of lower urinary tract symptoms (LUTS) in elderly men. However, such symptoms are often caused by primary detrusor overactivity or underactivity. Surgical management where BPO is absent or merely incidental has a lower chance of success, and exposes the patient to the potential complications of surgery. This review discusses the diagnostic challenges facing this common presentation. Recent findings Most evidence comes from small, historical prospective cohort studies. A Cochrane review found only two studies that met the prespecified inclusion criteria. It concluded that urodynamics changed decision-making regarding surgery for LUTS but it was not possible to determine whether this impacted upon outcome. A systematic review of several noninvasive alternatives to urodynamics could not recommend any of them over urodynamic pressure-flow study assessment. Further research is currently in progress, the 'UPSTREAM' study, which is a randomized, multicentre trial. Men are randomized to undergo investigation with clinical evaluation and uroflowmetry, or to additionally receive urodynamics. The primary aim is to determine the impact of urodynamics on the assessment pathway. Summary Assessment of BPO involves determining whether it has a contributory role in individual patients. This is a crucial factor in outcome, as surgery can give poor results if the symptoms are principally caused by detrusor dysfunction (overactivity or underactivity). Urodynamics can help determine this if undertaken to a suitable standard. Further research will identify the precise role of this test modality.

Patients with Lynch syndrome are much more likely to have generally rare upper urinary tract urothelial carcinoma but not bladder urothelial carcinoma. While the risk has been quantified, to our knowledge there is no description of how this population of patients with Lynch syndrome and upper urinary tract cancer differs from the general population with upper urinary tract cancer.We obtained retrospective data on a cohort of patients with Lynch syndrome from the Hereditary Cancer Center in Omaha, Nebraska and compared the data to those on a control general population from western Sweden. These data were supplemented by a new survey about exposure to known risk factors.Of the patients with Lynch syndrome 91% had mutations in MSH2 rather than in MSH1 and 79% showed upper tract urothelial carcinoma a mean of 15.85 years after prior Lynch syndrome-type cancer. Median age at diagnosis was 62 years vs 70 in the general population (p0.0001). Only half of our patients had a significant smoking history and the male-to-female ratio was 0.95. Of patients with Lynch syndrome 51% had urothelial carcinoma in the ureter while it occurred in the renal pelvis in 65% of the general population (p = 0.0013). Similar numbers of high grade tumors were found in the Lynch syndrome and general populations (88% and 74%, respectively, p = 0.1108).Upper urinary tract tumors develop at a younger age and are more likely to be in the ureter with an almost equal gender ratio in patients with Lynch syndrome. It has high grade potential similar to that in the general population.

Research by the U.S. Department of Agriculture and others has shown that food prices in the U.S. vary widely, yet food stamp benefits are the same throughout the country. To examine the impact of local prices on the food-buying power of food stamp recipients, a market basket based on the USDA's Thrifty Food Plan (TFP), upon which food stamp allotments are based, was priced in selected areas of New York State in late May–June and late September–October of 1989. In both survey periods, the mean market basket costs in supermarkets varied from 93% of the current USDA TFP cost in an upstate urban county (Onondaga County), to near 96% of the USDA cost in rural Tioga County, to near 104% in the borough of Brooklyn in New York City. Costs in smaller stores ranged from 107 to 111% of the USDA TFP cost. In June 1989, a household receiving the maximum food stamp allotment would fall from 4 to about 12% short of the resources needed to buy the market basket in the supermarkets sampled in Tioga County and Brooklyn, and at least 17% short in the smaller stores in all three areas. Results indicate that in New York State, local food costs higher than national average costs can contribute to food insecurity. Recommendations are made regarding policies to improve the food security of low income consumers.

Despite a sustained public education campaign aimed at reducing the risks of sudden infant death syndrome (SIDS), it remains one of the leading causes of infant death. This study aims to determine physicians’ knowledge of SIDS and whether physicians are discussing how to reduce the risk of SIDS with parents. A cross-sectional survey is sent to 912 pediatricians, family practitioners, and obstetrician-gynecologists in Central New York State. The response rate is 23.5%. Almost all respondents (99.5%) agree that certain measures can be taken to reduce the risks of SIDS, but 30.3% incorrectly state that the safest sleep position is something other than on the back. Although 97.6% agree that it is important to discuss SIDS with parents, 30% admit to not discussing this information. To continue to decrease the SIDS rate, physicians must take responsibility for educating themselves and parents about safe sleep practices and other SIDS risk factors.

By moving the substrate relative to a shadow mask in a reactive ion etching system, we are able to precisely tailor the thickness of critical layers. To minimize disturbing the plasma, all the mechanical components are kept below the anode. The system is highly reproducible, and can be programmed to yield arbitrary vertical profiles along one horizontal axis. Using silicon‐on‐insulator substrates, the resonance wavelength was modified as a function of position with better than 1 nm control in the vertical dimension. This technique should prove useful for optical devices where the thickness of the layers controls the device characteristics.

A Hall probe was inserted into the magnet of an optically detected magnetic resonance (ODMR) spectrometer to study residual field at zero current, homogeneity, and hysteretic effects. Residual fields were on the order of 10 mT at zero current. The magnet was homogeneous to within one part in 8000 or better over a region of 2.5 cm along its vertical axis. Several hysteresis loops were studied for field sweeps. The largest shifts were about 10 mT. Using the information collected, recommendations are made on how to improve precise field measurements for ODMR.

Abstract 2710 Introduction Recent refinement in B-cell lymphoma classification by the WHO in 2008 has defined an entity that exists in the gray zone between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Varying in morphology, immunohistochemical, or genetic features, B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (Intermediate DLBCL/BL) has been reported to have a poor clinical outcome. We aim to describe the clinical factors affecting outcomes and compare therapy response in a representative population. Methods A retrospective search of the Nebraska Lymphoma Study Group Registry from 1983–2009 meeting the diagnostic criteria for Intermediate DLBCL/BL yielded clinical data at presentation, follow-up, and treatment information. Treatments were grouped as CHOP-like +/− Rituximab (R) vs. intensive regimens (e.g. CODOX-M +/− R, R-EPOCH). Diagnostic slides were re-reviewed to verify the diagnosis. Probabilities of progression-free survival (PFS) and overall survival (OS) were approximated using Kaplan-Meier method. Cox proportional regression analysis was used to evaluate the clinical variables associated with risk of treatment-failure and death. Results Our cohort of 63 patients had a median age of 69 (19–93), male sex in 49%, a Karnofsky performance status of at least 80 at time of diagnosis in 73%, an elevated serum lactate dehydrogenase (LDH) in 62%, and stage IV disease in 46%. International Prognostic Index (IPI) scores were low in 38%, low-intermediate in 27%, high-intermediate in 24% and high in 11%. The probability of PFS at 5 and 10 years was 25% (95% CI 15–37%) and 10% (95% CI 4–21%) respectively, with a median time to treatment-failure of only 5.7 months. The 5 and 10 year probability of OS was 32% (95% CI 21–44%) and 20% (95% CI 10–32%) respectively, with a median survival of 10.4 months. Univariate regression analysis showed the following factors to be associated with an increased risk for treatment-failure: Ann Arbor stage IV disease (HR 2.49, 95% CI 1.33–4.68); elevated LDH (HR 1.85, 95% CI 1.02–3.37) and having at least 2 extra-nodal sites (HR 2.12, 95% CI 1.12–4.04). The following factors were associated with an increased risk of death: elevated LDH (HR 2.03, 95% CI 1.08–3.81), stage IV disease (HR 1.88, 95% CI 1.00–3.45), and having at least 2 extra-nodal sites (HR 2.26, 95% CI 1.15–4.40). The IPI scores of low-intermediate, high-intermediate, and high risk were associated with treatment-failure (HR 2.01, 95% CI 1.00–4.11; 4.62, 95% CI 2.11–10.14; 6.11, 95% CI 2.31–16.17) respectively, and death (HR 2.57, 95% CI 1.23–5.37; 3.13, 95% CI 1.41–6.94; 8.30, 95% CI 3.07–22.43) respectively. The median OS of patients who received CHOP/CHOP-like regimens +/− R was 8.7 months, whereas those who received a more intensive regimen +/− R was 45 months (p=0.38). The median PFS was 5.4 months for CHOP/CHOP-like regimens +/− R and 52.3 months for a more intensive regimen (p=0.08) (Fig.1).Figure 1.Progression free survival intensive versus CHOP/CHOP-like regimens +/− Rituximab, p=0.08Figure 1. Progression free survival intensive versus CHOP/CHOP-like regimens +/− Rituximab, p=0.08 Summary Our analysis confirmed poor clinical outcome with stage IV disease, elevated serum LDH, at least 2 extra-nodal sites at presentation, or worse IPI score. There was a better outcome with intensive chemotherapy regimens. This study underscores the importance of early identification and proper treatment choice. Disclosures: No relevant conflicts of interest to declare.

In one alternative, an audio signal is analyzed using multiple pschoacoustic criteria to identify a region of the signal in which time scaling and/or pitch shifting processing whould be inaudible or minimally audible, and the signal is time scaled and/or pitch shifted within that region. In another alternative, the signal is divided into auditory events, and the signal is time scaled and/or pitch shifted within an auditory event. In a further alternative, the signal is divided into auditory events, and the auditory events are analyzed using a psychoacoustic criterion to identify those auditory events in which the time scaling and/or pitch shifting procession of the signal would be inaudible or minimally audible. Further alternatives provide for multiple channels of audio.

It has been widely conjectured that solar flares are energized by the magnetic energy stored in complex active regions. Paradoxically, however, in attempting to show that magnetic changes cause or characterize flares, solar magnetic observations have produced equivocal results.

Management has had to endorse huge investment spending programs on new product development to insure market position and profits for the future. This places a tremendous burden upon the New Product Department. This article shows why the responsibilities for communicating and administering the technical development phases should be assigned to the central Marketing Research Department.

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A vapor pressure osmometer (VPO) was successfully studied in 1975. An improved osmometer with greater range and temperature stability was evaluated. Repeatability on 290 mOs/kg standard solution was 289.5±1.08. The mean and standard deviation on 36 water-free milk samples was 280.5±4 compared to 280.1±3 in the previous study. Instrument data from 2 osmometers and 2 cryoscopes produced acceptable chi-square values, and the correlation coefficients between methods were better than 0.99 for samples containing 1—21% added water. In a survey involving 760 samples, more than 37% of producer samples in one cheese plant contained > 3 % added water. Additional evidence of added water in market milk samples suggests the immediate application of the VPO to help prevent milk adulteration. The vapor pressure osomometer method for quantitating added water in milk has been adopted as official first action.

A preliminary survey to assess and quantify attitudes to Artificial Insemination by Donor (AID) has been conducted with the aid of an article in a national magazine. The consensus of 375 individuals (mostly with a vested interest in infertility) concerning their attitudes to semen donation, hypothetical receipt of donor semen, legal aspects and the keeping of donor records, etc., have been analysed and their answers correlated to their age, sex, ethnic grouping, educational level, religion, and marital and fertility status as well as their place of residence. Within the limitations of this study, three major conclusions can be drawn. Firstly there are probably many potential semen donors in the general community and recruitment techniques need to be improved to capitalize on this source. Secondly, a centralized non-identifying National Register of donor information may be tolerated, and finally, the couples questioned felt an AID child should not be likened to one received through adoption. These and other findings would suggest that attitudes towards AID are changing and consequently some of the practices within AID programmes may need to be altered. Further statistically conducted surveys are warranted to determine these current attitudes.

The hypothesis that the percentage of dead spermatozoa in an ejaculate is related to their storage time in the extra-gonadal reserve was tested using a protocol where men followed a set ejaculatory pattern. Semen samples were requested as follows: abstinence from ejaculation for at least 3 days (not more than 7 days) followed by production of the first sample, then one ejaculation per day for 4 consecutive days before the second sample; and, lastly, abstinence for a further 4 days and production of the final sample. Within the time scale of the experiment there was no relationship between the percentage of dead spermatozoa in the ejaculate and the preceding period of abstinence, nor was the percentage of dead spermatozoa related to the total number of spermatozoa present. The percentage of non-motile, but vital, spermatozoa similarly exhibited a random pattern. Thus whatever mechanisms are contributing to the mortality of spermatozoa, they are independent of storage time in the extra-gonadal reserve, and total spermatozoal count. Therefore, in the absence of necrozoospermia, this parameter probably contributes little to the overall diagnosis of infertility, but does allow assessment of the functional spermatozoa present.

Spermatozoal depletion of the extra-gonadal reserve (EGR) has been monitored in 14 men by analysing ejaculates collected daily for 5 days. It has been concluded that EGR is stabilized within 2 days and that an estimate of daily spermatozoal output can be obtained either by averaging the values from days 3 to 5 or by using the day 5 value alone. This latter parameter may prove useful clinically.

A vapor pressure osmometer (VPO) was successfully studied in 1975. An improved osmometer with greater range and temperature stability was evaluated. Repeatability on 290 mOs/kg standard solution was 289.5 +/- 1.08. The mean and standard deviation on 36 water-free milk samples was 280.5 +/- 4 compared to 280.1 +/- 3 in the previous study. Instrument data from 2 osmometers and 2 cryoscopes produced acceptable chi-square values, and the correlation coefficients between methods were better than 0.99 for samples containing 1--21% added water. In a survey involving 760 samples, more than 37% of producer samples in one cheese plant contained greater than 3% added water. Additional evidence of added water in market milk samples suggests the immediate application of the VPO to help prevent milk adulteration. The vapor pressure osomometer method for quantitating added water in milk has been adopted as official first action.

SYNOPSISSeventy-three patients who had been continuously receiving lithium carbonate for 6 months or more had their thyroid function evaluated clinically and biochemically. Goitre was found in 37 %, exophthalmos in 23 %, positive thyroid auto-antibodies in 24 % and abnormal TRH tests in 49 %. It would appear that thyroid failure due to lithium is usually dependent on antibody mediated damage. It is unlikely that lithium has a direct effect on the hypothalamic–pituitary axis.

A simple apparatus is described which is used to monitor equipment in the high voltage terminal of a particle accelerator and display the reading on a meter at ground potential. A servo mechanism is used to rotate an insulating rod coupled to a grounded potentiometer. The system, whilst being relatively inexpensive, provides an accuracy better than 1%.

Dermatofibrosarcoma Protuberans (DFSP) is a rare skin tumor, characterized by frequent local recurrence but is seldom metastatic. It is histologically characterized by storiform arrangement of spindle cells. Cytogenetically, most tumors are characterized by translocation 17:22 leading to overexpression of tyrosine kinase PDGFB which can be targeted with tyrosine kinase inhibitor, Imatinib. We describe the first case of unresectable pancreatic metastases from DFSP treated with neoadjuvant Imatinib and subsequently R0 metastectomy. Additionally, a comprehensive systematic review of DFSP pancreatic metastases and the current published data on the use of Imatinib in DFSP is summarized.