Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial.

BACKGROUND: Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed. METHODS: Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR). RESULTS: A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49-0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors. CONCLUSIONS: Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.

Camrelizumab for relapsed or refractory classical Hodgkin lymphoma: Extended follow-up of the multicenter, single-arm, Phase 2 study.

Camrelizumab (a humanized high-affinity IgG4 mAb against programmed death-l) showed potent antitumor activity, well tolerance and controllable safety in patients with relapsed or refractory classical Hodgkin lymphoma (r/r cHL), based on the primary analysis of a Phase 2 study. Here, we present the extended follow-up outcomes. Seventy-five patients who had failed to achieve a remission or experienced progression after autologous stem cell transplantation or had received at least two lines of systemic chemotherapies were enrolled to receive camrelizumab 200 mg every 2 weeks. With a median follow-up of 36.2 months (range, 7.2-38.1), objective response rate per independent central review was 76.0% (95% confidence interval [CI], 64.7-85.1). Among the 57 responders, 31 (54.4%) had ongoing responses. Median duration of response was 31.7 months (95% CI, 16.7-not reached). Median progression-free survival was 22.5 months (95% CI, 14.7-not reached). Thirty-six-month overall survival rate was 82.7% (95% CI, 72.0-89.5). Reactive capillary endothelial proliferation (RCEP) occurred in 97.3% of patients (73/75), but all RCEP were Grade 1 or 2 in severity and 67.1% of these patients (49/73) achieved complete resolution. Occurrence of new RCEP lesions was rare (8/42 [19.0%] at 12 months; 2/32 [6.3%] at 24 months). No treatment-related deaths occurred, and no new toxicities were reported. With extended follow-up, camrelizumab monotherapy continues to provide a robust and durable response, long survival and manageable safety in r/r cHL patients.

Bendamustine versus chlorambucil in treatment of chronic lymphocytic leukaemia in China: a randomized, open-label, parallel-controlled, phase III clinical trial.

BACKGROUND: Chronic lymphoblastic leukemia (CLL) is the most common adult leukemia and mainly affects the elderly. Chemoimmunotherapy still has a role in the standard frontline therapy for specific population. However, the clinical activity of bendamustine has not been investigated in unfit Chinese patients with CLL. This study aimed to compare the efficacy and safety of bendamustine versus chlorambucil for untreated Chinese patients with Binet stage B/C CLL. METHODS: In this multi-center, randomized, open-label, parallel-controlled, phase III trial, patients with previously untreated CLL were enrolled and randomly assigned (1:1) to receive bendamustine or chlorambucil. The primary endpoint was the objective response rate. Secondary endpoints included progression-free survival, the duration of response, and overall survival. Adverse events were recorded to evaluate safety. RESULTS: Of 158 screened patients, 147 were enrolled and randomly allocated to receive bendamustine (n = 72) or chlorambucil (n = 75). After a median follow-up of 25.6 months (IQR 12.5-27.7), 69.0% (95% CI, 56.9-79.5) of bendamustine-treated patients achieved objective response and 37.0% (95% CI, 26.0-49.1) of chlorambucil with a difference of 32.0% (95%CI: 16.6-47.5), demonstrating the superiority of bendamustine to chlorambucil (p < 0.001). The median progression-free survival was longer for bendamustine (16.5 months; 95% CI, 11.3-24.7) versus chlorambucil (9.6 months; 95% CI, 8.7-11.8; p < 0.001). A longer median duration of response was seen in those receiving bendamustine (19.2 months; 95% CI, 11.8-29.1) than chlorambucil (10.7 months; 95% CI, 5.6-13.6; p = 0.0018). Median overall survival was not reached in either group. Overall survival at 18 months was 88% for bendamustine versus 85% for chlorambucil. Most common adverse events in both groups were neutropenia and thrombocytopenia. CONCLUSION: In untreated Chinese patients with Binet stage B/C CLL, bendamustine induced the better objective response and resulted in longer progression-free survival than chlorambucil. Overall, these results validate the role of bendamustine as an effective and safe first-line therapy in this population.

IgH translocation with undefined partners is associated with superior outcome in multiple myeloma patients.

BACKGROUND: In multiple myeloma (MM), impact of specific chromosomal translocations involving IgH (14q21 locus, including t(4;14), t(11;14), and t(14;16)) has been explored extensively. However, over 15% MM patients harboring IgH translocation with undefined partners have long been ignored. METHODS: A prospective non-randomized cohort study with a total of 715 newly-diagnosed MM cases was conducted, 13.6% of whom were t(14;undefined) positive. The whole cohort was divided into four groups: no IgH split (47.7%); t(14;undefined) (13.6%); t(11;14) (17.6%); and t(4;14) or t(14;16) group (21.1%). RESULTS: Median OS for the four groups was 84.2, not reached (NR), 58.7, and 44.2 months, respectively, with P values for t(14;undefined) vs no IgH split, t(11;14), and t(4;14)/t(14;16) groups of 0.197, 0.022, and 0.001, respectively. In bortezomib-based group, the survival advantage gained by t(14;undefined) group was much more significant compared to t(11;14) and t(4;14)/t(14;16) groups. Importantly, t(14;undefined) turned out to be an independent predictive factor for longer OS of MM patients in multivariate analysis, especially in the context of bortezomib treatment. Similar results were also observed in the PUMCH external validation cohort. CONCLUSION: Collectively, our data confirmed and externally validated the favorable prognosis of the t(14;undefined) groups, especially in the era of novel agents.

Treatment of Xanthelasma Palpebrarum With Intralesional Pingyangmycin.

BACKGROUND: Xanthelasma palpebrarum (xanthelasma) is the most common type of cutaneous xanthoma, and many patients tend to seek medical treatments for cosmetic reasons. Many methods treating xanthelasma have been proposed, but none of these options can be regarded as a perfect solution. OBJECTIVE: To study and evaluate the intralesional injection treatment of xanthelasma with pingyangmycin, which has been widely used as a broad-spectrum antitumor antibiotic. MATERIALS AND METHODS: 21 lesions in 12 patients were treated by intralesional pingyangmycin. Photographs were taken before and after each treatment session. Patients were followed up for 7 to 36 months. RESULTS: All patients except one received satisfactory results after up to 2 sessions. Only 1 patient had a local recurrence 1 year after the treatment. No severe complications such as infection, atrophy, ulceration, or scar were noticed. CONCLUSION: Intralesional pingyangmycin is a cheap, effective, and safe treatment for xanthelasma, which has been well accepted by patients.

Multiple myeloma patients with low proportion of circulating plasma cells had similar survival with primary plasma cell leukemia patients.

The common features shared by primary plasma cell leukemia (pPCL) and multiple myeloma (MM) with circulating plasma cells (CPCs) are peripheral blood invasion and expansion of plasma cells independent of the protective bone marrow (BM) microenvironment niche. However, few studies have addressed the relationship between pPCL and MM with CPCs. Here, we quantitated the number CPCs by conventional morphology in 767 patients with newly diagnosed MM; their clinic features were compared with those of 33 pPCL cases. When the presence of CPCs was defined as more than 2 % plasma cells per 100 nucleated cells on Wright-Giemsa stained peripheral blood smears, the incidence of MM with CPCs was 14.1 % in newly diagnosed MM. Patients with CPCs shared many clinical features with pPCL, especially clinical parameters related to tumor burden. However, no commonalities were found in immunophenotyping and cytogenetics. The prognosis of pPCL was poor, with a median progression free survival (PFS) of 12 months and an overall survival (OS) of 15 months. MM patients with CPCs had a clearly inferior PFS and OS as compared with the control cohort. Most interestingly, although the CPCs were not high enough to meet the diagnostic criteria for pPCL, the survival of MM patients with CPCs was comparable with that of pPCL, with a median PFS of 17 months and an OS of 25 months.

Is vaginal mucosal graft the excellent substitute material for urethral reconstruction in female-to-male transsexuals?

PURPOSE: Construction of a neourethra is always considered to be a difficult part in phalloplasty, especially for the female-to-male (FTM) transsexual patients. We report our experience with prefabricated pars pendulans urethrae using vaginal mucosal graft for phalloplasty in FTM transsexuals. MATERIALS AND METHODS: We retrospectively reviewed notes on the 22 FTM patients treated with pedicled-flap phalloplasty with prefabricated pars pendulans urethrae using vaginal mucosal graft between January 2008 and December 2012. Surgical outcome, urological function, and complications were recorded. Histological difference between normal mucosa and skin, and pathological changes of vaginal mucosal graft were also observed. RESULTS: All the reconstructive penis survived, and patients could void in a standing position finally at a median follow-up of 25.4 ± 6.0 months. Urethral fistula and urethral stricture rates were 31.8 % (7/22 patients) and 4.5 % (1/22 patients), respectively. The occurrence of the urethral stricture was remarkably low compared with previous reports. Our histological results also showed a pronounced similarity between vaginal and buccal mucosa. Morphologically, they resembled urethral epithelium more closely than the forearm skin. Following the free transfer, the vaginal mucosal graft also showed a good revascularization and the inflammatory reaction and the extent of fibrosis of the mucosa decreased to the normal level after a 6-month prefabrication. CONCLUSION: With prefabrication of vaginal mucosal graft, we reconstruct a competent phallic neourethra in these FTM transsexuals. According to its histological similarities and source character, the vaginal mucosa is the excellent substitute material for promising urethral reconstruction in FTM transsexuals.

Liver X receptor activation induces apoptosis of melanoma cell through caspase pathway.

Liver X receptors (LXRs) are nuclear receptors that function as ligand-activated transcription factors regulating lipid metabolism and inflammation. Recent discoveries found LXRs could regulate tumor growth in a variety of cancer cell lines. In this study, we investigated the effect of LXR activation on melanoma cell proliferation and apoptosis both in vitro and in vivo. Treatment of B16F10 and A-375 melanoma cells with synthetic LXR agonist T0901317 significantly inhibited the proliferation of melanoma cells in vitro. Meanwhile, T0901317 induced the apoptosis of B16F10 melanoma cells in a dose-dependent manner. Furthermore, western blot assay showed that the pro-apoptotic effect of T0901317 on B16F10 melanoma cells was mediated through caspase-3 pathway. Oral administration of T0901317 inhibited the growth of B16F10 melanoma in C56BL/6 mice. Altogether, this study demonstrates the critical role of LXRs in the regulation of melanoma growth and presents the LXR agonist T0901317 as a potential anti-melanoma agent.

A multicenter, open-label phase II study of recombinant CPT (Circularly Permuted TRAIL) plus thalidomide in patients with relapsed and refractory multiple myeloma.

Circularly permuted TRAIL (CPT), a recombinant mutant of human Apo2L/TRAIL, is a novel antitumor candidate for multiple myeloma (MM) and other hematologic malignancies. In this phase II study, the safety and efficacy of CPT plus thalidomide was investigated in thalidomide-resistant MM patients. A total of 43 patients were recruited into three CPT plus thalidomide cohorts based on CPT dosage in sequence: 5 mg/kg (n = 11), 8 mg/kg (n = 17), and 10 mg/kg (n = 15). CPT was administered via intravenous infusion on days 1-5, and thalidomide was given orally at 100 mg once daily in each 21-day cycle. The overall response rate (ORR) of 41 efficacy-evaluable patients was 22.0% (2 complete response, 3 near complete response, and 4 partial response). No significant difference in the ORR was observed among the three dose cohorts; however, the ORR tended to be higher with the higher-dose regimen. Median progression-free survival and median duration of response were 6.6 months and 6.1 months, respectively. The most common treatment-related adverse events (TRAEs) were neutropenia (46.5%), leukopenia (41.9%), fever (37.2%), elevated AST (32.6%), and elevated ALT (20.9%). TRAEs of Grade 3-4 were mainly neutropenia (18.6%), anemia (9.3%), elevated AST (7.0%), and leukopenia (4.7%). No significant differences were found in the incidence and severity of TRAEs among the three cohorts. In conclusion, CPT plus thalidomide was well tolerated with no occurrence of dose-limiting toxicities and demonstrated promising antitumor activity in RRMM patients. CPT at 10 mg/kg for 5 days in combination with thalidomide and dexamethason will be studied in the next clinical trial.

[Analysis of clinical characteristics for large granular lymphocytic leukemia].

OBJECTIVE: To explore the clinical and laboratory characteristics for large granular lymphocytic leukemia (LGL). METHODS: A total of 35 LGL patients were retrospectively analyzed from March 2004 to May 2013 at our department. RESULTS: Their median age of diagnosis was 51 years. The anemia-related symptoms included splenomegaly (n = 11, 31.4%). And one patient (2.8%) with a history of rheumatoid arthritis. Anemia was the most frequent hematological abnormality (n = 27, 77.1%). The range of LGL count in peripheral blood was (0.82-23.7) ×10(9)/L. Among them, 19 patients (54.2%) showed the CD3(+)CD57(+) CD56(-)indolent LGL phenotype. Two patients showed complex karyotype. T cell receptor ß chain variable region (TCRVß) analysis was positive in 8 patients. The median overall survival of aggressive LGL patients was significant shorter than that of indolent patient(16 months vs not reached, P = 0.000). Univariate analysis showed the median overall survival of patients with B symptom was significant shorter than that without B symptom (19 vs 45 months, P = 0.039); the median overall survival of patients with thrombocytopenia was significant shorter than that with platelet normal (16 vs 42 months, P = 0.000). Multivariate analysis showed B symptom (P = 0.736) and thrombocytopenia (P = 0.977) at diagnosis were not prognostic factors. CONCLUSIONS: Chinese LGL patient with rheumatoid arthritis is infrequent compared with foreign reports. TCRVß analysis is important for its diagnosis. The overall survival of aggressive LGL patients is significantly inferior to indolent patients, and need earlier intensive therapy in order to achieve longer survival.

Gemcitabine-based conditioning compared to BEAM/BEAC conditioning prior to autologous stem cell transplantation for non-Hodgkin lymphoma: No difference in outcomes.

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an effective treatment for non-Hodgkin lymphoma (NHL). The limited availability of carmustine has prompted the exploration of novel alternative conditioning regimens. This study aimed to compare the efficacy and safety profile of GBM/GBC (gemcitabine, busulfan, and melphalan or cyclophosphamide) conditioning compared with the standard BEAM/BEAC regimens (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide) for ASCT in patients with NHL. METHODS: A retrospective analysis was conducted on 231 NHL patients, who underwent ASCT from October 2010 to October 2021 at the Institute of Hematology & Blood Disease Hospital, including both first-line and salvage settings. This resulted in the inclusion of 112 patients in the GBM/GBC arm and 92 in the BEAM/BEAC arm. Propensity score matching was employed to validate the results. RESULTS: Disease subtype distribution was similar between the GBM/GBC and BEAM/BEAC groups, with diffuse large B-cell lymphoma being the most common (58.9% vs. 58.7%), followed by PTCL (17.0% vs. 18.5%) and MCL (14.3% vs. 14.1%). At 3 months post-ASCT, complete response (CR) rates were comparable (GBM/GBC 93.5% vs. BEAM/BEAC 91.1%; p = 0.607). The 4-year progression-free survival (78.4% vs. 82.3%; p = 0.455) and 4-year overall survival (88.1% vs. 87.7%; p = 0.575) were also similar. Both groups exhibited low non-relapse mortality at 4 years (GBM/GBC 1.8% vs. BEAM/BEAC 3.5%; p = 0.790) with no transplant-related mortalities reported. The GBM/GBC cohort demonstrated a higher incidence of grade 3/4 oral mucositis and hepatic toxicity, whereas the BEAM/BEAC group had more frequent cases of bacteremia or sepsis (13 cases vs. 5 in GBM/GBC). CONCLUSIONS: The GBM/GBC regimen is effective and well-tolerated, offering outcomes that are highly comparable to those in NHL patients conditioned with BEAM/BEAC, as demonstrated in a prognostically matched cohort.

High-Frequency Ultrasound-Guided Temporal Fat Transplantation: A Safe and Visualized Approach.

SUMMARY: Autologous fat injection is one of the most popular methods for the treatment of temporal depression; however, accurate puncture into the target layer without vascular compromise is hard to achieve. With the aid of high-frequency ultrasonography, the authors performed autologous fat transplantation after visualization in five cases, with satisfactory results. The authors observed the course of superficial temporal vessels, the orbitozygomatic artery, and sentinel veins preoperatively, and used high-frequency ultrasonography to guide lipotransfer into the desired layer intraoperatively, to avoid intravascular injection. With the aid of high-frequency ultrasonography, the authors can easily prevent vascular complications and personalize surgical procedures, as anatomical variations of vasculature can also be detected by means of this method.

The age-dependent changes in risk weights of the prognostic factors for multiple myeloma.

OBJECTIVE: Multiple myeloma is a highly heterogenous plasma cell malignancy, commonly seen in older patients. Age is one of the important prognostic factors. However, nearly all the prognostic staging systems are based on clinical trials, where patients were relatively fit and young. It is unknown how the presence of biochemical or cytogenetic prognostic factors and their risk weights changes with older age. To further investigate this question, we retrospectively analyzed the data from a consecutive cohort of patients treated with either bortezomib or thalidomide-based therapy. METHODS: This retrospective study was carried out on a cohort of 1125 newly diagnosed multiple myeloma patients, from January 2008 to December 2019. Patients received bortezomib or thalidomide-based induction and maintenance therapy. Patients accepted hematopoietic stem cell transplantation if eligible. Statistical analysis was conducted by Stata/MP 16.0 and SPSS 26.0. RESULTS: With age increasing, the proportion of patients with ISS 3, performance status score ≥2, and the incidence rate of gain(1q) significantly increased. We also found that ISS became less important in older patients. However, cytogenetic abnormalities exerted a consistently adverse impact on survival, both in young and old patients. Older patients had an inferior outcome than their young counterparts. All patients in our cohort benefitted more from bortezomib than thalidomide-based induction therapy, except for patients ≥71 years old. CONCLUSIONS: ISS may lose prognostic value in patients ≥71 years old. Older patients had an inferior outcome and needed more effective and less toxic treatment.Plain Language SummaryMultiple myeloma is a type of blood cancer commonly seen in older people. To treat this disease, genetic abnormality, the poor physical status of patients and the abundance of tumor cells are the main difficulties. We often draw these conclusions from clinical trials. However, clinical trials always enrolled relatively younger patients, so the presence and significance of these factors may vary from clinical trials to the real world. We conducted the study to find out the real risk in both young and old patients. We found that older patients were more likely to have anemia, poor nutritional status and renal function. We also found older patients had more risk of relapse, progression or death than young patients. Frail physical status is the key obstacle to treating older patients, and tumor burden no longer impacts the outcome of these people. Bortezomib is a powerful drug to treat this disease, but patients ≥71 years old had less benefit than younger ones. More studies should focus on older or frail patients as these patients need more effective and less toxic treatment.

[Analysis of clinical and laboratory characteristics and survival with hairy cell leukemia].

OBJECTIVE: To explore the clinical and laboratory characteristics and survival of Chinese patients with hairy cell leukemia (HCL). METHODS: A total of 30 HCL patients from August 1990 to March 2012 were retrospectively analyzed. RESULTS: There were 22 cases with classical HCL (HCL-C) and 8 with variant HCL (HCL-V). Splenomegaly was the most common physical finding. Leukocytosis was found in all cases of HCL-V. But pancytopenia only accounted for 36.4% (8/22) in HCL-C. And 3/5 of HCL-V had abnormal chromosome karyotypes. Ribosomal-lamellae complexes (RLC) were found only in about 3/12 of HCL cases. Chemotherapy regimens including purine nucleoside analogues achieved a better complete remission (CR) rate than other regimens (3/4 vs 1/18, P = 0.012) in HCL-C. The median follow-up period was 27 (1 - 142) months. There was no follow-up loss. Eleven cases progressed and 6 died. The median overall survival (OS) was not reached. And the 1, 3, 6-year OS rates were 84%, 78% and 58% respectively. The median progression-free survival (PFS) was (63 ± 24) months and the 1, 2, 5-year PFS rates were 86%, 72% and 44% respectively. The median PFS of HCL-V was significant shorter than HCL-C ((23 ± 3) vs (78 ± 12) months, P = 0.014). In HCL-C group, fever (P = 0.038) and anemia (P = 0.000) at diagnosis were poor prognostic factors. But purine nucleoside analogues made no significant difference in PFS. CONCLUSIONS: Pancytopenia is infrequent in Chinese HCL patients. And classical RLC is rare under electron microscope. Purine nucleoside analogues may achieve a better CR rate, but fail to improve PFS rate. As compared with HCL-C, HCL-V is common with genetic abnormalities and has a worse prognosis with a shorter PFS.

[Richter syndrome: clinical characteristics and treatment experiences].

OBJECTIVE: To summarize the clinical characteristics of Richter syndrome and explore the methods of successful treatment and timely diagnosis. METHODS: Five patients with Richter syndrome in the last three years (from January 2009 to December 2011) were analyzed retrospectively at our hospital, including their clinical features and therapy before and after transformation. RESULTS: There were 4 males and 1 female with a median age on a diagnosis of chronic lymphocytic leukemia (CLL) at 47 (44 - 68) years. The median duration from a diagnosis of CLL to transformation was 52 (5 - 90) months. As for cytogenetic abnormalities, 3/4 patients had 17p deletion by fluorescence in situ hybridization (FISH). The clinical manifestations on transformation included regional enlargement of lymph node (n = 2) and systemic enlargement of lymph nodes (n = 3). All diagnoses were confirmed by lymph node biopsy and all transformed into diffuse large B cell lymphoma (classical transformation). The subgroups were germinal center B-cell like (GCB) (n = 3) and non-GCB (n = 1). After transformation, one patient underwent sibling allo-stem cell transplantation and survived 24 months until April 2012. Another patient with auto-stem cell transplantation relapsed and died 12 months later. One patient lost the treatment opportunity due to worsening condition. Another 2 patients gained partial remission after therapy and survived 20 and 8 months respectively. CONCLUSIONS: Richter syndrome may occur during a late stage of CLL. Such a high-risk cytogenetic abnormality as del17p may be correlated with transformation. Early identification and optimal therapy may extend the survival of Richter syndrome. Allo-stem cell transplantation remains a curable option.

The Antiemetic Mechanisms of Gingerols against Chemotherapy-Induced Nausea and Vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a common and painful side effect that occurs in cancer patients receiving chemotherapeutic drugs. Although an abundance of agents are applied to prevent CINV, there is still lack of effective control in delayed nausea and vomiting. Ginger (Zingiber officinale Rosc.), a traditional antiemetic herb, draws attention due to its therapeutic effect in treating acute and delayed CINV. Its main bioactive pungent constituents, gingerols, contribute to the antiemetic effect against CINV primarily. A growing number of reports have made progress in investigating the mechanisms of gingerols and their single ingredients against CINV. In this review, we searched for relevant studies in PubMed database to summarize the mechanism of gingerols in the prevention of CINV and provided a preliminary prediction on the potential targets and signaling pathways using network pharmacology, laying a foundation for further researches.

Gastrointestinal inflammation plays a critical role in chemotherapy-induced nausea and vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of patients with cancer receiving chemotherapeutic drugs. However, the pathological mechanism of CINV is biologically multifaceted and has not yet been fully elucidated. Despite this, increasing evidence indicates that gastrointestinal (GI) inflammation dramatically contributes to the incidence of CINV. It is well established that 5-hydroxytryptamine and substance P are critical meditators in both of CINV and GI inflammation by binding to their corresponding receptors. Meanwhile, antiemetic drugs used for the prophylaxis of CINV have demonstrated surprising effects on relieving GI inflammation, and anti-inflammatory drugs are also effective in preventing CINV. The commonalities between the pathogenesis and clinical treatment of GI inflammation and CINV indicate that GI inflammation is an essential mechanism in CINV. In this review, we provide novel insights into the crucial role of GI inflammation in CINV, with the aim to discover the novel antiemetic drugs against CINV from the perspective of alleviating GI inflammation.

Gasdermin E: A Prospective Target for Therapy of Diseases.

Gasdermin E (GSDME) is a member of the gasdermin protein family, which mediates programmed cell death including apoptosis and pyroptosis. Recently, it was suggested that GSDME is activated by chemotherapeutic drugs to stimulate pyroptosis of cancer cells and trigger anti-tumor immunity, which is identified as a tumor suppressor. However, GSDME-mediated pyroptosis contributes to normal tissue damage, leading to pathological inflammations. Inhibiting GSDME-mediated pyroptosis might be a potential target in ameliorating inflammatory diseases. Therefore, targeting GSDME is a promising option for the treatment of diseases in the future. In this review, we introduce the roles of GSDME-driven programmed cell death in different diseases and the potential targeted therapies of GSDME, so as to provide a foundation for future research.

Indirubin-3'-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is still an incurable malignancy of plasma cells. Proteasome inhibitors (PIs) work as the backbone agent and have greatly improved the outcome in majority of newly diagnosed patients with myeloma. However, drug resistance remains the major obstacle causing treatment failure in clinical practice. Here, we investigated the effects of Indirubin-3'-monoxime (I3MO), one of the derivatives of Indirubin, in the treatment of MM. METHODS: MM patient primary samples and human cell lines were examined. I3MO effects on myeloma treatment and the underling molecular mechanisms were investigated via in vivo and in vitro study. FINDINGS: Our results demonstrated the anti-MM activity of I3MO in both drug- sensitive and -resistance MM cells. I3MO sensitizes MM cells to bortezomib-induced apoptosis. Mechanistically, I3MO acts as a multifaceted regulator of cell death, which induced DNA damage, cell cycle arrest, and abrogates NF-κB activation. I3MO efficiently down-regulated USP7 expression, promoted NEK2 degradation, and suppressed NF-κB signaling in MM. Our study reported that I3MO directly bound with and caused the down-regulation of PA28γ (PSME3), and PA200 (PSME4), the proteasome activators. Knockdown of PSME3 or PSME4 caused the inhibition of proteasome capacity and the overload of paraprotein, which sensitizes MM cells to bortezomib-mediated growth arrest. Clinical data demonstrated that PSME3 and PSME4 are over-expressed in relapsed/refractory MM (RRMM) and associated with inferior outcome. INTERPRETATION: Altogether, our study indicates that I3MO is agent triggering proteasome inhibition and represents a promising therapeutic strategy to improve patient outcome in MM. FUNDINGS: A full list of funding can be found in the acknowledgements.

Laparoscope-assisted creation of a neovagina using pedicled ileum segment transfer.

BACKGROUND: To present our experience of vaginal reconstruction with the use of a pedicled ileum segment and laparoscope assistance, and to analyze its complications and long-term anatomic and functional results. METHODS: The abdominal and perineal approaches were performed simultaneously with the patient in a special position. Under the guidance of laparoscopy, the target ileal segment was harvested and transposed down to the perineum through an artificial tunnel between the bladder and the rectum. A silicon vaginal tutor was introduced into the vaginal cavity and maintained all day long for 2-3 months. The complications and the anatomical and functional results were summarized and analyzed. RESULTS: From February 2002 to June 2010, 82 patients underwent laparoscope-assisted total vaginal reconstruction with a pedicled ileum segment at our department. Complications developed in 16 of 82 patients, including rectum and/or bladder injury during operation, acute renal failure, delayed healing of the ileocutaneous anastomosis, introital stenosis, and partial or complete intestinal obstruction. The abdominal cutaneous scar was acceptable after the surgery. The vulva was not altered, which was especially significant for patients with congenital vaginal atresia. The neovagina was patent, soft, moist, and flexible. The mean width and depth of the neovagina at the latest postoperative visit measured 3.2 and 15 cm, respectively. CONCLUSIONS: The favorable long-term anatomical and functional results demonstrate that our technique is ideal for patients with congenital vaginal atresia or patients who need secondary vaginal reconstruction. For the primary male-to-female transsexuals or hermaphrodites, it can be an alternative method for vaginal construction.