Predictive model for treatment outcomes of peripheral T-cell lymphoma, not otherwise specified, in Taiwanese patients.

PURPOSE: We aimed to explore the clinical outcomes and prognostic factors for PTCL-NOS patients in the real world. METHODS: Clinical data were retrospectively collected from adult patients with PTCL-NOS treated at a single center in Taiwan. RESULTS: 104 PTCL-NOS patients with a median age of 53.0 years were enrolled. Patients with the International Prognostic Index (IPI) or prognostic index for peripheral T-cell lymphoma (PIT) scores of zero had a longer overall survival (OS) and progression free survival (PFS), while patients with IPI or PIT scores ≥1 did poorly. For patients who are eligible for transplantation, the use of pralatrexate as salvage chemotherapy has shown better OS (2-year OS 83.3% vs. 24.4%, P = 0.011) compared to patients who did not. By multivariate analysis, age >60 years, male, B symptoms, ECOG >1, lung involvement, and thrombocytopenia were independent adverse factors for OS. Incorporating factors in multivariate analysis, we established a novel predictive index for PTCL-NOS which efficiently stratifies patients into low (0-1 factor), intermediate-1 (2 factors), intermediate-2 (3 factors), and high risk (4-6 factors) groups with 2-year OS rates of 81.5%, 32.9%, 8.8%, and 0%, respectively (P < 0.001). CONCLUSION: PTCL-NOS patients have a dismal prognosis in Taiwan. Novel agents may improve the outcomes of PTCL-NOS patients. The usefulness of the novel prognostic index for PTCL-NOS needs further validation.

Characterization of newly established Pralatrexate-resistant cell lines and the mechanisms of resistance.

BACKGROUND: Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic resistance or develop acquired resistance. Here, we evaluated the mechanisms underlying acquired resistance to PDX and explored potential therapeutic strategies to overcome PDX resistance. METHODS: To investigate PDX resistance, we established two PDX-resistant T-lymphoblastic leukemia cell lines (CEM and MOLT4) through continuous exposure to increasing doses of PDX. The resistance mechanisms were evaluated by measuring PDX uptake, apoptosis induction and folate metabolism-related protein expression. We also applied gene expression analysis and methylation profiling to identify the mechanisms of resistance. We then explored rational drug combinations using a spheroid (3D)-culture assay. RESULTS: Compared with their parental cells, PDX-resistant cells exhibited a 30-fold increase in half-maximal inhibitory concentration values. Induction of apoptosis by PDX was significantly decreased in both PDX-resistant cell lines. Intracellular uptake of [14C]-PDX decreased in PDX-resistant CEM cells but not in PDX-resistant MOLT4 cells. There was no significant change in expression of dihydrofolate reductase (DHFR) or folylpolyglutamate synthetase (FPGS). Gene expression array analysis revealed that DNA-methyltransferase 3ß (DNMT3B) expression was significantly elevated in both cell lines. Gene set enrichment analysis revealed that adipogenesis and mTORC1 signaling pathways were commonly upregulated in both resistant cell lines. Moreover, CpG island hypermethylation was observed in both PDX resistant cells lines. In the 3D-culture assay, decitabine (DAC) plus PDX showed synergistic effects in PDX-resistant cell lines compared with parental lines. CONCLUSIONS: The resistance mechanisms of PDX were associated with reduced cellular uptake of PDX and/or overexpression of DNMT3B. Epigenetic alterations were also considered to play a role in the resistance mechanism. The combination of DAC and PDX exhibited synergistic activity, and thus, this approach might improve the clinical efficacy of PDX.

Complete remission of stage IV erythrodermic mycosis fungoides with large cell transformation through combination of pralatrexate and romidepsin followed by allogeneic hematopoietic stem cell transplantation.

We report the case of a 59-year-old woman with stage IV erythrodermic mycosis fungoides (MF) and large cell transformation who, despite failing multiple previous treatments, achieved complete remission through a combination of pralatrexate and romidepsin followed by allogeneic hematopoietic stem cell transplantation (alloSCT). Further studies are needed in focussing on this combined regimen in treating cutaneous T-cell lymphoma (CTCL) and its efficacy as a bridging regimen in facilitating successful alloSCT.

Generation of pralatrexate resistant T-cell lymphoma lines reveals two patterns of acquired drug resistance that is overcome with epigenetic modifiers.

While pralatrexate (PDX) has been successfully developed for the treatment of T-cell lymphoma, the mechanistic basis for its T-cell selectivity and acquired resistance remains elusive. In an effort to potentially identify synergistic combinations that might circumnavigate or delay acquired PDX resistance, we generated resistant cells lines over a broad concentration range. PDX-resistant cell lines H9-12 and H9-200 were developed, each exhibiting an IC50 of 35 and over 1000 nM, respectively. These lines were established in vitro from parental H9 cells. Expression analysis of the proteins known to be important determinants of antifolate pharmacology revealed increase expression of dihydrofolate reductase (DHFR) due to gene amplification, and reduced folate carrier1 downregulation, as the putative mechanisms of resistance in H9-12 and H9-200 cells. Cross resistance was only seen with methotrexate but not with romidepsin, azacitidine (AZA), decitabine, gemcitabine, doxorubicin, or bortezomib. Resistance to PDX was reversed by pretreatment with hypomethylating agents in a concentration-dependent fashion. Comparison of gene expression profiles of parental and resistant cell lines confirmed markedly different patterns of gene expression, and identified the dual specificity phosphatase four (DUSP4) as one of the molecular target of PDX activity. Reduced STAT5 phosphorylation following exposure to PDX was observed in the H9 but not in the H9-12 and H9-200 cells. These data suggest that combination with hypomethylating agents could be potent, and that DUSP4 and STAT5 could represent putative biomarkers of PDX activity.

Cost-utility analysis of pralatrexate for relapsed or refractory peripheral T-cell lymphoma based on a case-matched historical control study along with single arm clinical trial.

BACKGROUND: Patients with relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) treated with pralatrexate have previously shown superior overall survival (OS) compared to those who underwent conventional chemotherapy (CC, 15.4 vs. 4.07 months). We conducted an economic evaluation of pralatrexate from a societal perspective in Korea based on data from the PROPEL phase II study. METHODS: Using a Markov model with a weekly cycle, we simulated the experience of patients with R/R PTCL receiving pralatrexate or CC for 15 years. The model consists of five health states; initial treatment, treatment pause, subsequent treatment, stem cell transplantation (SCT) success, and death. Comparative effectiveness was based on PROPEL phase II single-arm study and its matched historical control analysis. Costs included drug, drug administration, monitoring, adverse event management, and SCT costs. RESULTS: The incremental cost-effectiveness ratio of the base case was $39,153 per quality-adjusted life-year (QALY) gained. The results of one-way sensitivity analysis ranged from $33,949 to $51,846 per QALY gained, which remained within an implicit willingness-to-pay (WTP) threshold of anticancer drugs in Korea. CONCLUSIONS: Pralatrexate is a cost-effective intervention with improved OS and incremental costs within the WTP limit. Pralatrexate could function as a new therapeutic option for patients suffering from life-threatening R/R PTCL.

Survival benefit in patients with peripheral T-cell lymphomas after treatments with novel therapies and clinical trials.

The peripheral T-cell lymphomas (PTCL) are rare and heterogeneous diseases characterized by an unfavorable prognosis. Chemotherapy is standard upfront treatment in most patients, but responses are short-lived with few FDA-approved "novel" agents available. We sought to define the impact of these novel agents as single agents or in clinical trials on the outcomes of patients with PTCL. From January 1994 to May 2019, adult patients with PTCL who were managed at our institution were included in this analysis. In addition to patients with incomplete data, those diagnosed with large granular lymphocytic leukemia and cutaneous T-cell lymphoma (CTCL) except for transformed mycosis fungoides were excluded. Statistical analyses were performed using SAS version 9.4. There were 219 patients included in the analysis. The median age at diagnosis was 56 years (range, 18-90 years). First line therapies mostly consisted of combination chemotherapy (75%). There was a statistical difference among patients who received chemotherapy, novel agents alone and in chemotherapy-free combinations, other, and no treatment (P < .0001). In patients who were treated with second line chemotherapy, novel agents alone and in combination without chemotherapy, or other, there was a still a survival benefit favoring novel agents (P = .0417). In the third line, there was no statistical difference among the three groups (P = .569). All patients who received novel therapies and underwent autologous stem cell transplant (autoSCT) achieved a complete response (CR) and had a better survival compared with patients who underwent chemotherapy who had a 70% CR rate prior to autoSCT (P = .046). Exposure to FDA-approved novel agents, immunoepigenetic trials, and clinical trials in general was associated with an overall survival (OS) benefit (P = .003, P = .04, and P = .006, respectively). These data suggest that patients who receive novel agents have superior outcomes compared with patients without exposure to novel therapies who receive chemotherapy-predicated treatments.

Systemic Treatment Options for Advanced-Stage Mycosis Fungoides and Sézary Syndrome.

PURPOSE OF REVIEW: Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Globally, the most common subtypes of CTCL are mycosis fungoides and Sézary syndrome. CTCL can confer significant morbidity and even mortality in advanced disease. Here we review the current and potential future treatments for advanced-stage CTCL. RECENT FINDINGS: Heterogeneity of treatment choice has been demonstrated both in US and non-US centers. Systemic treatment choice is currently guided by prognostic features, incorporating stage, immunophenotypic and molecular findings, and patient-specific factors such as age and comorbidities. Randomized controlled studies are uncommon, and the literature is composed predominantly of retrospective, cohort, and early-phase studies. International consensus guidelines are available; however, the lack of comparative trials means that there is no clear algorithmic approach to treatment. This review article reports on the systemic treatment options in current use for advanced CTCL, and on the possible future therapies, acknowledging that an algorithmic approach is not yet forthcoming to guide treatment prioritization.

Phase I/II study of pralatrexate in Japanese patients with relapsed or refractory peripheral T-cell lymphoma.

Pralatrexate is a novel antifolate approved in the USA for the treatment of relapsed or refractory peripheral T-cell lymphoma. To assess its safety, efficacy, and pharmacokinetics in Japanese patients with this disease, we undertook a phase I/II study. Pralatrexate was given i.v. weekly for 6 weeks of a 7-week cycle. All patients received concurrent vitamin B12 and folic acid. In phase I, three patients received pralatrexate 30 mg/m2 and none experienced a dose-limiting toxicity. In phase II, we treated 22 additional patients with that dose. The median number of treatment cycles was 1 (range, 1-9). Nine of 20 evaluable patients (45%) achieved an objective response by central review, including two complete responses. All responses occurred within the first treatment cycle. At the time of data cut-off, median progression-free survival was 150 days. Median overall survival was not reached. In the total population, the most commonly reported adverse events included mucositis (88%), thrombocytopenia (68%), liver function test abnormality (64%), anemia (60%), and lymphopenia (56%). Grade 3/4 adverse events included lymphopenia (52%), thrombocytopenia (40%), leukopenia (28%), neutropenia (24%), anemia (20%), and mucositis (20%). The pharmacokinetic profile showed no drug accumulation with repeat dosing. These results indicate that pralatrexate is generally well tolerated and effective in Japanese patients with relapsed or refractory peripheral T-cell lymphoma. This trial was registered with ClinicalTrials.gov (NCT02013362).

The survival outcome of patients with relapsed/refractory peripheral T-cell lymphoma-not otherwise specified and angioimmunoblastic T-cell lymphoma.

Survival outcome of patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL-NOS (n = 180) or AITL (n = 141) between 1999 and 2015, were analysed. Failure-free survival (FFS) and overall survival (OS) were calculated from the time of first disease progression (FFS1, OS1), from second disease progression (FFS2, OS2) and from third progression (FFS3, OS3). With a median follow-up duration of 52 months, 240 patients (135 PTCL-NOS, 105 AITL) experienced progression/relapse. In patients with PTCL-NOS, the median durations of FFS1, FFS2 and FFS3 were 3·1, 2·5 and 2·1 months, respectively. In patients with AITL, they were 5·5, 2·9 and 2·3 months, respectively. There was no improvement in FFS1 and OS1 by the time of recurrence during this period (1999-2004, 2005-2009 and 2010-2015). The median FFS after pralatrexate and romidepsin was only 3·0 and 2·5 months, respectively. The 5-year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5-year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed.

Phase 1 and 2 study of carboplatin and pralatrexate in patients with recurrent, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.

BACKGROUND: The objective of this phase 1 and 2 trial was to identify the appropriate dose of combined carboplatin and pralatrexate for patients with recurrent, platinum-sensitive ovarian, fallopian tube, and primary peritoneal cancer. METHODS: In phase 1, patients received carboplatin (at an area under the curve of 5) and increasing doses of pralatrexate until the maximum-tolerated dose (MTD) of pralatrexate was achieved. The primary endpoint was the response rate. Additional endpoints were safety, response duration, progression-free survival, overall survival, and pharmacokinetics. RESULTS: Thirty patients were enrolled in phase 1, and 20 were enrolled in phase 2. Of all 50 patients, 49 completed the study. The mean patient age was 59 years, and patients completed a median of 6 cycles. The MTD for pralatrexate was 105 mg/m2 . The clinical benefit rate (complete responses plus partial responses plus stable disease) was 86%. Of 26 patients who received the MTD, 12 had a partial response, 11 had stable disease, and 2 had disease progression. The progression-free survival rate at 3 and 6 months was 87% and 79%, respectively; and the overall survival rate was 98% at 6 and 12 months and 66% at 24 months. Of 30 patients, 18 (60%) in phase 1 experienced an adverse event of any grade; and, of those, 4 patients (13%) had a grade 3 or greater adverse event. In phase 2, 12 patients (60%) had an adverse event of any grade, and 4 (20%) had grade 3 or greater toxicity. There was a significant reduction in the total body clearance of pralatrexate when it was received concurrently with carboplatin. CONCLUSIONS: Most patients responded to carboplatin-pralatrexate combination. This regimen is well tolerated and effective in this patient population. Cancer 2016;122:3297-3306. © 2016 American Cancer Society.

A phase 1, open-label, dose-escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma.

Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m(2) and intravenous bortezomib at a dose of 1·3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m(2) . Two patients experienced dose-limiting toxicity of mucositis. The most frequent non-haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.

Pralatrexate in Combination with Bortezomib for Relapsed or Refractory Peripheral T Cell Lymphoma in 5 Elderly Patients.

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas with poor prognosis. Elderly (age ≥ 65years) patients generally have impaired bone marrow function, altered drug metabolism, comorbidities, and poor functional status. Thus, treatment of elderly patients with relapsed or refractory PTCL remains a challenge for clinicians. A recent study disclosed that pralatrexate has a synergistic effect in combination with bortezomib. Weekly pralatrexate and bortezomib were administered intravenously for 3 weeks in a 4-week cycle. Of 5 patients, one achieved complete response after 4 cycles which has lasted 12 months until now. Another patient attained partial response after 2 cycles. Only 1 patient experienced grade 3 thrombocytopenia and neutropenia. Two patients suffered from grade 3 mucositis. Combination therapy with pralatrexate and bortezomib may be used as a salvage therapy for relapsed or refractory PTCL in the elderly with a favorable safety profile.

A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors.

BACKGROUND: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU). METHODS: Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m(2) on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m(2) /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase. RESULTS: Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity. CONCLUSIONS: The recommended dose of PDX was 148 mg/m(2) . A subset of heavily pretreated patients had PFS durations of ≥6 months with this regimen.

Emerging drugs for T-cell lymphoma.

INTRODUCTION: T-cell lymphomas are rare and conventional treatments are not typically curative. Integration of biologic agents into routine practice is especially difficult given the breadth of emerging drugs currently or recently in trials. AREAS COVERED: This is an overview of the management of T-cell lymphoma as it stands today. The authors review clinically active biological and novel chemotherapeutic agents, which have a niche in current practice or are being actively developed and have a potential future role in the management of this challenging group of diseases. Clinical trial data were retrieved from journals and current major conference proceedings following interrogation of online search engines EXPERT OPINION: Pralatrexate, the histone deacetylase inhibitors and brentuximab vedotin have reached the market and have provided new and useful treatment options. No novel agent has yet demonstrated a survival advantage for patients with this disease, or shown an ability to improve the low response rate to first-line chemotherapy that these diseases frequently exhibit. New randomized studies of these emerging drugs that may finally move the field forward with evidence of superiority from large Phase II and III trials currently open to accrual.

Pralatrexate inhibited the replication of varicella zoster virus and vesicular stomatitis virus: An old dog with new tricks.

Varicella zoster virus (VZV) is associated with herpes zoster (HZ) or herpes zoster ophthalmicus (HZO). All antiviral agents currently licensed for the management of VZV replication via modulating different mechanisms, and the resistance is on the rise. There is a need to develop new antiviral agents with distinct mechanisms of action and adequate safety profiles. Pralatrexate (PDX) is a fourth-generation anti-folate agent with an inhibitory activity on folate (FA) metabolism and has been used as an anti-tumor drug. We observed that PDX possessed potent inhibitory activity against VZV infection. In this study, we reported the antiviral effects and the underlying mechanism of PDX against VZV infection. The results showed that PDX not only inhibited VZV replication in vitro and in mice corneal tissues but also reduced the inflammatory response and apoptosis induced by viral infection. Furthermore, PDX treatment showed a similar anti-VSV inhibitory effect in both in vitro and in vivo models. Mechanistically, PDX inhibited viral replication by interrupting the substrate supply for de novo purine and thymidine synthesis. In conclusion, this study discovered the potent antiviral activity of PDX with a novel mechanism and presented a new strategy for VZV treatment that targets a cellular metabolic mechanism essential for viral replication. The present study provided a new insight into the development of broad-spectrum antiviral agents.

Pralatrexate for Peripheral T-Cell Lymphoma (PTCL): Chance Only Supports The Prepared Mind.

BACKGROUND: Due to their primary effects on DNA synthesis, antimetabolites are most effective against actively dividing cells and are significantly specific to the cell cycle phase. Pralatrexate (PDX), an antifolate metabolite designed to accumulate in cancer cells, was the first new agent approved by the US Food and Drug Administration for the treatment of resistant/recurrent peripheral T-cell lymphomas. PDX was a drug that is frequently used not only for PTCL, but also for cutaneous T-cell lymphoma (CTCL), extranodal natural killer (NK) / T-cell lymphoma. OBJECTIVE: This article reviews Pralatrexate's history, pharmacokinetics, clinical phase studies including phases I, II and III, types of cancers it is effective on, drug side effects, inhibition mechanism and even its use in the treatment of other cancers with innovative methods, including its antiviral effect against SARS-CoV-2 infection. METHODS: A comprehensive internet-based research was planned, covering all published and unpublished studies on the subject. We conducted this review in accordance with Preferred Reporting Items for systematic reviews and metaanalysis (PRISMA-P), and Cochrane Collaboration reporting items for systematic reviews and meta-analysis. The results of the studies in the articles were recorded to include all phase studies. RESULTS: Pralatrexate was structurally designed to have enhanced cellular transport via RFC (reduced folate carrier type) and be subject to more polyglutamation compared to methotrexate. The enhanced polyglutamylation ability of pralatrexate is associated with increased tumor cell death and ultimately improved anticancer activity. Pralatrexate is considered a promising drug for patients with recurrent and treatment-resistant PTCL with a good survival advantage. At the same time, it is an antifolate agent with a significant advantage over methotrexate as it does not cause myelosuppression. CONCLUSION: While there are manageable side effects such as thrombocytopenia, neutropenia, and mucositis, it is critical to explore new approaches, targeted agents, novel cellular therapies, and immunotherapies to determine optimal pretreatment in the rare but heterogeneous disease PTCL, and future studies and experienced haematologists are needed.

Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway.

Gemcitabine is the first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine-resistance frequently leads to poor prognosis. Exploring new chemotherapeutic agents is important for patients with gemcitabine-resistant pancreatic cancer. In this study, we established a new acquired gemcitabine-resistant pancreatic cancer cell line BxPC-GEM-20 from parental BxPC-3. We found that pralatrexate significantly inhibited the growth of BxPC-GEM-20. The half-maximal inhibitory concentration of pralatrexate on BxPC-GEM-20 cell was about 3.43 ± 0.25 nM. Pralatrexate was found to effectively inhibit the clonal growth of BxPC-GEM-20 cell. Additionally, pralatrexate at 20 mg/kg had an excellent tumor inhibitory effect with an inhibitory rate of 76.92% in vivo. This pralatrexate therapy showed good safety profile that with little to no additional influence on the hepatic, renal function as well as body weight changes in nude mice. Pralatrexate was confirmed to prevent cells from entering the G2/M phase, leading to the promotion of apoptosis and autophagy. Further analysis demonstrated that the reduced phosphorylation of mTOR played a significant role in the tumor cell damage caused by pralatrexate. Pralatrexate effectively inhibited the mTOR/4E-BP1 pathway. Activation of mTOR pathway can further obstruct the repressive effect of pralatrexate on gemcitabine-resistant pancreatic cancer. In summary, pralatrexate induces effective inhibition of gemcitabine-resistant pancreatic cancer. This may lead to the expansion of pralatrexate's application and offer benefit to gemcitabine-resistant pancreatic cancer patients in the future.

Intestinal T-Cell Lymphoma With Lung and Lymph Node Involvement at Relapse.

Patients with intestinal T-cell lymphomas (ITLs) usually present with perforation of the small intestine and colon at diagnosis. At relapse or in the advanced stage, ITLs involve in other extranodal sites, but biopsy-proven lung involvement has been rarely reported. A 76-year-old male presented with sudden-onset abdominal pain, which was found to be caused by the perforation of colon. Emergency operation was carried out, and histopathological examination of the resected colon led to the diagnosis of ITL, not otherwise specified (NOS). He achieved complete metabolic remission (CMR) after eight courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. Two months later, computed tomography showed infiltration and ground-glass opacity in the left pulmonary area in addition to the enlargement of mediastinal and left subclavian lymph nodes, although he did not complain of any pulmonary symptoms. Histopathological findings of the biopsied samples from the pulmonary area were consistent with relapsed ITL, NOS. He achieved CMR after three courses of GDP (gemcitabine, dexamethasone, and cisplatin) chemotherapy; but 1 month after the completion of GDP chemotherapy, he relapsed again with involvement of multiple lymph nodes, not in the pulmonary area. He died owing to the progression of disease. This is the third case of ITLs with lung involvement. Active biopsy should be performed when pulmonary nodules, infiltration, or ground-glass opacity are found in ITLs. A regimen for salvage chemotherapy specifically for ITLs is not yet established, and GDP chemotherapy may be an alternative option for relapsed ITLs in addition to new agents, such as romidepsin and pralatrexate.

Pralatrexate Sustainably Released from Polypeptide Thermogel Is Effective for Chondrogenic Differentiation of Mesenchymal Stem Cells.

Folic acid was reported to significantly improve chondrogenic differentiation of mesenchymal stem cells. In a similar mechanism of action, we investigated clinically approved antifolates by the U.S. Food and Drug Administration as chondrogenic-promoting compounds for tonsil-derived mesenchymal stem cells. A poly(ethylene glycol)-poly(l-alanine) thermogelling system was used as a three-dimensional cell culture matrix, where stem cells and antifolates could be incorporated simultaneously during a heat-induced in situ sol-to-gel transition. The antifolates could be supplied over several days by the sustained release of the drug from the thermogel. Initially, seven antifolates were prescreened based on cell viability and expression of a typical chondrogenic biomarker of type II collagen (COL II) at the mRNA level. Then, dapsone, pralatrexate, and trimethoprim were selected as candidate compounds in the second round screening, and detailed studies were carried out on the mRNA and protein expression of various chondrogenic biomarkers including COL II, SRY box transcription factor 9, and aggrecan. Three-dimensional cultures of stem cells in the thermogel in the absence of a chondrogenic promoter compound and in the presence of kartogenin (KGN) were performed as a negative control and positive control, respectively. The chondrogenic biomarkers were significantly increased in the selected antifolate-incorporating systems compared to the negative control system, without an increase in type I collagen (an osteogenic biomarker) expression. Pralatrexate was the best compound for inducing chondrogenic differentiation of the stem cells, even better than the positive control (KGN). Nuclear translocation of the core-binding factor ß subunit (CBFß) and enhanced nuclear runt-related transcription factor 1 (RUNX1) by antifolate treatment suggested that the chondrogenesis-enhancing mechanism is mediated by CBFß and RUNX1. An in silico modeling study confirmed the mechanism by proving the high binding affinity of pralatrexate to a target protein of filamin A compared with other antifolate candidates. To conclude, pralatrexate was rediscovered as a lead compound, and the polypeptide thermogel incorporating pralatrexate and mesenchymal stem cells can be a very effective system in promoting chondrogenic differentiation of stem cells and might be used in injectable tissue engineering for cartilage repair.