Introducing double fortified salt in social safety net programmes in Madhya Pradesh and Gujarat in India: Success factors, challenges and lessons learned.

Double fortified salt (DFS; with iron and iodine) was introduced in social safety net programmes (SSNPs) in Madhya Pradesh (MP) and Gujarat states in 2018. Nutrition International (NI) provided critical support for the intervention. An impact evaluation in MP found high DFS uptake, exceeding 90%. Conduct a process evaluation of the DFS programmes in MP and Gujarat states to identify success factors, challenges, and recommend considerations for scale-up. Twenty-eight qualitative interviews were conducted with NI staff, national and state level government officials, and DFS producers in 2022. Enabling environmental factors included national-level support for food fortification, consensus that anaemia was essential to address, and institutional trust in NI for technical assistance. In programme implementation, the primary challenges were reports of black specks in DFS and the darkening of food cooked with DFS. NI supported the government in improving handling practices, ensuring a regular and stable supply, introducing quality monitoring efforts and launching targeted behaviour change communication (BCC) campaigns regarding the value of DFS. Long-term implementation of the programmes is a weak point, as DFS production is more expensive than iodised salt, there is no existing market outside of institutional demand, and BCC must be long-term, high-quality, and requires resourcing for continued high uptake among SSNP beneficiaries. Strong government buy-in and technical support along the supply chain to address quality issues and beneficiary acceptance were key factors for the successful introduction of DFS. Comparative studies of DFS programmes should be conducted to improve confidence in the success factors that lead to high DFS uptake.

A blueprint for fortification planning and programming: Lessons learned from an analytical review of existing fortification frameworks.

With multiple food fortification frameworks, countries can find it challenging to determine optimal methods for planning and implementing food fortification programmes to combat vitamin and mineral deficiencies, especially without additional technical support. To address this challenge, this study aimed to review existing frameworks to determine consistencies, differences, strengths, and weaknesses across the frameworks, and based on the review findings, formulate an enhanced and streamlined fortification framework. Nineteen frameworks were ultimately examined following a comprehensive literature review and key informant interviews. Generally, the reviewed frameworks amply describe motives and methods for the determination of fortification need and feasibility, industry engagement/quality assurance and quality control, and impact evaluations/surveillance. However, there was limited inclusion or discussion throughout the reviewed frameworks around harmonization of fortification with existing micronutrient interventions; fortification policy and/or strategy; enforcement, incentives, and penalties to ensure producer compliance with industry standards; and periodic fortification programme review and reassessment. The findings were used to develop a comprehensive Fortification Blueprint that aims to provide structured guidance and a library of tools and resources to fortification programme managers and key stakeholders to ensure optimal and sustainable programme design.

Cardiac Metastasis After Curative Treatment of Hepatocellular Carcinoma: Assessment of Risk Factors, Treatment Options, and Prognosis.

Hepatocellular carcinoma (HCC) is primary hepatic malignancy with a high incidence of recurrence. The risk of recurrence directly correlates to patient's overall prognosis. Management of advanced HCC involves a combination of surgical resection, locoregional therapy, and systemic treatment. Distant metastases are rare, and intraventricular cardiac metastases are even more infrequent. This brief review details an illustrative case of cardiac metastasis after curative treatment of primary HCC and then summarizes the literature on risk factors, treatment options, and patient prognosis in the setting of distant metastases from HCC. Prognosis of metastasis to the heart is generally poor, and available evidence emphasizes the importance of maintaining regular posttreatment screening for metastases in patients with HCC. Given the variable presentation and high risk of recurrence, it is critical to have individualized multimodality treatment plans.

Reducing the Burden of Anemia and Neural Tube Defects in Low- and Middle-Income Countries: An Analysis to Identify Countries with an Immediate Potential to Benefit from Large-Scale Mandatory Fortification of Wheat Flour and Rice.

Using a predetermined set of criteria, including burden of anemia and neural tube defects (NTDs) and an enabling environment for large-scale fortification, this paper identifies 18 low- and middle-income countries with the highest and most immediate potential for large-scale wheat flour and/or rice fortification in terms of health impact and economic benefit. Adequately fortified staples, delivered at estimated coverage rates in these countries, have the potential to avert 72.1 million cases of anemia among non-pregnant women of reproductive age; 51,636 live births associated with folic acid-preventable NTDs (i.e., spina bifida, anencephaly); and 46,378 child deaths associated with NTDs annually. This equates to a 34% reduction in the number of cases of anemia and 38% reduction in the number of NTDs in the 18 countries identified. An estimated 5.4 million disability-adjusted life years (DALYs) could be averted annually, and an economic value of 31.8 billion United States dollars (USD) generated from 1 year of fortification at scale in women and children beneficiaries. This paper presents a missed opportunity and warrants an urgent call to action for the countries identified to potentially avert a significant number of preventable birth defects, anemia, and under-five child mortality and move closer to achieving health equity by 2030 for the Sustainable Development Goals.

The Unfinished Agenda for Food Fortification in Low- and Middle-Income Countries: Quantifying Progress, Gaps and Potential Opportunities.

Large-scale food fortification (LSFF) is a cost-effective intervention that is widely implemented, but there is scope to further increase its potential. To identify gaps and opportunities, we first accessed the Global Fortification Data Exchange (GFDx) to identify countries that could benefit from new fortification programs. Second, we aggregated Fortification Assessment Coverage Toolkit (FACT) survey data from 16 countries to ascertain LSFF coverage and gaps therein. Third, we extended our narrative review to assess current innovations. We identified 84 countries as good candidates for new LSFF programs. FACT data revealed that the potential of oil/ghee and salt fortification is not being met due mainly to low coverage of adequately fortified foods (quality). Wheat, rice and maize flour fortification have similar quality issues combined with lower coverage of the fortifiable food at population-level (< 50%). A four-pronged strategy is needed to meet the unfinished agenda: first, establish new LSFF programs where warranted; second, systems innovations informed by implementation research to address coverage and quality gaps; third, advocacy to form new partnerships and resources, particularly with the private sector; and finally, exploration of new fortificants and vehicles (e.g. bouillon cubes; salt fortified with multiple nutrients) and other innovations that can address existing challenges.

Perioperative Management of the Liver Transplant Recipient.

Perioperative management of the liver transplant recipient is a team effort that requires close collaboration between intensivist, surgeon, anesthesiologist, hepatologist, nephrologist, other specialists, and hospital staff before and after surgery. Transplant viability must be reassessed regularly and particularly with each donor organ. Regular discussions with patient and family facilitate realistic determinations of goals based on patient aspirations and clinical realities. Early attention to hemodynamics with optimal resuscitation and judicious vasopressor support, respiratory care designed to minimize iatrogenic injury, and early renal support is key. Preoperative and postoperative nutritional support and physical rehabilitation should remain a focus.

Phase I Study of Enavatuzumab, a First-in-Class Humanized Monoclonal Antibody Targeting the TWEAK Receptor, in Patients with Advanced Solid Tumors.

This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies. Mol Cancer Ther; 17(1); 215-21. ©2017 AACR.

A pilot study utilizing multi-omic molecular profiling to find potential targets and select individualized treatments for patients with previously treated metastatic breast cancer.

The primary objective was to determine if multi-omic molecular profiling (MMP) informed selection of approved cancer treatments could change the clinical course of disease for patients with previously treated metastatic breast cancer (MBC) (i.e., produce a growth modulation index (GMI) ≥1.3). GMI was calculated as the ratio of progression free survival on MMP-selected therapy/time to progression on last prior treatment. To meet the primary objective at least 35 % of the subjects should demonstrate a GMI ≥1.3. Secondary endpoints included determining the response rate (according to RECIST 1.1), the percent of patients with non-progression at 4 months, and overall survival in patients whose therapy is selected by molecular profiling and proteomic analysis. Eligible patients had MBC, with ≥3 prior lines of therapy. A multi-omic based approach was performed incorporating multiplexed immunohistochemistry, c-DNA microarray, and phosphoprotein pathway activation mapping by reverse phase protein array. MMP was performed on fresh core biopsies; results were generated and sent to a Treatment Selection Committee (TSC) for review and treatment selection. Three sites enrolled 28 patients, of which 25 were evaluable. The median range of prior treatment was 7 (range 3-12). The MMP analysis and treatment recommendation were delivered within a median of 15.5 days from biopsy (range 12-23). The TSC selected MMP-rationalized treatment in 100 % (25/25) of cases. None of the MMP-based therapies were the same as what the clinician would have selected if the MMP had not been performed. GMI ≥1.3 was reported in 11/25 (44 %) patients. Partial responses were noted in 5/25 (20 %), stable disease in 8/25 (32 %) and 9/25 (36 %) had no progression at 4 months. This pilot study demonstrates the feasibility of finding possible treatments for patients with previously treated MBC using a multiplexed MMP-rationalized treatment recommendation. This MMP approach merits further investigation.

Whole genome sequencing reveals potential targets for therapy in patients with refractory KRAS mutated metastatic colorectal cancer.

BACKGROUND: The outcome of patients with metastatic colorectal carcinoma (mCRC) following first line therapy is poor, with median survival of less than one year. The purpose of this study was to identify candidate therapeutically targetable somatic events in mCRC patient samples by whole genome sequencing (WGS), so as to obtain targeted treatment strategies for individual patients. METHODS: Four patients were recruited, all of whom had received > 2 prior therapy regimens. Percutaneous needle biopsies of metastases were performed with whole blood collection for the extraction of constitutional DNA. One tumor was not included in this study as the quality of tumor tissue was not sufficient for further analysis. WGS was performed using Illumina paired end chemistry on HiSeq2000 sequencing systems, which yielded coverage of greater than 30X for all samples. NGS data were processed and analyzed to detect somatic genomic alterations including point mutations, indels, copy number alterations, translocations and rearrangements. RESULTS: All 3 tumor samples had KRAS mutations, while 2 tumors contained mutations in the APC gene and the PIK3CA gene. Although we did not identify a TCF7L2-VTI1A translocation, we did detect a TCF7L2 mutation in one tumor. Among the other interesting mutated genes was INPPL1, an important gene involved in PI3 kinase signaling. Functional studies demonstrated that inhibition of INPPL1 reduced growth of CRC cells, suggesting that INPPL1 may promote growth in CRC. CONCLUSIONS: Our study further supports potential molecularly defined therapeutic contexts that might provide insights into treatment strategies for refractory mCRC. New insights into the role of INPPL1 in colon tumor cell growth have also been identified. Continued development of appropriate targeted agents towards specific events may be warranted to help improve outcomes in CRC.

A Phase I cardiac safety and pharmacokinetic study of tivozanib hydrochloride in patients with advanced solid tumors.

Tivozanib hydrochloride (tivozanib) is a potent, selective tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life. Tivozanib's effects on the QTc interval in patients with advanced solid tumors were assessed. Patients received 1.5 mg of tivozanib orally, once daily, for 21 days. Safety evaluations, serial blood samples for pharmacokinetic measurements, and time-matched, triplicate, 12-lead electrocardiograms (ECG) were collected. Fifty patients were evaluable. The maximum change in QTcF was 9.3 milliseconds (90% confidence interval [CI] 5-13.6), occurring 2.5 hours after dosing on Day 21. The central tendency change across all time points was +2.2 milliseconds. The slope of the exposure-ΔQTcF relationship was 0.08464 ms/ng/mL, with a predicted QTcF change of 8.27 milliseconds at the average tivozanib Tmax of 118.1 ng/mL (upper CI 12.6 milliseconds). There were no QTcF values >500 milliseconds or significant changes from baseline observed in heart rate, PR interval, and QRS complex. These data, evaluated along with other tivozanib preclinical and clinical study results, suggest that administration of 1.5 mg tivozanib for 21 days has a minimal effect on cardiac repolarization or ECG morphology in oncology subjects.

Small lymphocytic lymphoma obscuring microscopic tonsillar squamous cell carcinoma: an unknown occurrence with a known primary.

Head and neck squamous cell carcinoma (HNSCC) often presents with cervical lymph node metastases and at times the primary tumor cannot be identified despite extensive workup. Lymphoma is the second most common neoplasm in the head and neck region but is seldom synchronous with HNSCC and rarely involves regional mucosal sites. We report herein a rare occurrence of tonsillar involvement by small lymphocytic lymphoma (SLL) incidentally detected during the workup for a cervical lymph node SCC metastasis of a 52-year-old non-smoker male. The microscopic human papillomavirus-positive SCC involving the tonsillar surface and crypts was obscured by SLL leading to the initial designation of 'unknown primary'. The occult HNSCC are likely explained by small tumor size, quality and quantity of sampling, thoroughness of endoscopic, radiological and pathological assessment or a combination of the above. The coexistence of another tumor such as lymphoma has not yet been reported as a confounding factor in the workup for cervical SCC metastasis. Since oropharyngeal SCC can be very small and Waldeyer's ring is a common site for lymphoma involvement, identification of such rare collision tumors requires pathologists' awareness, extensive sampling and occasionally ancillary studies for the accurate diagnosis and staging essential for the correct management.

Effect of 25-hydroxyvitamin D status on serological response to influenza vaccine in prostate cancer patients.

BACKGROUND: Epidemiologic data suggest that there is an association between vitamin D deficiency and influenza infection. We conducted a prospective influenza vaccination study to determine the influence of vitamin D status on serological response to influenza vaccine in prostate cancer (CaP) patients. METHODS: During the 2006-2007 influenza season, CaP patients treated at Roswell Park Cancer Institute were offered vaccination with the trivalent influenza vaccine (Fluzone®, 2006-2007) and sera collected for hemagglutination inhibition (HI) assay titers before and 3 months after vaccination. Response to vaccination was defined as ≥1:40 titer ratio or a fourfold increase in titer at 3 months, against any of the three strains. Serum 25-hydroxyvitamin D (25-D3) levels were measured using DiaSorin ¹²5I radioimmunoassay kits. RESULTS: Thirty-five patients with CaP participated in the study. Median baseline 25-D3 level was 44.88 ng/ml (range: 9.16-71.98 ng/ml) Serological response against any of the three strains was noted in 80%. There was a significant effect of baseline 25-D3 level when tested as a continuous variable in relation to serological response (P = 0.0446). All patients in the upper quartile of 25-D3 level responded by mounting a serological response (P = 0.0344). None of the other baseline variables (age, race, chemotherapy status, or white cell count) had an effect on serological response. CONCLUSIONS: In this study in CaP patients, a replete vitamin D status was associated with more frequent serological response to influenza vaccine.

Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castration-resistant prostate cancer.

BACKGROUND: Preclinical data indicate that there is substantial antitumor activity and synergy between calcitriol and dexamethasone. On the basis of these data, the authors conducted a phase 2 trial of intravenous (iv) calcitriol at a dose of 74 microg weekly (based on a recent phase 1 trial) and dexamethasone in patients with castration-resistant prostate cancer (CRPC). METHODS: A 2-stage Kepner-Chang design was used. Oral dexamethasone at a dose of 4 mg was given weekly on Days 1 and 2, and iv calcitriol (74 microg over 1 hour) was administered weekly on Day 2 from 4 to 8 hours after the dexamethasone dose in patients with CRPC. Laboratory data were monitored weekly, and renal sonograms, computed tomography scans, and bone scans were obtained every 3 months. Disease response was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) and standard criteria for prostate-specific antigen (PSA) response. The calcitriol dose was delineated by from the authors' recent phase 1 trial. RESULTS: Of 18 evaluable patients, 15 patients were Caucasian (83%). No patients had a complete or partial response by either RECIST or PSA response criteria. Fourteen patients had progressive disease, 2 patients refused to continue treatment (after 64 days and 266 days), and 2 patients remain on the trial (for 306 days and 412 days).The median time to disease progression was 106 days (95% confidence interval, 80-182 days). Fourteen episodes of grade 3 or 4 toxicity were noted in 7 patients (hyperglycemia, hypocalemia, chest pain, dyspnea, hypercalcemia, hypophosphatemia, cardiac arrhythmia, and pain). Only 1 episode of grade 3/ 4 toxicity was related definitely to calcitriol (hypercalcemia). No treatment-related deaths were noted. CONCLUSIONS: High-dose, iv calcitriol at a dose of 74 microg weekly in combination with dexamethasone was well tolerated but failed to produce a clinical or PSA response in men with CRPC.

High-dose octreotide acetate for management of gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: Long-acting sandostatin (S-LAR; octreotide acetate) is well tolerated and effective for symptom control and possibly disease control in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We undertook a retrospective analysis to study the efficacy and tolerability of higher doses (more than 20-30 mg/month) of S-LAR in GEP-NETs. PATIENTS AND METHODS: With IRB approval, charts of all patients with GEP-NET who received S-LAR between June 2002 to September 2007 at Roswell Park Cancer Institute were reviewed and their data analyzed. RESULTS: Fifty-four patients with GEP-NET received S-LAR; thirty required dose escalation. Patients received a median of 5 doses of S-LAR at conventional dose followed by up-titration of the dose for symptom control (20) and radiological progression (17). Median high dose of S-LAR was 40 mg (range: 40-90 mg) with a median of 8.5 high doses received. No treatment related toxicities were seen. The estimated 1-year survival for patients on conventional dose alone was 0.77 (95% CI of 0.50 to 0.91) and those on high-dose was 0.88 (95% CI of 0.68 to 0.96) (p=0.4777) while median time to any other intervention was 2.9 months versus 17.7 months (p=0.12). CONCLUSION: Dose escalation of S-LAR is well tolerated and may provide longer disease control.

Surgical resection after TNFerade therapy for locally advanced pancreatic cancer.

CONTEXT: Treatment of pancreatic cancer remains a major oncological challenge and survival is dismal. Most patients, present with advanced disease at diagnosis and are not candidates for curative resection. Preoperative chemoradiation may downstage and improve survival in locally advanced pancreatic cancer. This has prompted investigators to look for novel neoadjuvant therapies. Gene therapy for pancreatic cancer is a novel investigational approach that may have promise. TNFerade is a replication deficient adenovirus vector carrying the human tumor necrosis factor (TNF)-alpha gene regulated under control of a radiation-inducible gene promoter. Transfection of tumor cells with TNFerade maximizes the antitumor effect of TNF-alpha under influence of radiation leading to synergistic effects in preclinical studies. CASE REPORT: We describe a case of locally advanced unresectable pancreatic cancer treated with a novel multimodal approach utilizing gene therapy with TNFerade and concurrent chemoradiation that was followed by successful surgical resection. CONCLUSION: Neoadjuvant TNFerade based chemoradiation therapy may be a useful adjunct to treatment of locally advanced pancreatic cancer.

Vitamin D deficiency and insufficiency among patients with prostate cancer.

OBJECTIVE: To assess the frequency of vitamin D deficiency among men with prostate cancer, as considerable epidemiological, in vitro, in vivo and clinical data support an association between vitamin D deficiency and prostate cancer outcome. PATIENTS, SUBJECTS AND METHODS: The study included 120 ambulatory men with recurrent prostate cancer and 50 with clinically localized prostate cancer who were evaluated and serum samples assayed for 25-OH vitamin D levels. Then 100 controls (both sexes), matched for age and season of serum sample, were chosen from a prospective serum banking protocol. The relationship between age, body mass index, disease stage, Eastern Cooperative Oncology Group performance status, season and previous therapy on vitamin D status were evaluated using univariate and multivariate analyses. RESULTS: The mean 25-OH vitamin D level was 25.9 ng/mL in those with recurrent disease, 27.5 ng/mL in men with clinically localized prostate cancer and 24.5 ng/mL in controls. The frequency of vitamin D deficiency (<20 ng/mL) and insufficiency (20-31 ng/mL) was 40% and 32% in men with recurrent prostate; 28% had vitamin D levels that were normal (32-100 ng/mL). Among men with localized prostate cancer, 18% were deficient, 50% were insufficient and 32% were normal. Among controls, 31% were deficient, 40% were insufficient and 29% were normal. Metastatic disease (P = 0.005) and season of blood sampling (winter/spring; P = 0.01) were associated with vitamin D deficiency in patients with prostate cancer, while age, race, performance status and body mass index were not. CONCLUSIONS: Vitamin D deficiency and insufficiency were common among men with prostate cancer and apparently normal controls in the western New York region.

A dramatic, objective antiandrogen withdrawal response: case report and review of the literature.

Antiandrogen withdrawal response is an increasingly recognized entity in patients with metastatic prostate cancer. To our knowledge, there have been no reports describing a durable radiologic improvement along with prostate-specific antigen (PSA) with discontinuation of the antiandrogen agent bicalutamide. We report a case in which a dramatic decline of serum PSA levels associated with a dramatic improvement in radiologic disease was achieved with bicalutamide discontinuation.

Phase II study of fulvestrant (Faslodex) in castration resistant prostate cancer.

BACKGROUND: Preclinical evidence supports the role of estrogen receptor signaling in prostate cancer. In this trial we investigated the tolerability and efficacy of fulvestrant, a pure estrogen receptor antagonist, in the treatment of castration resistant prostate cancer (CRPC). METHODS: Patients with CRPC were enrolled after written informed consent. Fulvestrant was administered by intramuscular injection at a dose of 500 mg on day 0, then 250 mg on day 14, day 28 and monthly thereafter. History, physical examination, serum prostate specific antigen (PSA) levels and toxicity was evaluated monthly. Radiographic studies were repeated every 3 months to assess disease. Treatment was continued until disease progression, unacceptable toxicity, non-compliance or consent withdrawal. RESULTS: Twenty patients were enrolled over a period of six months. All patients were Caucasians with median age of 69.5 years [range: 47-85 years]. Sixteen patients (80%) had radiological evidence of metastasis and four patients (20%) had rising PSA as the only evidence of progressive disease. Patients received a median of three treatment cycles of fulvestrant [range: 1-11]. Median time to progression was 4.3 months (95% confidence interval of 3-5.7 months) and median overall survival was 19.4 months (range: 9.9-19.4 months) after a median follow-up of 16 months. No patient showed >or=50% reduction in PSA or radiologic improvement. Few adverse events were noted, none of which were attributed directly to fulvestrant. CONCLUSION: Fulvestrant was well tolerated but failed to produce clinical or PSA response in men with CRPC.

Acute promyelocytic leukemia after mitoxantrone therapy for multiple sclerosis.

Mitoxantrone is a DNA-topoisomerase 2 inhibitor used as a single agent for treatment of relapsing-remitting or progressive multiple sclerosis (MS). We present here two patients treated with mitoxantrone for MS who subsequently developed acute promyelocytic leukemia (APL). These constitute, to our knowledge, the eighth and ninth reports of APL in patients treated with mitoxantrone for MS. Topoisomerase 2 inhibitors are associated with therapy-related acute myeloid leukemia (t-AML) with 11q23 abnormalities, but therapy-related APL (t-APL) is less common, and documentation of nine cases of t-APL after mitoxantrone therapy for MS suggests a specific association.