Prostate specific membrane antigen (PSMA) represents a validated target for prostate cancer therapeutics. The phase III VISION study with
lutetium (
Lu)-PSMA-617 represented a pivotal step forward ...and the FDA has now approved this agent in advanced metastatic castrate-resistant prostate cancer (mCRPC). A number of other PSMA targeted radiopharmaceuticals are now under development. Some of these agents are targeted to PSMA via monoclonal antibodies such as J591 and TLX591. Others are targeted to PSMA via small molecules such as PSMA-617, PSMA I&T, MIP-1095, etc. In addition to the use of various ligands, multiple isotopes are now in clinical trials. Beta emitters in development include
Lu,
iodide (
I), and
copper (
Cu). Targeted alpha emitters potentially include
actinium (
Ac),
thorium (
Th), and
lead (
Pb). Phase III trials are underway with both
Lu-PSMA-617 and
Lu-PSMA I&T in mCRPC. Single dose phase I trials are complete with
Ac-J591 but additional data are need to launch a phase III. Data are promising with
Ac-PSMA-617 but concerns remain over salivary and renal toxicity. Tandem therapies are also considered combining both beta and alpha-targeted therapy. Taken together the field of PSMA targeted radiopharmaceuticals is rapidly developing. The targeted alpha therapies are particularly promising and several developmental paths forward are being considered in the near future.
“Accelerated” chronic lymphocytic leukemia/small lymphocytic lymphoma (A-CLL) is a rare histological variant of CLL/SLL, which tends to exhibit an aggressive clinical behavior compared to CLL. Due to ...the rarity of A-CLL (<1% of all cases), the optimal management remains ill-defined. We report two cases of A-CLL from our institution, in which both relapsed following initial chemoimmunotherapy regimens. Both patients were treated with single agent ibrutinib, a Bruton's tyrosine kinase inhibitor (BTKi), and achieved rapid, deep and durable responses. With the absence of clear guidance on A-CLL treatment, BTKi agents should be considered in the frontline treatment of A-CLL.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Purpose: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine ...that has completed Phase I/II studies AACR, #CT129, 2017 in adult subjects with cancers involving the CNS. Four (4) subjects in the Phase I/II trials required surgery for persistent CNS lesions following DM-CHOC-PEN therapy with 39-98.8 mg/m2 of drug. DM-CHOC-PEN was identified in samples from all 4-subjects - 90-212 ng/g tumor. Thus, the drug penetrates the CNS and tumors and is available to act as a radiosensitizer; the latter has been supported with in vitro studies AACR, #4746, 2017. The current presentation reviews the long term Phase I clinical data that supports safety, dose-tolerance and use of DM-CHOC-PEN plus radiation in subjects with cancers involving the CNS - IND 68,876. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once to subjects with advanced cancer involving the CNS. A single dose (39 mg/m2 to 98.7 mg/m2 in escalating Phase I scheme) was administered once anywhere from 48 hours to 3-weeks prior to receiving stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT). Radiation was administered in doses of 15-30 Gy depending on the size and number of lesions. Results: Nineteen (19) subjects with cancer involving the CNS have been treated to date with DM-CHOC-PEN (6-NSCLC, 1-breast, 1-melanoma, 5-GBM, 3-sarcomas, 1-astrocytoma & 2-renal cell carcinomas). Subjects received 39, 50, 70, 86.8 or 98.7 mg/m2 of DM-CHOC-PEN. Five subjects received WBRT (30 Gy) and 14 subjects received SRS (15-24 Gy. One (1) subject with NSCLC did develop vasogenic edema and tumor necrosis which resolved and the subject is in complete remission 55+ mos. A second subject with a recurrent GBM developed Gr-3 confusion secondary to an enlarging lesion which was removed. Drug was present in ng/g of tumor conc.; confusion resolved. Ten (10) of the thirteen (13) subjects have had objective results (OS 8-58 mos.) Bioavailability for DM-CHOC-PEN revealed a rebound phenomenon @ ~ 50 hours post-infusion with a T-release of 26.7 h. and drug in the plasma (Cmax=17.5 µg/mL) until day 15 . The AUC was linear for all doses. Pre-clinical radiosensitization in vitro studies AACR #1917, 2017 supported the present trial. Photon induced charge transfer reactions with DM-CHOC-PEN will be discussed as a MOA. Conclusion: Data is presented that documents effectiveness and safety of DM-CHOC-PEN plus radiation as therapy for subjects with cancers involving the CNS. Observations during this trial supported the drug's ability to penetrate human tumors involving the CNS and acceptability as a method to improving responses to radiation. Complete data on subject responses and observed toxicities will be presented. Supported by - NCI/SBIR grants - R43 CA213545-02 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center.
Citation Format: Steven J. DiBiase, Roy S. Weiner, Tallat Mahmood, Kendra Harris, Ronald Kawauchi, Kiran Devisetty, James Herman, Manish Bhandari, Marcus Ware, Paul Friedlander, Lee R. Morgan, Ali Baghian. Phase I clinical trial: results from the use of 4-demethyl-4 cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) plus radiation as treatment for cancers involving the CNS abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT101.
Background: The prognosis of multiple myeloma (MM) has improved significantly over the last 20 years due to the introduction of autologous stem cell transplantation and novel drugs. The standard ...regimen for conditioning in MM is melphalan 200 mg/m2, since a study published in 2002 (Moreau et al.) showed a survival advantage of melphalan (MEL) only over melphalan- total body irradiation (MEL-TBI) conditioning. Ionizing radiation is an independent treatment modality and has activity in MM. We decided to reevaluate the outcome of MEL-TBI conditioning in the age of novel drugs.
Patients and Methods: In a retrospective chart review, we identified 50 patients with MM who underwent autologous hematopoietic cell transplantation at Tulane University Medical Center and were conditioned with MEL-TBI between December 1995 and March 2012. Stem cells were collected following a stimulation by 10 µg/ kg filgrastim for 4 days. In case of insufficient collection, plerixafor was administered. Between 1995 and 2003 cyclophosphamide priming was used in most cases. Patients received melphalan 140 mg/m2 as a single dose given intravenously on day -5. TBI was administered in fractionated doses of 150 cGy between days -4 and -1 (total dose 12 Gy). Peripherally harvested stem cells were infused on day 0. Standard supportive measures were followed. Log-rank test and Kaplan-Meier curves were used to calculate overall survival (OS) and progression-free survival. Significance levels were standard (p<0.05). The expected survival for each patient was compared with data from the Louisiana Tumor Registry (matched with 5 year age interval and 4 year time of diagnosis interval).
Results The OS from the date of diagnosis is shown in Fig. 1 (84.2 months). The mean survival from date of transplant to death or last follow-up is 70.1 months. No significant differences in OS were observed according to gender, race, age at transplant, or initial stage of disease. No significant differences were observed when patients transplanted in remission (CR, sCR or VGPR) were compared with patients with partial remission, stable or progressive disease. Patients treated more recently (2006-2013) had a trend to a longer survival compared with the earlier period (1995-2005). Seven out of 8 patients who were not in CR achieved CR post-transplant. The d100 survival in the earlier period was 83%, in the later period 97%. The 1 year survival increased from 72% in the earlier period to 91% in the later period. When the survival of patients transplanted at our center is compared with the observed survival of all MM patients in Louisiana, a dramatic difference becomes apparent (median survival 27 months versus 84 months, see Figure 1). Second malignancies were documented in 3 (6%) of our patients (T-cell lymphoma, renal cell carcinoma, possible myelodysplastic syndrome).
Conclusion: Mel-TBI conditioning results in long-term survival, especially if the early toxicity associated with total body irradiation is ameliorated. The survival reported in this study is almost twice as reported by Moreau et al. The improvement is in large part due to salvage treatments and improved supportive care. However, MEL-TBI may be superior in certain subgroups of patients. We plan to perform a larger study comparing MEL-TBI to MEL only with risk stratification and to investigate the possible interaction between cyclophosphamide priming and early toxicity. According to our data, MEL-TBI does not result in increased second malignancies. The survival of patients who underwent transplant with MEL-TBI is superior to patients in a population-based registry (matched for age and time of treatment).
Display omitted
No relevant conflicts of interest to declare.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction: While tetraploidy (92 chromosomes) and near-tetraploidy (>80 chromosomes) confer favorable prognosis in B-cell lineage pediatric acute lymphoblastic leukemia, their prognostic ...significance in acute myelogenous leukemia (AML) remains ill-defined. Moreover, the mechanisms underlying their pathobiology and impact on known prognostic factors in AML are unknown. Combining data collected at our institution along with a review of the literature, we provide the most complete analysis of tetraploidy and near-tetraploidy in AML including data on biology, treatment outcomes, impact on other prognostic markers, and survival to assist in clinical management.
Patients and methods: A systematic literature search was performed and included studies published from June 1st, 1994 to June 1st, 2017 in PubMed, Embase, and Web of Science. We used the key words tetraploidy, near-tetraploidy, acute myeloid leukemia, acute myelogenous leukemia, and AML. Data was tabulated regarding the following seven variables: Fluorescence in situ hybridization (FISH) analysis, molecular analysis, karyotype, risk status, overall survival (OS), history of allogeneic stem cell transplantation, and chemotherapy. Data was reported as percent and total number of cases with available data of each variable.
Results and discussion: We identified 104 AML cases with confirmed tetraploidy or near-tetraploidy (102 cases in 24 articles, and 2 cases from our institution). Incidence was nearly equal between tetraploidy (55/104) and near-tetraploidy (49/104). The median age at diagnosis was 54. A notable male predominance was observed with a male-to-female ratio of 2.2:1 (71 males and 33 females). While insufficient molecular data were available to include in risk stratification, cytogenetics including FISH and karyotype were available in all cases. We stratified our cases irrespective of tetraploidy or near-tetraploidy into favorable risk (defined by the presence of the following genetic alterations in core-binding factors: inv(16) or t(16;16) or t(8;21), or t(15;17)), unfavorable risk (defined by complex karyotype ≥3 clonal chromosomal abnormalities, monosomal karyotype, 5q-, 7q-, -5,-7, t(6;9), inv(3), t(3;3), 11q23 - non t(9;11), t(9;22)) and intermediate risk (the rest). Consistent with the literature, cases with other cytogenetic abnormalities in addition to those defined in the favorable-risk group, were included within the favorable-risk category (Byrd Blood 2002). Interestingly, t(8;21) was the only favorable risk feature represented, seen in 13 patients (12.5%), thus grouped under favorable-risk AML. 51 patients (49.0%) were grouped under unfavorable-risk AML and included 24 patients with complex karyotype, 9 patients with -7, 7 patients with 5q-, 4 patients with -5, 1 patient with 7q-, 1 patient with t(9;22), 3 patients with both -5 and -7, 1 patient with both 5q- and -7, and 1 patient with both -5 and 7q-. Intermediate risk was observed in 40 patients (38.5%) who were found to have normal or non-defined cytogenetics. We used the Kaplan-Meier method to stratify survival data, and the log-rank test to compare the survival between subgroups. The overall outcomes were poor, the median OS (mOS) of the whole cohort was 6 months (M) (Figure 1A). The prognosis was equally poor for both tetraploidy (mOS 6.2M) and near-tetraploidy (mOS 6M) (P=0.81; Figure 1B). Surprisingly, risk stratification showed no impact on overall survival (P=0.57; Figure 1C), which suggest that the unfavorable risk imposed by tetraploidy or near-tetraploidy may overcome favorable-risk features, such as t(8;21), challenging current data on AML risk stratification. Twenty-one patients (20.2%) had an allogeneic stem cell transplantation. Interestingly, we noticed a significant improvement in outcomes (mOS 17M) in patients who received an allogeneic stem cell transplantation compared to those who did not (mOS 4M) (P=0.0085; Figure 1D).
Conclusion: Regardless of the risk status, the prognosis of tetraploid or near-tetraploid AML is dismal and should be incorporated within the unfavorable risk group. Prompt evaluation for allogeneic stem cell transplant should be initiated at diagnosis. Indeed, longer survival can be achieved with chemotherapy followed by allogeneic stem cell transplantation at first complete remission.
Display omitted
No relevant conflicts of interest to declare.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Targeting the B-cell receptor (BCR) pathway in chronic lymphocytic leukemia (CLL) with the Bruton Tyrosine Kinase (BTK) inhibitor Ibrutinib has transformed the treatment paradigm of this disease. ...Ibrutinib is currently indicated for treatment of CLL regardless of the line of therapy. However, ibrutinib is not curative, and relapses secondary to C481S mutation in BTK and gain of function mutations in PLCγ2 (R665W and L845F) are being reported.
The protease mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) is the active component of the CARD11-BCL10-MALT1 (CBM) signaling complex. CBM mediates NF-κB activation downstream of BTK and PLCγ2 within the BCR pathway, which makes of MALT1 an ideal therapeutic target in ibrutinib-resistant clones. Notably, the chemical compound MI2 (C19H17Cl3N4O3) binds to- and suppresses the protease activity of MALT1, and was found to be active against activated B-cell-like diffuse large B-cell lymphoma. However, the role of MALT1 inhibition in CLL has not been investigated.
We studied the efficacy of MI2 against a cohort of CLL samples (N=21), and explored its mechanism of action. PBMCs from patients with CLL were tested against serial dilutions of MI2 (0.125-8μM) for 48 h in 96-well plates, and MTS assay was performed to quantify cell viability. We observed a dose-dependent cytotoxicity in all samples, with an inhibitory concentration at 25% (IC25) < 2μM observed in the majority of the samples. MI2 cytotoxicity was independent of the IGHV mutational status, CD38 expression, cytogenetics, previous therapy status, and MALT1 protein level (immunoblot on purified CLL cells). To study the drug apoptosis and drug selectivity, we examined apoptotic induction in both CLL cells and T-cells of the same patients. PBMCs from five patients with CLL were treated with MI2 for 48 h and compared to untreated control. At the end of the incubation, cells were stained with CD5, CD19, and Annexin-V, then analyzed using flow cytometry. We found that MI2 induced a dose-dependent apoptosis in CLL cells (defined as CD5+/CD19+) in all samples, with only mild toxicity to their corresponding T-cells (T-cells represent a fraction of each patient’s PBMCs defined as CD5+/CD19-). This minimal toxicity to T-cells was not statistically significant when compared to untreated control T-cells, and may reflect a T-cell receptor signaling-independence of circulating T-cells, which are mostly composed of terminally differentiated effectors. To determine whether the induced apoptosis is caspase-dependent, we treated PBMCs of CLL patients (N=5) with MI2 (0.5-4 μM) in the presence or absence of 100μM of the pan-caspase inhibitor z-VAD-fmk for 48 h. We found that z-VAD-fmk completely prevented the induction of apoptosis in CD19+/CD5+ CLL cells as determined by Annexin-V staining (flow cytometry), and decreased MI2-induced PARP cleavage (Immunoblot).
To determine the effect of the microenvironment on MI2 toxicity, we cultured primary CLL cells with and without MI2 (0.5-4µM) for 48 h, in the presence or absence of Nurse-Like Cells (NLC) (N=5) or anti-IgM (N=4). NLCs and anti-IgM cross-linking of BCR are in-vitromodels for the protective effect of the microenvironment. Co-culture with NLCs or with anti-IgM improved the viability of the untreated primary CLL samples. Similar to ibrutinib, MI2 continues to be effective against CLL cells in the presence of NLCs or anti-IgM, but higher concentrations are required to achieve the desired cytotoxicity against CLL cells. There was no cytotoxic effect on NLCs.
To investigate the effect of MI2 on tumor biology, 1 μg of total RNA from purified CLL cells (treated for 8 h with MI2, N=3; and untreated control, N=3) was subjected to RNA sequencing. Out of 56,650 tested genes, there were 438 genes whose expression changed ≥2-fold at P<0.05 (312 down- and 126 up-regulated), several genes are known NF-κB targets. The observer-independent method, Gene Set Enrichment Analysis (GSEA), clearly identified the canonical NF-κB among of the top affected pathways.
Further studies aim to verify the RNA sequencing data at the protein level, to determine MI2 efficacy against ibrutinib-resistant clones in vitro, and against CLL growth in mice in vivo.
Supported by Hope Foundation SWOG Early Exploration and Development (SEED) Award. We thank the Louisiana Cancer Research Center (LCRC) biospecimen core and our patients for the donation of samples to make this research possible.
No relevant conflicts of interest to declare.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and Objectives
Since a study published in 2002 showed a survival advantage of melphalan‐only conditioning for stem cell transplantation (HSCT) over melphalan‐total body irradiation ...(mel‐TBI) in patients with multiple myeloma (MM), most centers abandoned mel‐TBI. Mel‐TBI causes more early toxicity and is more complicated to administer, but we speculated it may result in longer term survival with radiation as an independent treatment modality. Therefore, we analyzed the long‐term outcome of patients with MM who received mel‐TBI as part of conditioning at our center.
Patients and Methods
From 1995 to 2013, 50 patients with MM underwent autologous HSCT at Tulane University Medical Center using mel‐TBI conditioning. We used Kaplan‐Meier survival analysis and compared our patients with data available from the Louisiana Tumor Registry.
Results
The mean survival of our patients was 70.98 months from time of transplant and 84.2 months from time of initial diagnosis. No differences were observed according to gender, ethnicity, or age at transplant. The expected median survival in a population‐based registry (matched for age and year of treatment) was 27 months (P<.001).
Conclusions
Total body irradiation in conjunction with melphalan as conditioning is feasible and can lead to long‐term survival. More research is necessary to determine which patients benefit most. Mel‐TBI should also be explored in conjunction with immunotherapy.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Background The aim of this study was to investigate the effect of 12 weeks of aerobic training, 4 weeks of detraining and use gonadotropin-releasing hormone agonist (GnRHa) on serum C-reactive ...protein (CRP) and cortisol levels in girls with central precocious puberty (CPP). Methods Forty-five girls (aged 6-8 years) with precocious puberty were randomly divided into three groups (medication, training and medicine + training groups). Fifteen healthy girls (without precocious puberty) were also included as the control group. Serum CRP and cortisol levels were measured at baseline by the enzyme-linked immunosorbent assay (ELISA) technique. Then, the experimental groups performed an aerobic training program for 3 days/week 20-75 min per day at 45-75% maximum heart rate for 12 weeks. The medication groups also received GnRHa during the study, once a month (1 mL every 4 weeks) by intramuscular injection. Serum CRP and cortisol levels were measured again 48 h after the last training session and also after 4 weeks of detraining. Results Analysis of variance (ANOVA) with repeated measures showed a significant decrease in CRP (p = 0.02) and cortisol levels (p = 0.01) in the training group and the medicine + training group. Detraining led to return of CRP and cortisol levels to the pre-training levels (p = 0.001). No significant difference in serum CRP (p = 0.43) and cortisol levels (p = 0.06) was observed in the medication group. Further, no significant difference was observed between groups in CRP and cortisol. Conclusions Long-term regular moderate training decreases inflammation indices, and detraining eliminates the benefits of training in girls with precocious puberty.
Objective: In order to achieve development goals, in addition to providing students with physical health, their mental and social health should be considered as a necessity and priority in ...development programs. This program, called the Nemad Project in Iran was formally established in 2015. This study aims to explore the challenges of the Nemad project in Iranian schools based on stakeholders' views.Method: The present qualitative study, with a contractual content analysis approach, was conducted on 21 experts in the field of social harm prevention and mental health promotion at the senior, intermediate, and operational levels in educational institutions and schools, Ministry of Health, the Judiciary and the Planning and Budget Organization. These experts also included project technical officers. Participants were selected using snowball and purposeful sampling methods. Data were collected through semi-structured interviews and analyzed by coding, classification, and extraction of the main themes.Results:Six main themes were derived that included inefficiency in resource management (with subcategories of inadequate facilities and equipment, inadequate human resource management, and information management system deficiencies), weakness in program organization (with subcategories of poor cross-sectoral and weak inter-sectoral subgroups), challenges of laws/regulations/policies (with sub-categories of defective protocols and guidelines and lack of specific task descriptions), barriers and challenges to implementation of policies (with macro and school policy implementation subcategories), structural factors (with subcategories of financial resources allocation problems, inconsistency in managerial levels, and deficiencies in decision-making principles), weaknesses in educational processes (with subcategories of inadequate teacher education, weaknesses in parenting courses, and weaknesses in student education), and ultimately, weaknesses in monitoring and evaluation (with the subcategory of lack of a monitoring and evaluation system).Conclusion:According to experts, implementation of mental and social programs in schools is not in a desirable situation and is faced with certain challenges. To enhance the management of the Nemad project in Iranian schools, it is necessary to compile flowcharts of service delivery and inter-device communication, allocate resources to meet the expectations of each organization, do performance-based budgeting, take a comprehensive look at parental issues, and design a system of monitoring and evaluating the requirements.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
PDF
