Background: After deinitive chemoradiotherapy for non-metastatic nasopharyngeal carcinoma(NPC), more than 10% of patients will experience a local recurrence. Salvage treatments present signiicant challenges for locall...Background: After deinitive chemoradiotherapy for non-metastatic nasopharyngeal carcinoma(NPC), more than 10% of patients will experience a local recurrence. Salvage treatments present signiicant challenges for locally recurrent NPC. Surgery, stereotactic ablative body radiotherapy, and brachytherapy have been used to treat locally recurrent NPC. However, only patients with small-volume tumors can beneit from these treatments. Re-irradiation with X-ray—based intensity-modulated radiotherapy(IMXT) has been more widely used for salvage treatment of locally recurrent NPC with a large tumor burden, but over-irradiation to the surrounding normal tissues has been shown to cause frequent and severe toxicities. Furthermore, locally recurrent NPC represents a clinical entity that is more radioresistant than its primary counterpart. Due to the inherent physical advantages of heavy-particle therapy, precise dose delivery to the target volume(s), without exposing the surrounding organs at risk to extra doses, is highly feasible with carbon-ion radiotherapy(CIRT). In addition, CIRT is a high linear energy transfer(LET) radiation and provides an increased relative biological efectiveness compared with photon and proton radiotherapy. Our prior work showed that CIRT alone to 57.5 Gy E(gray equivalent), at 2.5 Gy E per daily fraction, was well tolerated in patients who were previously treated for NPC with a deinitive dose of IMXT. The short-term response rates at 3–6 months were also acceptable. However, no patients were treated with concurrent chemotherapy. Whether the addition of concurrent chemotherapy to CIRT can beneit locally recurrent NPC patients over CIRT alone has never been addressed. It is possible that the beneits of high-LET CIRT may make radiosensitizing chemotherapy unnecessary. We therefore implemented a phase I/II clinical trial to address these questions and present our methodology and results.Methods and design: The maximal tolerated dose(MTD) of re-treatment using raster-scanning CIRT plus concurrent cisplatin will be determined in the phase I, dose-escalating stage of this study. CIRT dose escalation from 52.5 to 65 Gy E(2.5 Gy E × 21–26 fractions) will be delivered, with the primary endpoints being acute and subacute toxicities. Eicacy in terms of overall survival(OS) and local progression-free survival of patients after concurrent chemotherapy plus CIRT at the determined MTD will then be studied in the phase II stage of the trial. We hypothesize that CIRT plus chemotherapy can improve the 2-year OS rate from the historical 50% to at least 70%.Conclusions: Re-treatment of locally recurrent NPC using photon radiation techniques, including IMXT, provides moderate eicacy but causes potentially severe toxicities. Improved outcomes in terms of eicacy and toxicity proile are expected with CIRT plus chemotherapy. However, the MTD of CIRT used concurrently with cisplatin-based chemotherapy for locally recurrent NPC remains to be determined. In addition, whether the addition of chemotherapy to CIRT is needed remains unknown. These questions will be evaluated in the dose-escalating phase I and randomized phase II trials.展开更多
Hepatocellular carcinoma(HCC)is the second most common cause of cancerrelated death worldwide.Despite the advent of screening efforts and algorithms to stratify patients into appropriate treatment strategies,recurrenc...Hepatocellular carcinoma(HCC)is the second most common cause of cancerrelated death worldwide.Despite the advent of screening efforts and algorithms to stratify patients into appropriate treatment strategies,recurrence rates remain high.In contrast to first-line treatment for HCC,which relies on several factors,including clinical staging,tumor burden,and liver function,there is no consensus or general treatment recommendations for recurrent HCC(R-HCC).Locoregional therapies include a spectrum of minimally invasive liver-directed treatments which can be used as either curative or neoadjuvant therapy for HCC.Herein,we provide a comprehensive review of recent evidence using salvage loco-regional therapies for R-HCC after failed curative-intent.展开更多
BACKGROUND For recurrent achalasia after initial peroral endoscopic myotomy(POEM)failure,repeat POEM(Re-POEM)has been reported as a treatment option.However,severe esophageal interlayer adhesions caused by previous pr...BACKGROUND For recurrent achalasia after initial peroral endoscopic myotomy(POEM)failure,repeat POEM(Re-POEM)has been reported as a treatment option.However,severe esophageal interlayer adhesions caused by previous procedures impede the successful establishment of a submucosal tunnel and lead to aborted Re-POEM procedures.Our team previously described POEM with simultaneous submucosal and muscle dissection(POEM-SSMD)as a feasible solution for achalasia with severe interlayer adhesions.AIM To investigate the effectiveness and safety of Re-POEM with simultaneous submucosal and muscle dissection(Re-POEM-SSMD).METHODS A total of 1049 patients with achalasia who underwent successful endoscopic myotomy at the Digestive Endoscopic Center of Chinese PLA General Hospital from December 2014 to May 2022 were reviewed.Patients with recurrent achalasia who experienced initial POEM clinical failure were retrospectively included in this study.The primary endpoint was retreatment clinical success,defined as an Eckardt score≤3 during the postretreatment follow-up and no need for additional treatment.Procedure-related adverse events,changes in manometric lower esophageal sphincter(LES)pressure and reflux complications,as well as procedure-related parameters,were recorded.RESULTS Sixteen patients underwent Re-POEM(9 patients)or Re-POEM-SSMD(7 patients)successfully at a median of 45.5 mo(range,4-95 mo)after initial POEM.During a median followup period of 31 mo(range,7-96 mo),clinical success(Eckardt score≤3)was achieved in 8(88.9%)and 6(85.7%)patients after Re-POEM and Re-POEM-SSMD,respectively(P=0.849).The median Eckardt score dropped from 4(range,3-8)at preretreatment to 1(range,0-5)at postretreatment in the Re-POEM group(P=0.025)and from 5(range,2-8)to 2(range,0-4)in the Re-POEM-SSMD group(P<0.001).The mean manometric LES pressure decreased from 23.78±9.04 mmHg to 11.45±5.37 mmHg after Re-POEM(P<0.001)and from 26.80±7.48 mmHg to 11.05±4.38 mmHg after Re-POEM-SSMD(P<0.001).No serious adverse events were recorded in both groups.CONCLUSION In conclusion,Re-POEM-SSMD appears to be a safe and effective salvage therapy for recurrent achalasia with severe interlayer adhesions.展开更多
Objective Preclinical evidence and clinical trials have suggested synergistic effects of epigenetic modifiers in combination with cytotoxic agents for the treatment of leukemia.However,their efficacy in patients with ...Objective Preclinical evidence and clinical trials have suggested synergistic effects of epigenetic modifiers in combination with cytotoxic agents for the treatment of leukemia.However,their efficacy in patients with relapsed/refractory acute myeloid leukemia(R/R AML)remains unclear.Methods Clinical data of R/R AML patients who received a CDCAG regimen(chidamide,decitabine,cytarabine,aclarubicin,and granulocyte colony-stimulating factor)from July 1,2018 to October 31,2021 at our center were retrospectively assessed,and the safety and efficacy of the CDCAG regimen were evaluated.Patients were followed up until November 30,2021,with a median follow-up of 21.6 months(95%CI:10.0–33.2 months).Results A total of 67 patients were enrolled.Two patients died within 3 weeks after the initiation,and therefore only 65 patients underwent the assement for clinical response and survival.It was found that 56.9%patients achieved complete remission with a median overall survival(OS)of 9.6 months.The median OS of responders was 25.9 months,while that of non-responders was 5.0 months(P<0.0001).Patients with gene mutations had a superior overall response rate(ORR)(80.4%vs.45.5%,P=0.043)compared to those without gene mutations.The presence of DNA methyltransferase 3 A(DNMT3A),ten-eleven translocation-2(TET2),and isocitrate dehydrogenase 1/2(IDH1/2)mutations did not affect the response rate(88.2%vs.68.9%,P=0.220)and reflected a better OS(not attained vs.9.0 months,P=0.05).The most common non-hematologic adverse events were pulmonary infection(73.1%),followed by febrile neutropenia(23.9%)and sepsis(19.4%).Conclusions The CDCAG regimen was effective and well-tolerated in R/R AML patients,increasing the potential for allogeneic hematopoietic stem cell transplantation.Moreover,patients with DNMT3A,TET2,and IDH1/2 mutations might benefit from this regimen.展开更多
BACKGROUND The prognosis of paediatric primary refractory/relapsed acute myeloid leukaemia(R/R AML)remains poor.Intensive therapy is typically used as salvage treatment for those with R/R AML.No data are currently ava...BACKGROUND The prognosis of paediatric primary refractory/relapsed acute myeloid leukaemia(R/R AML)remains poor.Intensive therapy is typically used as salvage treatment for those with R/R AML.No data are currently available about the use of the CLAG-M protocol as salvage therapy in paediatric patients with R/R AML.CASE SUMMARY An 8-year-old patient was diagnosed with acute myeloid leukaemia by bone marrow morphology and immunophenotype.The patient showed poor response to two cycles of induction therapy with 60%blast cells in the bone marrow after the second induction cycle.The patient achieved complete remission after being treated with the CLAG-M protocol as salvage therapy before undergoing umbilical cord blood stem cell transplantation.Morphological complete remission with haematological recovery has hitherto been maintained over 4 mo.Abnormal gene mutations detected at diagnosis were undetectable after haematopoietic stem cell transplantation.CONCLUSION Here we present a paediatric patient with primary refractory acute myeloid leukaemia who was successfully treated with the CLAG-M protocol.Given the positive results of the presented patient,large-scale clinical studies are required to assess the role of the CLAG-M protocol in the salvage treatment of refractory or relapsed AML in childhood.展开更多
Treatment decisions in autoimmune hepatitis are complicated by the diversity of its clinical presentations,uncertainties about its natural history,evolving opinions regarding treatment end points,varied nature of refr...Treatment decisions in autoimmune hepatitis are complicated by the diversity of its clinical presentations,uncertainties about its natural history,evolving opinions regarding treatment end points,varied nature of refractory disease,and plethora of alternative immu-nosuppressive agents. The goals of this article are to review the difficult treatment decisions and to provide the bases for making sound therapeutic judgments. The English literature on the treatment problems in au-toimmune hepatitis were identifi ed by Medline search up to October 2009 and 32 years of personal experi-ence. Autoimmune hepatitis may have an acute severe presentation,mild in? ammatory activity,lack autoan-tibodies,exhibit atypical histological changes (centri-lobular zone 3 necrosis or bile duct injury),or have variant features reminiscent of another disease (overlap syndrome). Corticosteroid therapy must be instituted early,applied despite the absence of symptoms,or modified in an individualized fashion. Pursuit of normal liver tests and tissue is the ideal treatment end point,but this objective must be tempered against the risk of side effects. Relapse after treatment withdrawal requires long-term maintenance therapy,preferably with azathioprine. Treatment failure or an incomplete response warrants salvage therapy that can include conventional medications in modified dose or empiricaltherapies with calcineurin inhibitors or mycophenolate mofetil. Liver transplantation supersedes empirical drug therapy in decompensated patients. Elderly and pregnant patients warrant treatment modifications. Difficult treatment decisions in autoimmune hepatitis can be simplified by recognizing its diverse manifestations and individualizing treatment,pursuing realistic goals,applying appropriate salvage regimens,and identifying problematic patients early.展开更多
In autoimmune hepatitis, patients who are intolerant or with toxicity experience, non-responders, relapsers or refractory are challenging. Non-standard drugs are being tried to preemptively avoid corticosteroid-relate...In autoimmune hepatitis, patients who are intolerant or with toxicity experience, non-responders, relapsers or refractory are challenging. Non-standard drugs are being tried to preemptively avoid corticosteroid-related side effects. Prognosis and quality of life of life rely on treatment optimization. Recently, emergence of powerful immunosuppressive agents, mainly from liver transplantation, challenged the supremacy of the corticosteroid regime and promise greater immunosuppression than conventional medications, offer site-specific actions and satisfactory patient tolerance. Successes in experimental models of related diseases have primed these molecular interventions. We performed a literature review on alternative treatments. Azatioprine intolerance is the principal indication for mycophenolate use butit can be used as a front-line therapy. Cyclosporine A and tacrolimus have been tested for non-responders or relapsers. Rituximab may be used as salvage therapy. Anti-tumor necrosis factor-alpha agents may be used for incomplete responses or non-responders. Methotrexate is possibly an alternative for induction of remission and maintenance in refractory patients. Cyclophosphamide has been included in the induction regimen with corticosteroids. Ursodeoxycholic acid action is mainly immunomodulatory. Non-standard treatments are coming slowly to the attention, but its use should be cautious performed by experienced centers.展开更多
基金Shanghai Hospital Development Center(Joint Breakthrough Project for New Frontier Technologies.Project No.SHDC 12015118)Science and Technology Commission of Shanghai Municipality(Project No.15411950102&15411950106)Natural Science Foundation of Shanghai(Project No.14ZR1407100)
文摘Background: After deinitive chemoradiotherapy for non-metastatic nasopharyngeal carcinoma(NPC), more than 10% of patients will experience a local recurrence. Salvage treatments present signiicant challenges for locally recurrent NPC. Surgery, stereotactic ablative body radiotherapy, and brachytherapy have been used to treat locally recurrent NPC. However, only patients with small-volume tumors can beneit from these treatments. Re-irradiation with X-ray—based intensity-modulated radiotherapy(IMXT) has been more widely used for salvage treatment of locally recurrent NPC with a large tumor burden, but over-irradiation to the surrounding normal tissues has been shown to cause frequent and severe toxicities. Furthermore, locally recurrent NPC represents a clinical entity that is more radioresistant than its primary counterpart. Due to the inherent physical advantages of heavy-particle therapy, precise dose delivery to the target volume(s), without exposing the surrounding organs at risk to extra doses, is highly feasible with carbon-ion radiotherapy(CIRT). In addition, CIRT is a high linear energy transfer(LET) radiation and provides an increased relative biological efectiveness compared with photon and proton radiotherapy. Our prior work showed that CIRT alone to 57.5 Gy E(gray equivalent), at 2.5 Gy E per daily fraction, was well tolerated in patients who were previously treated for NPC with a deinitive dose of IMXT. The short-term response rates at 3–6 months were also acceptable. However, no patients were treated with concurrent chemotherapy. Whether the addition of concurrent chemotherapy to CIRT can beneit locally recurrent NPC patients over CIRT alone has never been addressed. It is possible that the beneits of high-LET CIRT may make radiosensitizing chemotherapy unnecessary. We therefore implemented a phase I/II clinical trial to address these questions and present our methodology and results.Methods and design: The maximal tolerated dose(MTD) of re-treatment using raster-scanning CIRT plus concurrent cisplatin will be determined in the phase I, dose-escalating stage of this study. CIRT dose escalation from 52.5 to 65 Gy E(2.5 Gy E × 21–26 fractions) will be delivered, with the primary endpoints being acute and subacute toxicities. Eicacy in terms of overall survival(OS) and local progression-free survival of patients after concurrent chemotherapy plus CIRT at the determined MTD will then be studied in the phase II stage of the trial. We hypothesize that CIRT plus chemotherapy can improve the 2-year OS rate from the historical 50% to at least 70%.Conclusions: Re-treatment of locally recurrent NPC using photon radiation techniques, including IMXT, provides moderate eicacy but causes potentially severe toxicities. Improved outcomes in terms of eicacy and toxicity proile are expected with CIRT plus chemotherapy. However, the MTD of CIRT used concurrently with cisplatin-based chemotherapy for locally recurrent NPC remains to be determined. In addition, whether the addition of chemotherapy to CIRT is needed remains unknown. These questions will be evaluated in the dose-escalating phase I and randomized phase II trials.
文摘Hepatocellular carcinoma(HCC)is the second most common cause of cancerrelated death worldwide.Despite the advent of screening efforts and algorithms to stratify patients into appropriate treatment strategies,recurrence rates remain high.In contrast to first-line treatment for HCC,which relies on several factors,including clinical staging,tumor burden,and liver function,there is no consensus or general treatment recommendations for recurrent HCC(R-HCC).Locoregional therapies include a spectrum of minimally invasive liver-directed treatments which can be used as either curative or neoadjuvant therapy for HCC.Herein,we provide a comprehensive review of recent evidence using salvage loco-regional therapies for R-HCC after failed curative-intent.
文摘BACKGROUND For recurrent achalasia after initial peroral endoscopic myotomy(POEM)failure,repeat POEM(Re-POEM)has been reported as a treatment option.However,severe esophageal interlayer adhesions caused by previous procedures impede the successful establishment of a submucosal tunnel and lead to aborted Re-POEM procedures.Our team previously described POEM with simultaneous submucosal and muscle dissection(POEM-SSMD)as a feasible solution for achalasia with severe interlayer adhesions.AIM To investigate the effectiveness and safety of Re-POEM with simultaneous submucosal and muscle dissection(Re-POEM-SSMD).METHODS A total of 1049 patients with achalasia who underwent successful endoscopic myotomy at the Digestive Endoscopic Center of Chinese PLA General Hospital from December 2014 to May 2022 were reviewed.Patients with recurrent achalasia who experienced initial POEM clinical failure were retrospectively included in this study.The primary endpoint was retreatment clinical success,defined as an Eckardt score≤3 during the postretreatment follow-up and no need for additional treatment.Procedure-related adverse events,changes in manometric lower esophageal sphincter(LES)pressure and reflux complications,as well as procedure-related parameters,were recorded.RESULTS Sixteen patients underwent Re-POEM(9 patients)or Re-POEM-SSMD(7 patients)successfully at a median of 45.5 mo(range,4-95 mo)after initial POEM.During a median followup period of 31 mo(range,7-96 mo),clinical success(Eckardt score≤3)was achieved in 8(88.9%)and 6(85.7%)patients after Re-POEM and Re-POEM-SSMD,respectively(P=0.849).The median Eckardt score dropped from 4(range,3-8)at preretreatment to 1(range,0-5)at postretreatment in the Re-POEM group(P=0.025)and from 5(range,2-8)to 2(range,0-4)in the Re-POEM-SSMD group(P<0.001).The mean manometric LES pressure decreased from 23.78±9.04 mmHg to 11.45±5.37 mmHg after Re-POEM(P<0.001)and from 26.80±7.48 mmHg to 11.05±4.38 mmHg after Re-POEM-SSMD(P<0.001).No serious adverse events were recorded in both groups.CONCLUSION In conclusion,Re-POEM-SSMD appears to be a safe and effective salvage therapy for recurrent achalasia with severe interlayer adhesions.
基金the National Natural Science Foundation of China(No.81960043 and No.81600180)Natural Science Foundation of Jiangxi Province(No.20192ACB20030 and No.20203BBGL73197)Science and Technology Innovation Base Construction Project of Jiangxi Province(No.20212BCG74001 and No.20211ZDG02006).
文摘Objective Preclinical evidence and clinical trials have suggested synergistic effects of epigenetic modifiers in combination with cytotoxic agents for the treatment of leukemia.However,their efficacy in patients with relapsed/refractory acute myeloid leukemia(R/R AML)remains unclear.Methods Clinical data of R/R AML patients who received a CDCAG regimen(chidamide,decitabine,cytarabine,aclarubicin,and granulocyte colony-stimulating factor)from July 1,2018 to October 31,2021 at our center were retrospectively assessed,and the safety and efficacy of the CDCAG regimen were evaluated.Patients were followed up until November 30,2021,with a median follow-up of 21.6 months(95%CI:10.0–33.2 months).Results A total of 67 patients were enrolled.Two patients died within 3 weeks after the initiation,and therefore only 65 patients underwent the assement for clinical response and survival.It was found that 56.9%patients achieved complete remission with a median overall survival(OS)of 9.6 months.The median OS of responders was 25.9 months,while that of non-responders was 5.0 months(P<0.0001).Patients with gene mutations had a superior overall response rate(ORR)(80.4%vs.45.5%,P=0.043)compared to those without gene mutations.The presence of DNA methyltransferase 3 A(DNMT3A),ten-eleven translocation-2(TET2),and isocitrate dehydrogenase 1/2(IDH1/2)mutations did not affect the response rate(88.2%vs.68.9%,P=0.220)and reflected a better OS(not attained vs.9.0 months,P=0.05).The most common non-hematologic adverse events were pulmonary infection(73.1%),followed by febrile neutropenia(23.9%)and sepsis(19.4%).Conclusions The CDCAG regimen was effective and well-tolerated in R/R AML patients,increasing the potential for allogeneic hematopoietic stem cell transplantation.Moreover,patients with DNMT3A,TET2,and IDH1/2 mutations might benefit from this regimen.
基金Supported by the National Natural Science Foundation of China,No.81670155.
文摘BACKGROUND The prognosis of paediatric primary refractory/relapsed acute myeloid leukaemia(R/R AML)remains poor.Intensive therapy is typically used as salvage treatment for those with R/R AML.No data are currently available about the use of the CLAG-M protocol as salvage therapy in paediatric patients with R/R AML.CASE SUMMARY An 8-year-old patient was diagnosed with acute myeloid leukaemia by bone marrow morphology and immunophenotype.The patient showed poor response to two cycles of induction therapy with 60%blast cells in the bone marrow after the second induction cycle.The patient achieved complete remission after being treated with the CLAG-M protocol as salvage therapy before undergoing umbilical cord blood stem cell transplantation.Morphological complete remission with haematological recovery has hitherto been maintained over 4 mo.Abnormal gene mutations detected at diagnosis were undetectable after haematopoietic stem cell transplantation.CONCLUSION Here we present a paediatric patient with primary refractory acute myeloid leukaemia who was successfully treated with the CLAG-M protocol.Given the positive results of the presented patient,large-scale clinical studies are required to assess the role of the CLAG-M protocol in the salvage treatment of refractory or relapsed AML in childhood.
文摘Treatment decisions in autoimmune hepatitis are complicated by the diversity of its clinical presentations,uncertainties about its natural history,evolving opinions regarding treatment end points,varied nature of refractory disease,and plethora of alternative immu-nosuppressive agents. The goals of this article are to review the difficult treatment decisions and to provide the bases for making sound therapeutic judgments. The English literature on the treatment problems in au-toimmune hepatitis were identifi ed by Medline search up to October 2009 and 32 years of personal experi-ence. Autoimmune hepatitis may have an acute severe presentation,mild in? ammatory activity,lack autoan-tibodies,exhibit atypical histological changes (centri-lobular zone 3 necrosis or bile duct injury),or have variant features reminiscent of another disease (overlap syndrome). Corticosteroid therapy must be instituted early,applied despite the absence of symptoms,or modified in an individualized fashion. Pursuit of normal liver tests and tissue is the ideal treatment end point,but this objective must be tempered against the risk of side effects. Relapse after treatment withdrawal requires long-term maintenance therapy,preferably with azathioprine. Treatment failure or an incomplete response warrants salvage therapy that can include conventional medications in modified dose or empiricaltherapies with calcineurin inhibitors or mycophenolate mofetil. Liver transplantation supersedes empirical drug therapy in decompensated patients. Elderly and pregnant patients warrant treatment modifications. Difficult treatment decisions in autoimmune hepatitis can be simplified by recognizing its diverse manifestations and individualizing treatment,pursuing realistic goals,applying appropriate salvage regimens,and identifying problematic patients early.
文摘In autoimmune hepatitis, patients who are intolerant or with toxicity experience, non-responders, relapsers or refractory are challenging. Non-standard drugs are being tried to preemptively avoid corticosteroid-related side effects. Prognosis and quality of life of life rely on treatment optimization. Recently, emergence of powerful immunosuppressive agents, mainly from liver transplantation, challenged the supremacy of the corticosteroid regime and promise greater immunosuppression than conventional medications, offer site-specific actions and satisfactory patient tolerance. Successes in experimental models of related diseases have primed these molecular interventions. We performed a literature review on alternative treatments. Azatioprine intolerance is the principal indication for mycophenolate use butit can be used as a front-line therapy. Cyclosporine A and tacrolimus have been tested for non-responders or relapsers. Rituximab may be used as salvage therapy. Anti-tumor necrosis factor-alpha agents may be used for incomplete responses or non-responders. Methotrexate is possibly an alternative for induction of remission and maintenance in refractory patients. Cyclophosphamide has been included in the induction regimen with corticosteroids. Ursodeoxycholic acid action is mainly immunomodulatory. Non-standard treatments are coming slowly to the attention, but its use should be cautious performed by experienced centers.
