Modest Side Effects Research Articles

Comparison of Two Hyaluronic Acid Preparations for the Treatment of Rizoarthrosis

Osteoarthritis of the trapeziometacarpal joint (TOA) or rizoarthrosis is a pathology particularly prevalent in post-menopausal women. It can be symptomatic, with associated pain, or asymptomatic, and in this latter case it is diagnosed by radiographical examination. TOA, when symptomatic, strongly affects quality of life. The treatment of TOA involves both pharmacological and non-pharmacological treatment (including local application of heat, ultrasound and splints). The major treatments, recommended by the European League Against Rheumatism consists of corticosteroids for pain control and hyaluronic acid (HA) for amelioration of functional capacity. The present study aimed at comparing the efficacy and tolerance of intra articular injections of two HA preparations, high-low molecular weight HA (HL) (Sinovial® HL) and high molecular weight HA (HMW) (Sinovial® Mini), in patients with TOA. The observational and retrospective study involved overall 125 subjects, ageing from 45 to 85 years, who had clinical symptoms of TOA lasting at least 6 months. The patients received HL (66 subjects) or HMW (59 subjects) in two injections at baseline and after 15 days. The subjects were followed for 6 months, and the outcome measurements included pain control (through VAS scale) functional hand capacity, using the Duruoz Hand Index (DHI) and the change of the duration of morning stiffness, using the Italian version of the Health Assessment Questionnaire (HAQ). HL was found superior to HMW in all the three parameters examined, with a quicker and stronger pain relief, recovery of hand function as well as in self-assessment by the subjects. Both treatments were associated with very modest side effects. In conclusion, our data show the efficacy of HL and HMW for the treatment of TOA and the superiority of HL to HMW. Although these data are observational and retrospective, they pose the basis for future prospective studies focused on the use of HL and HMW in TOA.

PSAT373 Metformin Decreases Serum Thyroglobulin Concentration in Non-Medullary Thyroid Carcinoma

Abstract Background The conventional treatment of non-medullary thyroid carcinoma (NMTC) includes surgical resection, TSH suppression and 131-iodine. Although highly successful, some patients develop persistent/recurrent NMTC requiring alternative therapies, including external radiation and multikinase inhibitors, which may have clinically significant adverse side effects. In vitro studies, in vivo studies in animals, and association studies in humans suggest that metformin, an inexpensive medication with a modest side effect profile, may help prevent or treat NMTC. No interventional metformin trials have been performed in humans. Hypothesis We performed a proof-of-concept intervention trial to test the hypothesis that metformin will decrease serum thyroglobulin concentration (Tg), a surrogate marker for NMTC, in humans with persistent/recurrent NMTC burden. Methods In this IRB approved study, we administered metformin to patients with persistent/recurrent NMTC and analyzed the change in Tg. When available and possible, tumor burden was evaluated by CT imaging. Ten patients with persistent/recurrent well-differentiated NMTC (6 classic papillary thyroid cancer, 1 tall cell variant of papillary thyroid cancer, 2 follicular thyroid cancer, and 1 hurthle cell thyroid cancer) were included. All had exhausted conventional therapies including total thyroidectomy and 131-iodine. All had biochemical evidence of NMTC with Tg > 2 ng/mL, and with non-detectable serum thyroglobulin antibody concentrations. Six had microscopic NMTC not detectable by conventional imaging, and four had NMTC detectable on CT imaging. Five patients elected to be treated with metformin (500 to 2000 mg/d) for two to five months. The remaining five served as untreated controls. Since the Tg variances in the two groups were not equal, the nonparametric Mann-Whitney test was used to determine if the change in Tg was different in the metformin treated and untreated groups. Results Tg decreased in all five patients receiving metformin and increased in all five controls. The mean Tg decrease with metformin therapy was 21.7 ± 8.4%, and the mean Tg increase in the control group was 16.6 ± 12.1%; p < 0.02. TSH was suppressed to < 0.1 mIU/L in both groups at baseline and did not change significantly during the study. Two of the five patients receiving metformin elected to continue the metformin for longer, and the CT imaging studies were evaluable by RECIST criteria. There was no decrease in tumor size in either patient. The progression-free survival was 6 months in one patient and 10 months in the other, which may be longer than that reported for similar historical controls that range from 3.6 to 5.8 months. Summary In summary, metformin caused a TSH-independent decrease of Tg in patients with persistent/recurrent NMTC, but no decrease in tumor size in two evaluable patients. More extensive studies are necessary to determine if metformin slows NMTC progression. Conclusion Metformin decreases Tg in NMTC. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Metformin Decreases Serum Thyroglobulin Concentration in Nonmedullary Thyroid Carcinoma.

ContextThe conventional treatment of nonmedullary thyroid carcinoma (NMTC) includes surgical resection, thyrotropin (TSH) suppression, and 131-iodine. Some patients develop persistent/recurrent metastatic disease requiring expensive alternative therapies, such as external radiation and multikinase inhibitors, which may have clinically significant side effects. Recent in vitro studies, in vivo studies in animals, and association studies in humans suggest that metformin, an inexpensive medication with a modest side effect profile, may help prevent or treat NMTC. No interventional trials analyzing the effect of metformin have been performed in humans.ObjectiveWe hypothesize that metformin administration will decrease serum thyroglobulin concentration (Tg), a surrogate marker for NMTC burden.MethodsThis retrospective institutional review board–approved study included 10 patients with persistent/recurrent NMTC who had exhausted conventional therapies including total thyroidectomy and 131-iodine. Five had detectable disease on computed tomography imaging. All had biochemical evidence of NMTC with Tg > 2.0 ng/mL with nondetectable serum thyroglobulin antibody concentrations. Five elected to have metformin treatment at doses varying from 500 to 2000 mg/day for 2 to 5 months. The remaining 5 served as untreated controls. Statistical significance was determined by the Mann–Whitney test.ResultsTg decreased (mean decrease = 21.7 ± 8.4%) in all 5 patients receiving metformin and increased (mean increase = 16.6 ± 12.1%) in all 5 controls (P < .01). TSH did not change significantly in either group.ConclusionIn summary, metformin caused a TSH-independent Tg decrease in patients with persistent/recurrent NMTC. More extensive studies are required to determine if metformin slows NMTC progression

Bimodal antibody-titer decline following BNT162b2 mRNA anti-SARS-CoV-2 vaccination in healthcare workers of the INT – IRCCS “Fondazione Pascale” Cancer Center (Naples, Italy)

BackgroundBoth SARS-CoV-2 mRNA-based vaccines [BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)] have shown high efficacy, with very modest side effects in limiting transmission of SARS-CoV-2 and in preventing the severe COVID-19 disease, characterized by a worrying high occupation of intensive care units (ICU), high frequency of intubation and ultimately high mortality rate. At the INT, in Naples, only the BNT162b2/Pfizer vaccine has been administered to cancer patients and healthcare professionals aged 16 and over. In the present study, the antibody response levels and their decline were monitored in an interval of 6–9 months after vaccine administration in the two different cohorts of workers of the INT – IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy): the group of individuals previously infected with SARS-CoV-2 and vaccinated with a single dose; and that of individuals negative for previous exposure to SARS-CoV-2 vaccinated with two doses 21 days apart.MethodsSpecific anti-RBD (receptor-binding domain) titers against trimeric spike glycoprotein (S) of SARS-CoV-2 by Roche Elecsys Anti-SARS-CoV-2 S ECLIA immunoassay were determined in serum samples of 27 healthcare workers with a previously documented history of SARS-CoV-2 infection and 123 healthcare workers without, during antibody titers’ monitoring. Moreover, geometric mean titers (GMT) and relative fold changes (FC) were calculated.ResultsBimodal titer decline was observed in both previously infected and uninfected SARS-CoV-2 subjects. A first rapid decline was followed by a progressive slow decline in the 6/9 month-period before the further vaccine boost. The trend was explained by 2 different mathematical models, exponential and power function, the latter revealing as predictive of antibody titer decline either in infected or in not previously infected ones. The value of the prolonged lower vaccine titer was about 1 log below in the 6/9-month interval after the single dose for previously infected individuals with SARS-CoV-2 and the two doses for those not previously infected. The titer change, after the boost dose administration, on the other hand, was ≥ 1.5 FC higher than the titers at the 6/9-month time-points in both cohorts. A similar quantitative immune titer was observed in both cohorts 8 days after the last boost dose. The subsequent immunoresponse trend remains to be verified.DiscussionThe results show that a very rapid first decline, from the highest antibody peak, was followed by a very slow decline which ensured immune protection lasting more than 6 months. The apparent absence of adverse effects of the rapid decline on the vaccine's immune protective role has been related to a large majority of low avidity antibodies induced by current vaccines. High avidity antibodies with prolonged anti-transmission efficacy show a longer half-life and are lost over a longer interval period. The cellular immunity, capable of preventing severe clinical diseases, lasts much longer. The unbalanced dual activity (cellular vs humoral) while effective in limiting ICU pressure and overall mortality, does not protect against transmission of SARS-CoV-2, resulting in high circulation of the virus among unvaccinated subjects, including the younger population, and the continuous production of variants characterized by changes in transmissibility and pathogenicity. The high mutation rate, peculiar to the RNA virus, can however lead to a dual opposite results: selection of defective and less efficient viruses up to extinction; risk of more efficiently transmitted variants as the current omicron pandemic.ConclusionsIn conclusion the current bimodal antibody-titer decline, following BNT162b2 mRNA anti-SARS-CoV-2 vaccination, needs a further extended analysis to verify the protective borderline levels of immunity and the optimal administration schedule of vaccine boosters. Our current results can contribute to such goal, besides a direct comparison of other FDA-approved and candidate vaccines.

Modern Therapy for Spinal and Paraspinal Ewing Sarcoma: An Update of the University of Florida Experience

In 2010, we published a comprehensive review of our institutional outcomes about treating children with spinal and paraspinal Ewing sarcoma using photon therapy. Multimodality therapy was associated with fair disease control but also with serious toxicity, including a 37% rate of grade 3 or greater toxicity. We therefore sought to assess our more recent experience about treating children with more modern technology and treatment regimens. Between 2010 and 2021, 32 pediatric patients with nonmetastatic spinal and paraspinal Ewing sarcoma were treated at University of Florida and enrolled in a retrospective outcome study. Median age at diagnosis was 9.8 years (range, 2.1-21.8 years). Within the cervical, thoracic, and lumbar spine regions, 3, 22, and 7 tumors arose, respectively. Median maximum tumor diameter was 5 cm (range, 3-19 cm). At diagnosis, 28 of 32 patients had motor, bowel, or bladder deficits. Chemotherapy was delivered according to contemporary North American and European interval-compressed regimens. Before radiation therapy, 14 patients underwent gross total resection, whereas 18 underwent a biopsy or subtotal resection with cord decompression. All patients were treated with proton therapy; 6 with hardware stabilization also received a component of intensity modulated photon therapy. Median prescription dose was 50.4 gray relative biological effectiveness (GyRBE; range, 45-55.8 GyRBE). Median maximum dose to the spinal cord was 50.2 GyRBE (range, 0-54.9 GyRBE). With a median follow-up of 4.1 years (range, 0.7-9.4 years), the 5-year local control, progression-free survival, and overall survival rates were 92%, 79%, and 85%, respectively. Ten of 30 living patients have residual motor, bowel, or bladder deficits. Overall, 22% of patients experienced Common Terminology Criteria for Adverse Events grade 3 late toxicity related to multimodality treatment: kyphosis (n=4), esophagitis (n=2), and chronic kidney disease (n=1). No patients developed grade 4 or greater toxicity, new neurologic deficits, or second malignancy. Modern treatment advances may offer an improved therapeutic ratio for pediatric patients with spinal and paraspinal Ewing sarcoma. With appropriate management, most patients can be cured with recovery of long-term neurologic function and modest side effects.

Single-Arm Phase 1b/2 Trial of the PI3Kδ Inhibitor Linperlisib Combining with Gemox in Relapsed and/or Refractory Diffuse Large B Cell Lymphoma

IntroductionDiffuse large B cell lymphoma (DLBCL) is an aggressive hematological malignancy where patients rapidly progress on standard therapies. In relapsed/refractory (r/r) DLBCL, there is an urgent need for safe and effective therapies, especially being feasible to combine with other treatment regimens. The gemcitabine (GEM) oxaliplatin (OX) chemotherapy regimen is a standard treatment option with modest side effects providing an opportunity for potential combination with novel agents.The PI3Kδ selective inhibitor linperlisib is a structurally distinct oral agent previously demonstrated to be clinically efficacious with a favorable safety profile in follicular lymphoma and peripheral T cell lymphoma trials.MethodsThis Phase1b/2 trial (NCT04500561) initiated in December 2019. As of July 22, 2021, there were 39 r/r DLBCL patients (pts) enrolled at 6 clinical sites in China. All DLBCL subtypes were represented, and pts had a median of 2 prior systemic therapies, including 1 pt with prior stem cell transplant. Pts were dosed in a 21-day cycle with linperlisib 80 mg QD orally combined with 6 cycles of GEMOX (Gemcitabine 1000 mg/m 2, IV on day 1, Q3W, and Oxaliplatin 1000 mg/m 2 IV on day2, Q3W], followed by linperlisib alone until disease progression, intolerable toxicity, or withdrawal. Safety was evaluated according to NCI-CTCAE v5.0. Efficacy evaluation was conducted every 2 cycles by IWG 2007 criteria.ResultsIn this Phase 1b study of linperlisib + GEMOX in r/r DLBCL, as of July 22, 2021, there were 35 evaluable pts. Two pts discontinued from study due to SAEs occurred at C1D16 and C1D15, and 2pts discontinued from the study due to withdrawing consent at C1D8 and C2D7, there were no post baseline imaging assessment for these patients.The r/r DLBCL pts were BCL-6 (+) (80%, 28 pts), BCL-6 (-) (11.4%, 4 pts), or unknown (8.6%, 3 pts); C-MYC (+) (80%, 28 pts), C-MYC (-) (2.8%, 1 pt), or unknown (17.1%, 6 pts), indicative of aggressive lymphomas. Most pts (74%,29pts) had received R-CHOP as a first line treatment, with later lines of R-EPOCH, R-ICE, lenolinamide, CAR-T, PD-1, and other regimens, with a median of 2 lines of prior systemic therapy. The overall response rate was 60% (21/35 pts) with 5 pts achieving a Complete Response (CR, 14%) and 16 pts with Partial Response (PR, 46%)(Figure 1). In addition, 4 pts had Stable Disease (SD, 11 %), with a 71% Disease Control Rate (DCR). The median time to response was 36 days. As of the data cutoff date, the median Progression Free Survival was 193 days and the median Duration of Response was not reached, and 17 evaluable pts (48.6%) remained on study. Ten pts received linperlisib monotherapy for at least 1 cycle after completing 6 cycles of linperlisib + GEMOX combination therapy, and 2 pts were continuing linperlisib monotherapy treatment for >9 months after enrolling.Linperlisib in combination with GEMOX was well-tolerated. All 39 pts experienced at least 1 Treatment Related Adverse Event (TRAE), of which the majority were Grade 1 or 2 (83.9%). The most common TRAEs (>10% all grades) were neutropenia (72%), leukopenia (62%),thrombocytopenia (56%), anaemia (51%), lymphopenia (15%), ALT increased (41%), ASP increased(54%), hyperamylasemia (23%), hypokalaemia (21%), nausea(31%), vomiting(23%), diarrhea(33%), and anaesthesia(13%).The most frequent ≥Grade 3 TRAE (>5%) were neutropenia (46.2%), thrombocytopenia (35.9%), leukopenia (25.6%), lymphopenia (7.7%). SAEs were reported in 14 pts, including 3 thrombocytopenia, 2 diarrhea, and one case of leukopenia, neutropenia, febrile neutropenia, fever, death NOS, cachexia, pleural effusion, cancer pain, hypotension, vomiting, laryngopharyngitis, pneumonitis, lung infection or skin infection. One pt had dose reduction to 60mg/day due to AE, 2 pts discontinued treatment due to a TRAE. The AEs observed were consistent with that in previous linperlisib monotherapy trials in FL, PTCL and lymphomas.ConclusionsThe combination of linperlisib and GEMOX treatment was well tolerated with a manageable AE profile, and led to a promising ORR in a difficult-to-treat r/r DLBCL. The preliminary data suggest that linperlisib + GEMOX is a safe and active combination. A Phase2 study of linperlisib in combination with GEMOX in r/r DLBCL is currently ongoing. Further, multiple combination treatments are planned as important avenues for future development of linperlisib. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcome and Toxicity of Proton Therapy for Vestibular Schwannoma: A Cohort Study.

To assess the efficacy and toxicity of proton radiotherapy in vestibular schwannoma. Retrospective chart review and volumetric MRI-analyses. Tertiary referral center. Vestibular schwannoma patients treated with protons between 2003 and 2018. Proton radiotherapy. Tumor control was defined as not requiring salvage treatment. Progressive hearing loss was defined as a decrease in maximum speech discrimination score below the 95% critical difference in reference to the pretreatment score. Hearing assessment includes contralateral hearing and duration of follow-up. Dizziness and/or unsteadiness and facial and trigeminal nerve function were scored. Patients who had surgery prior to proton radiotherapy were separately assessed. Of 221 included patients, 136 received single fraction and 85 fractionated proton radiotherapy. Actuarial 5-year local control rate was 96% (95% CI 90-98%). The median radiological follow-up was 4.5 years. Progressive postirradiation speech discrimination score loss occurred in 42% of patients with audiometric follow-up within a year. Facial paresis was found in 5% (usually mild), severe dizziness in 5%, and trigeminal neuralgia in 5% of patients receiving protons as primary treatment. Proton radiotherapy achieves high tumor control with modest side effects aside from hearing loss in vestibular schwannoma patients. Limited and heterogeneous outcome reporting hamper comparisons to the literature. Potential sequelae of radiation therapy impacting vestibular function, cognitive function, and quality of life warrant further evaluation. Subgroups that benefit most from proton radiotherapy should be identified to optimize allocation and counterbalance its costs.

SARS-CoV-2 vaccines: a triumph of science and collaboration.

Roughly 1 year after the first case of COVID-19 was identified and less than 1 year after the sequencing of SARS-CoV-2, multiple SARS-CoV-2 vaccines with demonstrated safety and efficacy in phase III clinical trials are available. The most promising vaccines have targeted the surface glycoprotein (S-protein) of SARS-CoV-2 and achieved an approximate 85%–95% reduction in the risk of symptomatic COVID-19, while retaining excellent safety profiles and modest side effects in the phase III clinical trials. The mRNA, replication-incompetent viral vector, and protein subunit vaccine technologies have all been successfully employed. Some novel SARS-CoV-2 variants evade but do not appear to fully overcome the potent immunity induced by these vaccines. Emerging real-world effectiveness data add evidence for protection from severe COVID-19. This is an impressive first demonstration of the effectiveness of the mRNA vaccine and vector vaccine platforms. The success of SARS-CoV-2 vaccine development should be credited to open science, industry partnerships, harmonization of clinical trials, and the altruism of study participants. The manufacturing and distribution of the emergency use–authorized SARS-CoV-2 vaccines are ongoing challenges. What remains now is to ensure broad and equitable global vaccination against COVID-19.

Early experience with hippocampal avoidance whole brain radiation therapy and simultaneous integrated boost for brain metastases.

Cranial irradiation results in cognitive decline, which is hypothesized to be partially attributable to hippocampal injury and stem cell loss. Recent advances allow for targeted reduction of radiation dose to the hippocampi while maintaining adequate dose coverage to the brain parenchyma and additional increasing dose to brain metastases, a approach called hippocampal avoidance whole brain radiation therapy with a simultaneous integrated boost (HA-WBRT + SIB.) We review our early clinical experience with HA-WBRT + SIB. We evaluated treatments and clinical outcomes for patients treated with HA-WBRT + SIB between 2014 and 2018. A total of 32 patients (median age, 63.5years, range 45.3-78.8years) completed HA-WBRT + SIB. Median follow-up for patients alive at the time of analysis was 11.3months. The most common histology was non-small cell lung cancer (n = 22). Most patients (n = 25) were prescribed with WBRT dose of 30Gy with SIB to 37.5Gy in 15 fractions. Volumetric modulated arc therapy reduced treatment time (p < 0.0001). Median freedom from intracranial progression and overall survival from completion of treatment were 11.4months and 19.6months, respectively. Karnofsky Performance Status was associated with improved survival (p = 0.008). The most common toxicities were alopecia, fatigue, and nausea. Five patients developed cognitive impairment, including grade 1 (n = 3), grade 2 (n = 1), and grade 3 (n = 1). HA-WBRT + SIB demonstrated durable intracranial disease control with modest side effects and merits further investigation as a means of WBRT toxicity reduction while improving long-term locoregional control in the brain.

Androgen Receptor Signaling in the Development of Castration-Resistant Prostate Cancer.

Most prostate cancers are androgen-sensitive malignancies whose growths depend on the transcriptional activity of the androgen receptor (AR). In the 1940s, Charles Huggins demonstrated that the surgical removal of testes in men can result in a dramatic improvement in symptoms and can induce prostate cancer regression. Since then, androgen deprivation therapies have been the standard first-line treatment for advanced prostate cancer, including: surgical castration, medical castration, antiandrogens, and androgen biosynthesis inhibitors. These therapies relieve symptoms, reduce tumor burden, and prolong patient survival, while having relatively modest side effects. Unfortunately, hormone deprivation therapy rarely cures the cancer itself. Prostate cancer almost always recurs, resulting in deadly castration-resistant prostate cancer. The underlying escape mechanisms include androgen receptor gene/enhancer amplification, androgen receptor mutations, androgen receptor variants, coactivator overexpression, intratumoral de novo androgen synthesis, etc. Whereas, the majority of the castration-resistant prostate cancers continuously rely on the androgen axis, a subset of recurrent cancers have completely lost androgen receptor expression, undergone divergent clonal evolution or de-differentiation, and become truly androgen receptor-independent small-cell prostate cancers. There is an urgent need for the development of novel targeted and immune therapies for this subtype of prostate cancer, when more deadly small-cell prostate cancers are induced by thorough androgen deprivation and androgen receptor ablation.

LPTO-09. INTRATHECAL TOPOTECAN FOR LEPTOMENINGEAL METASTASIS IN SOLID TUMORS: THE MD ANDERSON EXPERIENCE

BACKGROUND: Leptomeningeal metastasis (LM) is a devastating complication of cancer resulting in progressive neurologic decline. Although intrathecal (IT) methotrexate and cytarabine are commonly used for solid tumor LM, we routinely use IT topotecan due to previously demonstrated similar efficacy and modest side effect profile. We report updated data on our experience. METHODS: We reviewed clinical records of patients with solid tumor LM treated with IT topotecan at MD Anderson Cancer Center from 2008–2018. Patient characteristics and course were summarized by descriptive statistics. Overall survival (OS) was estimated with Kaplan-Meier, and the association of KPS with OS evaluated with log-rank test. RESULTS: 138 patients were treated with IT topotecan. The median age was 54 years (range, 22–76), 81% were female. Breast cancer (62%) was the most common primary, then lung (21%), melanoma (4%). Median time from primary diagnosis to LM was 3.4 (range, 0.07–25.2) years. LM was diagnosed by CSF cytology alone in 8 (6%), MRI alone in 21 (15%), CSF+MRI in 108 (78%). Patients most commonly presented with headache (39%) or sensory changes (18%), and had a median KPS of 80 (range, 60–100). 66% had prior/concurrent brain metastasis. 71 patients (52%) received WBRT following LM diagnosis. 41% had adverse effects, most commonly nausea/vomiting (22%) and headache (20%). The majority were grade 1 (63%); 7 were grade 4 (2 Ommaya malfunctions and 5 infections). Patients received a median of 9 (range, 1–79) doses, most stopped due to CNS progression (42%). Median OS was 6.5 months (95% CI 4.7, 7.8). OS was 3.8 mos with KPS ≤70, vs. 7.5 mos with KPS >70 (p< 0.001). CONCLUSIONS: IT topotecan has a modest side effect profile. Patients with higher functional status at diagnosis had significantly better survival. This study supports the continued use of IT topotecan as a well-tolerated option for LM.

Toxicity and Patient-Reported Outcomes of a Phase 2 Randomized Trial of Prostate and Pelvic Lymph Node Versus Prostate only Radiotherapy in Advanced Localised Prostate Cancer (PIVOTAL)

PurposeTo establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers.Methods and MaterialsIn this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions to pelvis). The primary endpoint was acute lower gastrointestinal (GI) Radiation Therapy Oncology Group (RTOG) toxicity at week 18, aiming to exclude a grade 2 or greater (G2+) toxicity-free rate of 80% in the P&P group. Key secondary endpoints included patient-reported outcomes and late toxicity.ResultsOne hundred twenty-four participants were randomized (62 PO, 62 P&P) from May 2011 to March 2013. Median follow-up was 37.6 months (interquartile range [IQR], 35.4-38.9 months). Participants had a median age of 69 years (IQR, 64-74 years) and median diagnostic prostate-specific androgen level of 21.6 ng/mL (IQR, 11.8-35.1 ng/mL). At week 18, G2+ lower GI toxicity-free rates were 59 of 61 (96.7%; 90% confidence interval [CI], 90.0-99.4) for the PO group and 59 of 62 (95.2%; 90% CI, 88.0-98.7) for the P&P group. Patients in both groups reported similarly low Inflammatory Bowel Disease Questionnaire symptoms and Vaizey incontinence scores. The largest difference occurred at week 6 with 4 of 61 (7%) and 16 of 61 (26%) PO and P&P patients, respectively, experiencing G2+ toxicity. At 2 years, the cumulative proportion of RTOG G2+ GI toxicity was 16.9% (95% CI, 8.9%-30.9%) for the PO group and 24.0% (95% CI, 8.4%-57.9%) for the P&P group; in addition, RTOG G2+ bladder toxicity was 5.1% (95% CI, 1.7%-14.9%) for the PO group and 5.6% (95% CI, 1.8%-16.7%) for the P&P group.ConclusionsPIVOTAL demonstrated that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile. Although safety data from the present study are encouraging, the impact of P&P IMRT on disease control remains to be established.

TDCS effects on cortical excitability in multiple sclerosis fatigue

Objectives Fatigue could affect up to 90% of patients with multiple sclerosis (MS) [1] . Facing the modest benefits and numerous side effects of pharmacological therapies, transcranial direct current stimulation (tDCS) has recently emerged as an appealing tool to treat several neuropsychiatric complaints, including MS fatigue [3] . Previous tDCS protocols did not assess long-term effects of tDCS on MS fatigue, neither did they investigate its potential mechanism of action in this context. Methods We hereby present the case of a 37-year-old MS patient who sought medical attention for debilitating fatigue. The patient has previously participated in a sham-controlled tDCS trial and was found to be among responders to real but not sham stimulation [3] . At presentation, he did not have secondary causes of fatigue. The protocol lasted for 9 weeks (5 consecutive daily sessions in week 1; 4 sessions per week in week 2 and 3; 3 sessions in week 4; 2 sessions in week 5; 1 session in week 6 and a follow-up in week 9). We tested tDCS effects over fatigue as well as other neuropsychological symptoms. Cortical excitability measures were obtained at baseline [2] and then at the end of week 1, week 3 and week 6. Results tDCS resulted in a significant improvement of fatigue which was obtained after the first week, but the most important anti-fatigue effects were documented after week 5. This effect was paralleled by amelioration of cognition and mood scores as well as changes in cortical excitability parameters (increase in short-interval intracortical inhibition and decrease in short-interval intracortical facilitation). Conclusion This is the first report that presents long-term assessment of tDCS effects in the context of fatigue and other MS-related symptoms. Left prefrontal tDCS appears to improve MS fatigue and seems to have a modulatory effect on inhibitory and facilitatory intracortical circuits.

A unique and promising combination of medications for the treatment of Alzheimer’s disease

At present there is no therapy for Alzheimer’s Disease which completely stops the progressive dementia effecting late onset Alzheimer’s Disease (AD) patients. It is felt that the main reason for this failure is that AD appears to be a disease caused by four major pathological processes. To date, efforts to develop treatments have addressed only one or another of these four etiologies. However, even a partially effective therapy against one cause allows the others, untreated, to continue their inexorable destruction of the neurons of the brain. It is suggested that a therapy is required which inhibits all four causes of the disease. Just such a therapy is proposed here with four specific drugs and a vitomer together in a combination treatment.The four major pathologic processes causing AD are: I. vascular hypoperfusion of the brain with associated mitochondrial dysfunction. II. destructive protein occlusions. III. uncontrolled oxidate stress and IV: pro-inflammatory immune processes secondary to microglial and astrocytic dysfunction in the brain.A detailed literature search has provided four drugs and a B6 vitomer which together provide an ideal combination to treat the four etiologies of AD. All four drugs are used clinically for various indications and would be used “off label” in combination to treat AD. The drugs have been used in preliminary studies to treat dementia with favorable indications in all of them inhibiting dementia with only modest side effects. In in vitro studies all five of the combination have been shown effective in inhibiting one or more of the four disease etiologies and together they are effective against all four.The four drugs are Trental, Nicergoline, Nilotinib, and Methylene blue. The vitamer is B6 pyridoxamine. The cumulative benefits of this combination should provide an effective treatment to completely stop the progressive dementia of AD, measured in 12–18months.The use of an endpoint of complete cessation of progressive dementia rather than the standard of a statistical determination of the slowing of progressive dementia allows the study to be conducted with a cohort of only 15 patients (no statistics and no placebo patients) as every AD patient would otherwise show progressive dementia without the effective treatment.

PrEP, Truvada, and Gilead

Who sets the price of pre-exposure prophylaxis for HIV in the UK, asks Andrew Jack Truvada is a fixed dose combination of tenofovir and emtricitabine produced by the US drug...

Increased local delivery of antagomir therapeutics to the rodent myocardium using ultrasound and microbubbles

Recent developments in microRNA (miRNA) research have identified these as important mediators in the pathophysiological response upon myocardial infarction (MI). Specific miRNAs can inhibit the translation of entire groups of mRNAs, which are involved in specific processes in the pathophysiology after MI, e.g. the fibrotic, apoptotic or angiogenic response. By modulating miRNAs in the heart, these processes can be tuned to improve cardiac function. Antagomirs are effective miRNA-inhibitors, but have a low myocardial specificity and cardiac antagomir treatment therefore requires high doses, which causes side effects. In the present study, ultrasound-triggered microbubble destruction (UTMD) was studied to increase specific delivery of antagomir to the myocardium. Healthy control mice were treated with UTMD and sacrificed at 30min, 24h and 48h, after which antagomir delivery in the heart was analyzed, both qualitatively and quantitatively. Additionally, potential harmful effects of treatment were analyzed by monitoring ECG, analyzing neutrophil invasion and cell death in the heart, and measuring troponin I after treatment. Finally, UTMD was tested for delivery of antagomir in a model of ischemia–reperfusion (I/R) injury. We found that UTMD can significantly increase local antagomir delivery to the non-ischemic heart with modest side-effects like neutrophil invasion without causing apoptosis. Delivered antagomirs enter cardiomyocytes within 30min after treatment and remains there for at least 48h. Interestingly, after I/R injury antagomir already readily enters the infarcted zone and we observed no additional benefit of UTMD for antagomir delivery. This study is the first to explore cardiac antagomir delivery using UTMD. In addition, it is the first to study tissue distribution of short RNA based therapeutics (~22 base pairs) at both the cellular and organ levels after UTMD to the heart in general. In summary, UTMD provides a myocardial delivery strategy for non-vascular permeable cardiac conditions later in the I/R response or chronic conditions like cardiac hypertrophy.

Abstract 3972: MicroRNAs as potential therapeutic agents for AML: Targeting the AML1-ETO Oncogene by pre-miR-520 and -373

Abstract Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of poorly differentiated myeloid cells in the bone marrow and blood of patients. Differentiation therapy is an attractive therapeutic approach for treating patients with AML. All-Trans Retionic Acid, induces differentiation of patients with the PML/RARa oncogene, but is ineffective in treating other more frequent types of AML. Here we describe the use of microRNAs to target the oncogene formed as a result of the (8;21) translocation, The goals was to identify miRNAs that could target the breakpoint region of the fusion protein, and determine if this would reduce expression of AML1-ETO and promote differentiation and/or apoptosis. Bioinformatics analysis was used to identify 28 different miRNAs that could potentially target AML1-ETO transcripts. Among those, miRNA-520 and -373 showed the highest degree of complimentary to AML1-ETO transcripts at the braikpoint. To look for miR-520 and -373 efficacy, we transfected two AML cell lines, Kasumi 1 and SKNO1, which have AML1-ETO translocation, with pre-miR-520 and -373 LNA probes, as well as HL60 cells which lack AML1-ETO. Expression of the LNA pre-miR-520/373 in Kasumi-1 and SKNO-1 cell lines decreased AML1-ETO transcripts and led to a significant reduction of AML1-ETO protein levels. The inhibition of AML1-ETO fusion protein also induced apoptosis of leukemic cells in vitro, but had no effect on HL60 cells. Moreover, the administration of LNA pre-miR-520 in an AML xenografts murine model increased apoptosis of leukemic cells and reduced tumor burden without obvious toxicity. We are currently testing the effects of miR-520 and -373 on differentiation and proliferation of primary blasts from patients with the AML1-ETO translocation. Our results suggest that small molecules such as miRNAs can be identified that directly target a frequent AML oncogene. miRNAs are naturally accruing molecules and have the potential advantage of producing modest side effects, with highly significant specificity. The approaches we developed in this study can be used to evaluate and optimize other pre-miRs and anti-miRs as therapeutic agents to target other types oncogenes not currently amenable to small molecule drugs. Citation Format: Patricia A. Toniolo, Patrick M. Pilarski, Christian Bach, James D. Griffin, Sophia Adamia. MicroRNAs as potential therapeutic agents for AML: Targeting the AML1-ETO Oncogene by pre-miR-520 and -373. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3972. doi:10.1158/1538-7445.AM2015-3972

The advantage of using 3-week data to predict response to aripiprazole at week 6 in first-episode psychosis

We investigated the efficacy and safety of aripiprazole in first-episode psychosis and explored the association between early response and later response to this medication. This was a 6-week, open-label, multicenter trial. The study population consisted of 59 patients with a DSM-IV diagnosis of a schizophreniform disorder, schizoaffective disorder, schizophrenia, or psychotic disorder not otherwise specified. The primary outcome measures were the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-Severity scale. To assess the safety, we measured the drug-related adverse events, weight, and lipid-related variables. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the response status at weeks 2 and 3 to predict the subsequent response at week 6. Among the 59 participants, 38 were able to complete the 6-week trial. Treatment with aripiprazole resulted in significant improvement in the PANSS and Clinical Global Impression scores over time. The response rate (defined as a ≥30% decrease in the PANSS total score from baseline to the last observation) was 69.1%. The most accurate prediction of later response in terms of negative predictive value and specificity was a reduction in the PANSS total score from baseline to week 3 of at least 20%. Aripiprazole had a modest side effect burden and was characterized by a safe profile with respect to weight and metabolic side effects. These results indicate that aripiprazole is effective and safe in the treatment of first-episode psychosis. The response at week 3, rather than week 2, predicted the later response more accurately.

A phase I dose-escalation and cohort expansion study of lirilumab (anti-KIR; BMS-986015) administered in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (Pts) with advanced refractory solid tumors.

TPS3110 Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptor (KIR) and programmed death-1 (PD-1) are immune receptors that down-regulate NK and T cell activity, respectively. Lirilumab, an anti-KIR antibody that potentiates innate immunity, has demonstrated modest side effects in a phase I monotherapy trial. Nivolumab, a PD-1 receptor blocking antibody that potentiates adaptive immunity, has shown clinical activity with various solid tumors in phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity with anti-KIR and anti-PD-1 antibodies could achieve more favorable biologic and clinical activity than either agent alone. Here, we describe a phase I study of lirilumab plus nivolumab in pts with advanced solid tumors, the first collaborative clinical trial being conducted by the International Immuno-Oncology Network (II-ON). Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with any solid tumor, except primary central nervous system tumors, will be enrolled. During cohort expansion, pts (N=16/cohort) with non-small cell lung carcinoma – squamous and non-squamous histology, renal cell carcinoma, melanoma, colorectal carcinoma, or ovarian carcinoma will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity in all pts, and pharmacodynamic effect on tumor infiltrating lymphocyte subsets from melanoma pts. Exploratory objectives include a thorough assessment of innate and adaptive immunity modulation by this combination in peripheral blood and/or tumor specimens, as well as preliminary associations with clinical outcome. As of Feb 1, 2013, three pts have started therapy. Clinical trial registration number: NCT01714739. Clinical trial information: NCT01714739.

A phase I study of lirilumab (BMS-986015), an anti-KIR monoclonal antibody, administered in combination with ipilimumab, an anti-CTLA4 monoclonal antibody, in patients (Pts) with select advanced solid tumors.

TPS3106 Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptors (KIR) and cytotoxic T lymphocyte antigen-4 (CTLA-4) are immune receptors that down-regulate NK and T cell activity, respectively. The anti-KIR antibody, lirilumab (BMSE986015), potentiates innate immunity by blocking signaling through inhibitory KIRs and has demonstrated modest side effects in a Phase I trial. The anti-CTLA-4 antibody, ipilimumab, potentiates adaptive immunity and has demonstrated improved overall survival in pts with advanced melanoma and preliminary evidence of clinical activity in Phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity by combining anti-KIR and anti-CTLA4 antibodies could achieve enhanced biologic and clinical activity compared to either agent alone. Here, we describe a Phase I study of lirilumab plus ipilimumab in pts with selected advanced solid tumors. Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with advanced melanoma, non-small cell lung cancer and castrate resistant prostate cancer, will be enrolled. During cohort expansion, 20 pts with each tumor type will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity of this combination in all pts, and the pharmacodynamic effects on tumor infiltrating lymphocytes in a cohort of melanoma pts. Exploratory objectives include a thorough assessment of the modulation of innate and adaptive immunity by this combination in peripheral blood and/or tumor specimens, and preliminary evaluation of the association of these changes with clinical outcome. Clinical trial registration number: NCT01750580 Clinical trial information: NCT01750580.