14-d Cycle Research Articles

TROPHU-U-01 cohort 5: Evaluation of maintenance sacituzumab govitecan (SG) plus zimberelimab (ZIM), ZIM, or avelumab in cisplatin-eligible patients (pts) with unresectable or metastatic urothelial cancer (mUC).

TPS598 Background: SG is an antibody-drug conjugate composed of an anti-trophoblast cell-surface antigen-2 (Trop-2) antibody coupled to a topoisomerase-I inhibitor, SN-38, via a hydrolyzable linker. In Cohort 1 of the phase 2 TROPHY-U-01 trial, SG monotherapy resulted in a 27% objective response rate (ORR) and median overall survival (OS) of 10.9 months with an overall manageable toxicity profile in pts with locally advanced or mUC who previously received platinum-based therapy and a checkpoint inhibitor (CPI; Tagawa S, et al. J Clin Oncol. 2021). These results led to accelerated FDA approval of SG in this population. The CPI ZIM is a fully human IgG4 monoclonal antibody targeting PD-1. CPIs are active in mUC, including avelumab that is FDA-approved as switch maintenance therapy for locally advanced or mUC that has not progressed with first-line platinum-based chemotherapy. Cohort 5 of the TROPHY-U-01 trial will evaluate the safety, tolerability, and efficacy of SG + ZIM vs ZIM alone vs avelumab as switch maintenance in pts with mUC who have received gemcitabine (GEM)/cisplatin without progressive disease (PD). Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 trial. Cohort 5 includes pts who have not progressed after completion of 4-6 cycles of GEM/cisplatin. Key eligibility requirements include ≥18 y; ECOG PS 0-1; available tissue for biomarker testing; adequate blood counts without transfusion or growth factor within 2 weeks of study drug initiation; creatinine clearance ≥30 mL/min. A safety lead-in of 6-8 pts will be conducted, where pts will be treated with SG 10 mg/kg IV on D1 and D8 of a 21-D cycle plus ZIM 360 mg IV q3wk on a 21-D cycle. On safety lead-in, if SG + ZIM is deemed safe, pts will be randomized 1:1:1. Those in Arm 1 will receive SG 10 mg/kg IV on D1 and D8 of a 21-D cycle followed by ZIM 360 mg IV, q3wk (D1 of a 21-D cycle). Pts in Arm 2 will receive avelumab 800 mg IV q2wk (D1 of a 14-D cycle). Pts in Arm 3 will receive ZIM 360 mg IV q3wk. All pts will continue treatment until PD, unacceptable toxicity, or loss of clinical benefit. The primary endpoint is progression-free survival based on central review by RECIST 1.1 criteria. Secondary endpoints include OS (all arms), safety/tolerability of SG in combination with ZIM (Arm 1). Cohort 5 aims to enroll an estimated 158 pts. A sample size of 50 pts per randomized arm is determined based on clinical consideration for exploring the activity of anticancer agents. Clinical trial information: NCT03547973 .

OMNIVERSE: A Phase 1b/2 Study of Oral Azacitidine Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed (ND) Acute Myeloid Leukemia (AML)

OMNIVERSE: A Phase 1b/2 Study of Oral Azacitidine Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed (ND) Acute Myeloid Leukemia (AML)

Tetracycline inhibition and transformation in microbial fuel cell systems: Performance, transformation intermediates, and microbial community structure

Tetracycline (TC) transformation in the anode of an air cathode microbial fuel cell (MFC) and in the cathode of an MFC-Fenton system was investigated. TC at 10 mg/L in the anolyte was removed by 43–74% in 14-d cycles, mainly attributed to adsorption. The electrochemical activity, COD and acetate consumption of the anodic biofilm were inhibited by TC; inhibition was reversed when TC addition was stopped. Over 84 d of MFC operation with TC, Geobacter and Mycobacterium in the anode biofilm decreased, while Janthinobacterium and Comamonas increased. Over 99% of TC at 10–40 mg/L was removed within 8 h in the MFC-Fenton cathode. O2−•/HO2• and •OH were responsible for the cathodic TC degradation. The maximum current was 0.93 mA (at 250 Ω) and increased by 36.3% by the MFC-Fenton reaction. Cathodic MFC-Fenton is an efficient and energy-saving process for TC removal, compared to slow and problematic anodic TC bio-oxidation.

Letter: Maintaining Neurosurgical Resident Education and Safety During the COVID-19 Pandemic.

Letter: Maintaining Neurosurgical Resident Education and Safety During the COVID-19 Pandemic.

Neoadjuvant Dose-dense Gemcitabine and Cisplatin in Muscle-Invasive Bladder Cancer: Results of a Phase 2 Trial

BackgroundAccelerated (also termed dose-dense, DD) chemotherapy regimens such as accelerated methotrexate, vinblastine, doxorubicin, and cisplatin have shown better efficacy and tolerability in the metastatic setting, and shortened the time to surgery in the neoadjuvant setting compared to standard-schedule regimens. We hypothesized that a DD schedule of gemcitabine and cisplatin (GC) would shorten the time to surgery and yield similar pathologic complete response rates (pT0) in patients with muscle-invasive bladder cancer (MIBC) compared with historical controls with standard GC. ObjectiveTo determine the safety and efficacy of neoadjuvant DDGC in MIBC. Design, setting, and participantsPatients with cT2–4a, N0–1, M0 MIBC were eligible and received three 14-d cycles of DDGC with pegfilgrastim support followed by radical cystectomy with lymph node dissection. The primary end point was the pT0 rate. Molecular subtypes were assigned and correlated with survival. Results and limitationsThirty-one patients were evaluable for toxicity and response, of whom 58% had baseline clinical stage >T2N0M0; the median age was 69 yr. Ten patients (32%, 95% confidence interval [CI] 16–49%) achieved ypT0N0 status at cystectomy. Another four patients (13%, 95% CI 1–25%) were downstaged to non–muscle-invasive (<pT2N0) disease. Most patients (54.8%) experienced only grade 1–2 treatment-related toxicities. However, seven patients (23%) had clinically significant vascular events, leading to early closure of the study. Thirty patients (94%) underwent cystectomy. The median time from the start of chemotherapy to cystectomy was 9.3 wk. There was no correlation between molecular subtypes and survival. ConclusionsDDGC yielded a similar pT0 rate to that noted retrospectively with standard GC. Vascular events precluded, delayed, or increased the risk of surgery for 23% of patients, resulting in early closure of the study. Additional prospective studies with embedded biomarker correlatives of GC in the neoadjuvant setting are critical to accurately define both the activity and toxicity of this combination in MIBC. Patient summaryNeoadjuvant chemotherapy before cystectomy is the standard of care for MIBC. This prospective phase 2 study tested a DD schedule of GC in MIBC. The study was closed early because of a higher than expected rate of vascular events. These data suggest that caution is required in using this regimen, particularly when there is better prospective evidence for the safety and efficacy of alternative regimens such as dose-dense or accelerated methotrexate, vinblastine, doxorubicin, and cisplatin.This clinical trial is registered at ClinicalTrials.gov as NCT01611662.

Lactation performance of Holstein cows treated with 2 formulations of recombinant bovine somatotropin in a large commercial dairy herd in Brazil

The objectives of this controlled study were to compare the effects of 2 different formulations of recombinant bovine somatotropin (rbST) on milk yield, milk composition (fat and protein), milk somatic cell count, and body condition score (BCS) among dairy cattle in a large commercial herd. Regulatory approved 500-mg zinc sesame oil base rbST (ZSO-rbST; Elanco Animal Health, Greenfield, IN) and vitamin E lecithin base rbST (VEL-rbST; LG Life Sciences, Seoul, South Korea) formulations were administered per the manufacturers' recommendations every 14 d over 17 injection cycles starting at 57 to 70 d of lactation (90 cows per rbST group). Control cows (n = 60) received no rbST. Somatotropin-treated animals (VEL-rbST and ZSO-rbST combined) had increased average milk yield and protein percentage and lower average BCS compared with control cows. For primiparous cows, average milk yield was 37.75 kg/d with the ZSO-rbST treatment and 35.72 kg/d with the VEL-rbST treatment. For multiparous cows, average milk yield was 40.13 kg/d with the ZSO-rbST treatment and 38.81 kg/d with the VEL-rbST treatment. There were no differences in milk fat percentage between VEL-rbST and ZSO-rbST treatments, but milk protein content was greater with VEL-rbST treatment than with ZSO-rbST treatment. Nonetheless, cows treated with ZSO-rbST yielded more kilograms of fat and protein per day than cows treated with VEL-rbST. No significant differences in BCS were found between both rbST treatment groups. The differential increase in milk yield between cows treated with ZSO-rbST and VEL-rbST was driven by rbST response differences both within the 14-d cycle and throughout the 17 injection cycles. The cows treated with VEL-rbST demonstrated a more variable 14-d milk yield response curve, with more pronounced valleys between injections compared with the ZSO-rbST formulation. In addition, only the ZSO-rbST treatment was effective in modifying the lactation persistency compared with control cows. Compared with the VEL-rbST formulation, the ZSO-rbST formulation yielded more kilograms of milk, fat, and protein with less milk variation throughout the seventeen 14-d lactation cycles for both primiparous and multiparous cows.

Fortnightly modulation of San Andreas tremor and low-frequency earthquakes

Earth tides modulate tremor and low-frequency earthquakes (LFEs) on faults in the vicinity of the brittle-ductile (seismic-aseismic) transition. The response to the tidal stress carries otherwise inaccessible information about fault strength and rheology. Here, we analyze the LFE response to the fortnightly tide, which modulates the amplitude of the daily tidal stress over a 14-d cycle. LFE rate is highest during the waxing fortnightly tide, with LFEs most strongly promoted when the daily stress exceeds the previous peak stress by the widest margin. This pattern implies a threshold failure process, with slip initiated when stress exceeds the local fault strength. Variations in sensitivity to the fortnightly modulation may reflect the degree of stress concentration on LFE-producing brittle asperities embedded within an otherwise aseismic fault.

Randomized phase II open-label study of mFOLFOX6 in combination with linifanib or bevacizumab for metastatic colorectal cancer.

3532 Background: Linifanib is a potent and selective inhibitor of VEGF/PDGF receptors. This trial assessed the efficacy and safety of mFOLFOX6 in combination with linifanib or bevacizumab as second-line treatment for metastatic colorectal cancer (mCRC). Methods: Patients (pts) with measurable mCRC refractory to 1 prior regimen and ECOG PS 0–1, stratified by prior bevacizumab treatment and radiotherapy, were randomized to receive mFOLFOX6 with bevacizumab 10 mg/kg on day (d) 1 of 14-d cycle (Arm A), mFOLFOX6 with daily linifanib 7.5 mg (Arm B), or mFOLFOX6 with daily linifanib 12.5 mg (Arm C). The primary endpoint was progression-free survival (PFS). Severity of adverse events (AEs) was graded using NCI-CTCAE v3.0. Results: 148 pts were randomized at 45 sites in 14 countries. 32 pts (21.6%) had received prior bevacizumab. PFS and response data are shown below (Table). Median survival (OS) was not reached at median follow up 7.6 months. Palmar-plantar erythrodysesthesia (PPE) was the only Grade 3/4 AE significantly higher on linifanib (high dose, 16.3%) vs. bevacizumab (0%). Rate of any Grade 3+ AE was significantly higher on linifanib vs. bevacizumab.Hypertension rates were 41.7% (Arm A), 40.0% (Arm B), and 36.7% (Arm C). AEs dose-related to linifanib were constipation, proctalgia, stomatitis, fatigue, weight decrease, decreased appetite, and PPE. Conclusions: The addition of linifanib to mFOLFOX6, compared to mFOLFOX6 + bevacizumab, did not provide a PFS advantage for mCRC. OS results will be updated for conference presentation. [Table: see text]

Phase II study of gemcitabine combined with oxaliplatin in relapsed or refractory paediatric solid malignancies: An innovative therapy for children with Cancer European Consortium Study

Aim To assess objective response rates after 4 cycles of gemcitabine in combination with oxaliplatin in children and adolescents with relapsed or refractory solid tumours. Methods This multicentre, non-randomised Phase II study included five strata: neuroblastoma, osteosarcoma, medulloblastoma and other CNS tumours strata with two-stage Simon designs and a miscellaneous, extra-cranial solid tumour stratum with descriptive design. Eligibility criteria included: age 6 months to 21 years; measurable, relapsed or refractory solid malignancy; no more than one previous salvage therapy. Gemcitabine was administered intravenously at 1000 mg/m 2 over 100 min followed by oxaliplatin at 100 mg/m 2 over 120 min on Day 1 of a 14-d cycle. Tumour response was assessed every 4 cycles according to WHO criteria. Results Ninety-three out of 95 patients enrolled in 25 centres received treatment: 12 neuroblastoma; 12 osteosarcoma; 14 medulloblastoma; 13 other CNS tumours and 42 miscellaneous non-CNS solid tumours. Median age was 11.7 years (range, 1.3–20.8 years). Tumour control (CR + PR + SD) at 4 cycles was obtained in 30/93 evaluable patients (32.3%; 95% confidence interval (CI), 22.9–42.7%), including four PR: 1/12 patients with osteosarcoma, 1/12 with medulloblastoma, 1/12 with rhabdomyosarcoma and 1/4 with other sarcoma. Five out of 12 eligible patients with neuroblastoma experienced stable disease. During a total of 481 treatment cycles (median 4, range 1–24 per patient), the most common treatment-related toxicities were haematologic (leukopenia, neutropenia, thrombocytopenia) and neurological (dysesthesia, paresthesia). Concluding statement The gemcitabine–oxaliplatin combination administered in a bi-weekly schedule has acceptable safety profile with limited activity in children with relapsed or refractory solid tumours.

Updated results of a phase II trial integrating gefitinib (G) into concurrent chemoradiation (CRT) followed by G adjuvant therapy for locally advanced head and neck cancer (HNC)

6028 Background: This study was undertaken to evaluate the tolerability and efficacy of substituting G for paclitaxel into a well- described CRT regimen (Clin Cancer Res 9: 5936; JCO 21: 320) and continuing G as adjuvant therapy. Endpoints included complete response (CR) rate to CRT, progression-free (PFS), disease-specific (DSS) and overall survival (OS), and local &amp; distant control rates. Methods: Previously untreated subjects with stage III, IVa, or IVb squamous cell, poorly differentiated carcinomas, or lymphoepithelioma were enrolled. Organ sparing surgery was allowed. Subjects received 2 cycles of carboplatin/paclitaxel induction followed by CRT with G (250 mg PO qd), 5- fluorouracil, hydroxyurea, and twice daily radiation on day 1–5 of five 14d cycles. G was continued for 2 years from the start of CRT. Results: From 2/03 to 10/04, 67 eligible subjects accrued including 51 males; median age 56; ECOG PS 0 in 47, 1 in 19, and 2 in 1; stage IV in 61 (91%). With median follow-up of 858 days, 9 have had progressive disease (PD, 3 distant, 5 local, 1 with both) and 15 have died (12 related to HNC). Estimated OS=83% at 2y, 73% at 3y; PFS=77% at 2y, 64% at 3y; and DSS=86% at 2y, 80% at 3y. In 56 evaluable subjects we observed 51 CR (91 %), 4 partial responses and 1 PD after CRT. Non-evaluable subjects underwent surgery prior to CRT (10), or died prior to evaluation (1). Grade 3/4 toxicity included mucositis (75%/10%), dermatitis (29%/3%), rash (4%/0%) and diarrhea (1%/0%). Sixty-two patients received maintenance gefitinib, with 60 reliably reporting doses (median days on gefitinib=667). Reasons for holding G included LFT abnormalities, patient refusal, diarrhea, rash, recurrence, hospitalization for acute illness, and early death. Conclusions: Adding G to concurrent CRT after induction therapy, and as adjuvant therapy is tolerable and feasible. Favorable survival and CR data suggest that this is a promising regimen for patients with locally advanced HNC. [Table: see text]

Environmental lighting alters the infection process in an animal model of AIDS

In this study, we examined the effects of altered environmental lighting on the infection process of a murine leukemia virus, E-55(+), which induces a thymic lymphoma/leukemia in 100% of BALB.K mice inoculated as adults. One to two weeks after inoculation, high levels of proviral DNA are usually found. This is followed by an asymptomatic period of many weeks during which proviral DNA becomes essentially undetectable. Leukemia develops approximately 28 weeks postinoculation. In this experiment, one group of mice was exposed a consistent 10L : 14D cycle while a second was maintained in constant light (LL). A third group was exposed to a rotating cycle characterized by phase shifting a 10L : 14D cycle every three 24-h days (rLD). All cycles began 2 weeks prior to inoculation and were maintained thereafter. Animals were sacrificed at 1, 5, 10, and 15 weeks, and hematopoietic tissue was examined for proviral DNA content. At 1 week, LL- and rLD-exposed animals showed considerably less proviral DNA in bone marrow and spleen compared with controls. At 15 weeks, thymuses from controls were showing signs of infection whereas tissue from LL and rLD mice remained at background levels. We conclude that environmental lighting does alter the infective pattern displayed by this retrovirus, although whether this effect is mediated by changes in the target stem cells or through immunoenhancement has not yet been determined.

Reproductive effects of olfactory bulbectomy in the Syrian hamster.

The effects of olfactory bulbectomy on circulating gonadotropin, prolactin and testosterone levels and on the testicular and pituitary responses to shortening of day length were studied in Syrian hamsters. Adult animals maintained on a 14L:10D cycle were sham-operated or sustained bilateral radical olfactory bulbectomies by aspiration to remove the main and accessory olfactory bulbs and the adjacent regions of the anterior olfactory nucleus. They were then maintained either on the long photoperiod or housed on a 10L:14D cycle. Testicular length was measured at weekly intervals over a 5-mo period. Sham-operated controls exhibited the normal pattern of testicular regression and eventual recrudescence on the short photoperiod. Testicular regression was significantly reduced in bulbectomized animals. Many of these animals showed no regression; others exhibited a reduced degree and/or shortened duration of regression. Serum levels of follicle-stimulating hormone (FSH) were substantially elevated in bulbectomized males maintained in long days. Their serum levels of luteinizing hormone (LH), prolactin and testosterone remained within the range for shams on long photoperiod. In short days, the bulbectomized animals showed the normal, pronounced decline in circulating prolactin levels. Serum FSH and LH levels also showed substantial declines, but the FSH levels were not reduced below the range for controls in long days, and the decline in LH levels was not as great as that for controls in short days.(ABSTRACT TRUNCATED AT 250 WORDS)

Frontal zone analysis at the mouth of Saanich Inlet, British Columbia, Canada

The presence of a biological front at the mouth of an inlet (fjord) on the coast of British Columbia, Canada was established. The presence of the biological front was consistent with physical predictions based on water velocity and depth. The frontal zone was characterized by a high primary productivity and surface chlorophyll. From spectral analysis of data the zone was found to fluctuate under tidal influence so that observations made at a single point showed a 14-d cycle in chlorophyll maxima which was about 180° out of phase with maxima in tidal exchange.

Evidence for a Sexual Cycle in the Florida Red Tide Dinoflagellate, Ptychodiscus brevis (=Gymnodinium breve)

Sexual stages (gametes, planozygotes) were observed in non-clonal strains of Ptychodiscus brevis stock cultures. Sexual stages were induced repeatedly in nonclonal isolates and crosses of six different isolates using nitrogen-deficient NH-15 medium, blue or green light, and/or lowered temperatures. Sexual stages also have been observed in field populations during Florida red tides. So far, hypnozygotic cysts have not been confirmed in laboratory cultures or field populations, although possible cysts have been observed during cold temperature experiments, initial experiments with multiple crosses, and during continuous 24-hour sampling during a red tide cruise in January 1980. Steidinger (1975a,b) proposed that blooms of the Florida toxic dinoflagellate, Ptychodiscus brevis (Davis) Steidinger, began 18-74 km offshore with a seed population and that the entire bloom cycle of initiation, support, and maintenance was mediated by hydrologic and meteorologic factors. Finucane (unpublished), Wilson (1967), and Steidinger & Ingle (1972) had postulated a benthic resting cyst stage for P. brevis and Steidinger suggested that cysts accumulated forming cyst beds. She further suggested that numerous cysts in these beds, when triggered by proper conditions, could excyst en masse to provide the seed population for a bloom. Oceanic fronts are thought to trigger excystment by changing the temperature over the sediment or lifting the cysts off the bottom into more suitable regions of light, temperature, and/or nutrients (Freeberg & Heyl, 1978; Hiaddad & Carder, 1979; Steidinger & Haddad, 1981). Although Wilson (1967) and Loper (unpublished) had observed possible gametic fusion, later sexual stages (planozygotes, hypnozygotes), necessary to confirm a sexual cycle, were not observed. This report describes gametes, planozygotes, and possible hypnozygotes (cysts) for P. brevis. MATERIALS AND METHODS Seven strains of Ptychodiscus brevis, isolated from waters off the west coast of Florida, were used in this study: a diploid (Loper et al., 1980) 1953 strain; haploid 1971, 1974, 1976, and 1977 strains; and haploid clonal 1978 P5 and P; strains. Cultures were maintained in stock TRIS-sulfide enriched NH-15 medium (based on Gates & Wilson, 1960, with four times as much TRIS and five times as much sulfide mix) of 30-32%o salinity at 24-26?C and ca. 6,200 /tW cm2/s (cool-white fluorescent bulbs) on a 10L:14D cycle. Culture transfers, inoculations, and medium additions were done with sterile Pasteur pipettes using a laminar flow hood. Sexual induction experiments TRANS. AM. MICROSC. Soc., 101(3): 287-293. 1982. ( Copyright, 1982, by the American Microscopical Society, Inc. This content downloaded from 157.55.39.243 on Wed, 05 Oct 2016 04:52:36 UTC All use subject to http://about.jstor.org/terms TRANS. AM. MICROSC. SOC. were conducted in the three-spot well/Petri dish isolation chambers described by Walker & Steidinger (1979). Crosses of the seven isolates were made by adding a small inoculum of each of two isolates to a spot-well. Cells were checked regularly for 3-8 weeks using a Zeiss Stereomicroscope IV-6 placed in the laminar flow hood. A Zeiss Photomicroscope III was used for more detailed observations, measurements, and photography. Sexual stages were looked for in the seven isolates and all possible crosses of the isolates grown in stock NH-15 medium. Additionally, isolates and crosses were subjected to inorganic nitrogen-deficient NH-15 medium, lowered salinity, lowered temperature, blue and green filtered light, and darkness in an attempt to induce sexual stages. Three crosses and the 1971 isolate also were subjected to seven modifications of stock NH-15 medium. Inorganic nitrogen-deficient medium was prepared by omitting KNO3, NH4Cl, and NH4VO3 from stock NH-15 medium. Five modified media were prepared by omitting: (1) vitamins; (2) vitamins and KNO3; (3) trace elements and chelator; (4) trace elements, chelator, and KNO3; or (5) vitamins, trace elements, and chelator. Two additional media were prepared by increasing: (1) vitamins by lOx and (2) trace elements and chelator by 10x. Initial experiments inoculating P. brevis directly into stock NH-15 or modified NH-15 media resulted in stress or death of the cells within 24-48 h. In all subsequent experiments, media were mixed either with equal volumes of inoculating medium or of filtered medium from a stationary 1974 P. brevis culture. The use of preconditioned medium eliminated this mortality. Double-distilled deionized water was used to lower the salinity of stock NH-15 medium to 26-28%o. Temperatures were lowered to 14-15?C, or 18?C, by placing the spot-well isolation chambers in water baths cooled by a chillercirculator. When testing the effect of cooler temperatures on sexual induction, stock cultures and crosses were subjected to lower temperatures immediately after inoculation. For cyst induction, crosses were made to obtain sexual stages before lowering the temperature to 18?C. Ziptone films were placed between the cultures and the fluorescent bulbs to produce blue and green light of approximately 488 and 532 nm, respectively.