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Initial II: New Stage
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Purpose: Pathologic stage II melanoma patients have variable outcomes when divided by substage. We hypothesized that an understanding of the patterns of initial relapse by substage will better inform follow-up guidelines.
Methods: We performed a retrospective review of 738 adult patients with pathologic stage II cutaneous melanoma treated at Memorial Sloan Kettering Cancer Center between 1993 and 2013. Clinical records were reviewed to determine time, location, and method of detection of initial relapse.
Results: At a median follow-up of 52 months, 219 patients relapsed. Relapses were detected more frequently in higher substages. Initial relapses were most commonly local/in-transit for IIA and IIB and systemic for IIC. Lung and brain were the most frequent sites of systemic relapse. Patient-detection was the most common method of relapse detection (59%) in all substages. The 5-year cumulative incidence for patient-detected relapse was 13.6% for IIA, 18.9% for IIB, and 23.3% for IIC and for image-detected relapse was 3.4, 7.9, and 16.6%, respectively. The 5-year cumulative incidence for physician-detected relapse was less than 10% across all substages and leveled off at 3 years for stage IIA and IIB and 2 years for stage IIC.
Conclusions: Relapses were most frequently patient-detected in all stage II substages, highlighting the importance of patient education and self-examination. The highest yield for routine imaging is in stage IIC patients during the first 4 years. Physician examination is unlikely to detect relapses beyond 3 years for stage IIA and IIB and beyond 2 years for stage IIC patients.
Site of first relapse by sub-stage. Percentage of stage IIA (a), stage IIB (b), or stage IIC (c) patients who relapsed with a local/in-transit (LCIT), regional nodal (NOD), or systemic (SYS) relapse. Percentages of LCIT, NOD, and SYS relapses are represented as percent of relapsing patients. *No relapse detected at the time of last follow-up. (d) Site of first systemic relapse by sub-stage. Percentages represent percentage of relapsing patients within the listed sub-stage.
Method of detection of first relapse. a) Divided by site of first relapse: local/in-transit (LCIT), nodal (NOD), and systemic (SYS). b) Divided by pathologic sub-stage.
Cumulative incidence of relapse by method of detection for stage IIA (a), stage IIB (b), and stage IIC (c) patients. d) 5-year cumulative incidence and 95% confidence interval (in parentheses) for relapse and death without relapse. Relapses are broken down by method of detection and sub-stage.
We reviewed 738 pathologic stage II cutaneous melanoma patients and determined their patterns of relapse and method of relapse detection by sub-stage. Based on results from this descriptive analysis, we make sub-stage-specific recommendations for follow-up guidelines in stage II melanoma patients.
Under the challenge process framework established by the Commission in the MF-II Challenge Process Order, mobile providers were required to submit current, standardized coverage data on qualified 4G LTE service. These data were used, in conjunction with subsidy data from the Universal Service Administrative Company (USAC), to establish the map of areas presumptively eligible for MF-II support (initial eligible areas map). Interested parties had an opportunity to challenge the initial determination that an area was ineligible for MF-II support during the MF-II challenge process.
To allow for the public to better understand the issues faced during the MF-II proceeding, staff has released the provider-specific 4G LTE coverage data submitted by mobile providers. These data, alongside the initial eligible areas, complete set of speed tests certified by challengers during the challenge process, and speed tests conducted by staff for the coverage maps investigation, are available under the Data tab above.
There are four functional Implementation Stages: Exploration, Installation, Initial Implementation, Full Implementation. Stages of implementation do not cleanly end as another begins. Instead, stages overlap with activities related to one stage still occurring as activities for the next stage begin. Likewise, it is often necessary to revisit previous stages when circumstances change (e.g., change in staff/leadership, data identifies an area where changes are required).
When a decision is made to begin implementing a new initiative, is your first reaction often excitement with a side of panic Do you already feel behind before you even started Have you ever wondered if there is a way to be proactive about implementation instead of reactive Check out this video for an overview of implementation stages and the purpose of intentionally working through each stage. Click to Tweet
Eyevensys has successfully completed Part 1 of a clinical safety study of its lead product EYS606, a non-viral vector encoding an anti-TNFα protein. Tumor necrosis factor alpha (TNFα) is a cytokine that has been shown to play a pivotal role in mediating intraocular inflammation. The trial enrolled nine patients (three patients per cohort) with late-stage, NIU in France and the U.K. The study revealed no serious adverse events related to the Eyevensys technology and the overall early safety profile was similar to that of other intraocularly administered ophthalmic treatments.
Despite their advanced disease stage at enrollment three of the 9 patients treated with EYS606 showed clinical improvements lasting for six months after one administration of the treatment. The first patient treated in the lowest dose cohort experienced a >10 ETDRS letter improvement in best corrected visual acuity while two patients treated in the highest dose cohort showed a significant reduction of macular edema via optical coherence tomography (OCT) associated with at least +12 ETDRS letters increase in BCVA from baseline.
Eyevensys is a private clinical stage biotechnology company developing its innovative technology to enable the sustained intraocular production of therapeutic proteins to treat a broad range of ophthalmic diseases.
Two additional capabilities were afforded by the 2011 Reauthorization,referred to as Cross-program and Cross-Agencyawards. Cross-program awards enable a Phase I STTRaward winner to receive a Phase II SBIR award or the reverse;while the concept of Cross-Agency awards enables anyAgency to fund an initiative in Phase II that was initially fundedby another Agency in Phase I. This can be particularly helpfulwhen the Agency that funded the Phase I award no longer hasthe funds to support a Phase II initiative. Be sure to consult withthe SBIR program manager responsible for your Phase I awardto determine how to take advantage of these opportunities.
(iv) A commitment that an Institutional Review Board (IRB) that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of each of the studies in the proposed clinical investigation and that the investigator will report to the IRB proposed changes in the research activity in accordance with the requirements of part 56.
(6) Protocols. (i) A protocol for each planned study. (Protocols for studies not submitted initially in the IND should be submitted in accordance with 312.30(a).) In general, protocols for Phase 1 studies may be less detailed and more flexible than protocols for Phase 2 and 3 studies. Phase 1 protocols should be directed primarily at providing an outline of the investigation - an estimate of the number of patients to be involved, a description of safety exclusions, and a description of the dosing plan including duration, dose, or method to be used in determining dose - and should specify in detail only those elements of the study that are critical to safety, such as necessary monitoring of vital signs and blood chemistries. Modifications of the experimental design of Phase 1 studies that do not affect critical safety assessments are required to be reported to FDA only in the annual report.
(7) Chemistry, manufacturing, and control information. (i) As appropriate for the particular investigations covered by the IND, a section describing the composition, manufacture, and control of the drug substance and the drug product. Although in each phase of the investigation sufficient information is required to be submitted to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary with the phase of the investigation, the proposed duration of the investigation, the dosage form, and the amount of information otherwise available. FDA recognizes that modifications to the method of preparation of the new drug substance and dosage form and changes in the dosage form itself are likely as the investigation progresses. Therefore, the emphasis in an initial Phase 1 submission should generally be placed on the identification and control of the raw materials and the new drug substance. Final specifications for the drug substance and drug product are not expected until the end of the investigational process.
(iii) As drug development proceeds and as the scale or production is changed from the pilot-scale production appropriate for the limited initial clinical investigations to the larger-scale production needed for expanded clinical trials, the sponsor should submit information amendments to supplement the initial information submitted on the chemistry, manufacturing, and control processes with information appropriate to the expanded scope of the investigation.
(b ) Drug product. A list of all components, which may include reasonable alternatives for inactive compounds, used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear but which are used in the manufacturing process, and, where applicable, the quantitative composition of the investigational drug product, including any reasonable variations that may be expected during the investigational stage; the name and address of the drug product manufacturer; a brief general description of the manufacturing and packaging procedure as appropriate for the product; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug product; and information sufficient to assure the product's stability during the planned clinical studies. Reference to the current edition of the United States Pharmacopeia - National Formulary may satisfy certain requirements in this paragraph. 59ce067264