TPS214 Background: Multiple systemic therapies have resulted in improved overall survival (OS) for mHSPC, including several AR-targeted agents (ARTA) and docetaxel chemotherapy. However, patients (pts) with high volume de novo metastatic prostate cancer still only have an OS of approximately 50 months. Thus, more effective combination strategies for initial treatment of mHSPC are urgently needed. CABO, a multi-tyrosine kinase inhibitor (including MET, VEGFR-1, -2,-3, AXL) has shown synergy with ABI as well as with CPI in preclinical studies. CABO and ABI have demonstrated an acceptable safety profile in metastatic castration resistant prostate cancer (mCRPC) (Choudhury et al Prostate 2018), and CABO and atezolizumab (ATEZO) in combination have showed a promising efficacy signal and manageable safety profile in mCRPC (COSMIC-021, NCT03170960; Agarwal ESMO 2021). The phase 3 CONTACT-02 trial (NCT04446117) is randomizing mCRPC pts to either CABO and ATEZO or a second generation ARTA. Given the robust preclinical and emerging clinical data for the use of both CABO and CPI therapy in advanced prostate cancer and the need to optimize therapy earlier in the course of disease, in the present trial we intend to evaluate the safety and tolerability of ABI, CABO, and CPI in mHSPC. Methods: CABIOS (NCT04477512) is a phase Ib, single center, open label trial of ABI, CABO and the CPI nivolumab (NIVO), an anti-PD-1 monoclonal antibody, in pts with mHSPC. Key inclusion criteria include histologically or cytologically confirmed metastatic prostate adenocarcinoma without neuroendocrine/small cell differentiation and radiographic evidence of metastatic disease. Ongoing androgen deprivation (ADT) within 12 weeks of study start is allowed. Key exclusion criteria include evidence of castration resistance, prior treatment with second-generation androgen receptor inhibitors, CYP17 inhibitors, CABO, or checkpoint inhibitor immunotherapy (anti-PD-1/PD-L1, CTLA-4), active autoimmune disease, and ongoing treatment with systemic corticosteroids daily. The primary objective of the trial is evaluation of the safety and tolerability of this combination therapy in the trial population; the primary endpoint is the frequency of dose-limiting toxicities (DLTs) as measured by CTCAE v5.0. The study will employ a 3 + 3 design evaluating ABI 1,000 mg once daily with prednisone 5 mg daily, NIVO 480 mg IV every 4 weeks, and a CABO starting dose of 20 mg once daily at dose level 1 (DL1). If 0 of 3 pts at DL1 experience a DLT, 3 pts will be enrolled at DL2 with CABO 40 mg once daily. If 1 of 3 pts at DL1 experience a DLT, 3 additional pts will be enrolled at DL1. If 0 of 3 pts experience a DLT at DL2, the study will move to a recommended phase 2 dose (RP2D) expansion cohort. Total sample size of approximately 20 pts is expected depending on DLT frequencies. Enrollment is ongoing. Clinical trial information: NCT04477512.
The late sequence resulted in less toxicity and was better tolerated. The early sequence maximum-tolerated dose (MTD) was 175/6/0.5 for five days. The late sequence MTD was PCT 175/5/0.75 for five days. The late sequence MTD with G-CSF was 175/5/1.0 for four days. The recommended phase II PCT dose is the late sequence 175/5/1.0 for four days with G-CSF.
Deposition of solids within flat drainage and sewerage conveyance pipes can result in problematic hydraulic restrictions, potential odor and corrosion conditions, and the initial flush of pollutants and solids to receiving waters. This paper reviews planning, design and operational details for managing problematic sedimentation problems within three new major sewer separation project areas in the City of Cambridge. These projects are elements of the City's $300 million dollar, 20-year program of area wide sewer separation and storm water management, and cover a combined area of 426 ha of dense residential, commercial and institutional land uses. Two of the three projects described use passive automatic flushing systems to manage problematic sedimentation problems, while the third project includes a network of in-line grit sump manholes, extensive catch basin rehabilitation, and isolation structures at river outfalls.The first project described summarizes the design of passive automatic flushing systems installed in the City of Cambridge's storm and sanitary sewer system tributary to the Alewife Brook as part of a $95 million dollar sewer separation program. Grit and debris deposition is severe in the existing combined sewers, storm drains, and sanitary trunk sewers due to the flat topography of the area. This condition is exacerbated by hydraulic constraints imposed on the system's outlet by the Alewife Brook (shallow stream) and downstream sanitary siphons (again because of the Alewife Brook). The use of pumps to lift flows from sewers and drains to permit self-scouring velocities is prohibitively expensive. To overcome this problem, five automated flushing systems using quick opening (hydraulic operated) gates discharging collected storm water are constructed in conjunction with downstream collector grit pits covering a distance of 1604 m for storm drain pipes ranging from 1.4 m circular to 1.2 m by 1.8 m rectangular. New 450 mm and 600 mm sanitary trunk sewers, 561 m long are flushed daily by two flushing systems using spent filtrate water from Cambridge's water treatment plant recently constructed nearby. The flushing systems are sized to achieve wave velocity of 1 m/s the end of the flushing segment. The flush vault volumes range from 11 to 40 m 3 for the storm drain systems and 6 m 3 for the sanitary system. Construction was completed in May 2002 and functional testing of the flushing systems occurred in 2004. Partial test results are reported. 629This paper also reviews the Crescent Carver sewer separation and storm water management project behind Harvard University. This project is an element of a multi-phased program designed to reduce sewage and storm water flooding within a 166 ha densely populated residential area. Six new storm water off-line retention tanks totaling 5700 m 3 have been constructed as the existing combined sewer system in the area is over a century old and cannot contain the high rate of storm water and sanitary flow during heavy rainstorms. These conditions result in sewage surchargi...
Infrequently, patients are diagnosed with Hodgkin's lymphoma and a morphologically distinct lymphoma. While specific subtypes of lymphomas (including Hodgkin's lymphoma) may present diagnostic difficulties, fine needle aspiration biopsy (FNAB) is sometimes useful in the evaluation and classification of these lymphoproliferative processes. We report a case of the blastic variant of mantle cell lymphoma following Hodgkin's lymphoma, interfollicular variant. A 66-year-old woman with a history of Hodgkin's lymphoma presented with increasing contralateral cervical adenopathy three years after receiving chemotherapy. FNAB with ancillary immunophenotypic characterization identified mantle cell lymphoma, blastic variant. Subsequent excisional biopsy confirmed this diagnosis and also aided in the exclusion of recurrent Hodgkin's lymphoma. In addition to identifying the previously unreported combination of blastic variant of mantle cell lymphoma and Hodgkin's lymphoma, this case emphasizes the utility of FNAB in evaluation of new masses in patient's with a previous diagnosis of Hodgkin's lymphoma.
Objective.—To report a method for flow cytometric immunophenotyping (FCI) bone marrow (BM) core biopsies in patients with hematologic malignancies of the BM who present with a failed BM aspiration (“dry tap”). Design and Setting.—Core biopsy specimens of BM were obtained from 8 patients who presented with previously undiagnosed hematologic malignancies arising in (7 cases) or secondarily involving (1 case) the BM and a dry tap. Suspensions of the BM core biopsy specimens were prepared and analyzed by FCI methods. Data Extraction and Data Synthesis.—The FCI data were analyzed in conjunction with cytomorphologic, histologic, immunohistochemical, and cytogenetic findings in all cases to determine a final diagnosis. Conclusions.—The prepared BM core suspensions were viable and allowed for a complete immunophenotype profile by FCI in all cases, resulting in a clear definition of the cell of origin of the hematologic malignancy. Because of lack of preservation of architectural features and the potential for artifactual alterations of the relative frequency of abnormal cells, the FCI data must always be correlated with histologic sections of the BM biopsy.
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