Intestinal natural killer/T-cell lymphoma presenting as a pancreatic head space-occupying lesion:A case report

BACKGROUND Intestinal natural killer/T-cell lymphoma(NKTCL)is a rare and aggressive non-Hodgkin’s lymphoma,and its occurrence is closely related to Epstein-Barr virus infection.In addition,the clinical symptoms of NKTCL are not obvious,and the specific pathogenesis is still uncertain.While NKTCL may occur in any segment of the intestinal tract,its distinct location in the periampullary region,which leads clinicians to consider mimics of a pancreatic head mass,should also be addressed.Therefore,there remain huge challenges in the diagnosis and treatment of intestinal NKTCL.CASE SUMMARY In this case,we introduce a male who presented to the clinic with edema of both lower limbs,accompanied by diarrhea,and abdominal pain.Endoscopic ultrasound(EUS)showed well-defined homogeneous hypoechoic lesions with abundant blood flow signals and compression signs in the head of the pancreas.Under the guidance of EUS-fine needle biopsy(FNB)with 19 gauge or 22 gauge needles,combined with multicolor flow cytometry immunophenotyping(MFCI)helped us diagnose NKTCL.During treatments,the patient was prescribed the steroid(dexamethasone),methotrexate,ifosfamide,L-asparaginase,and etoposide chemotherapy regimen.Unfortunately,he died of leukopenia and severe septic shock in a local hospital.CONCLUSION Clinicians should enhance their understanding of NKTCL.Some key factors,including EUS characteristics,the right choice of FNB needle,and combination with MFCI,are crucial for improving the diagnostic rate and reducing the misdiagnosis rate.

Immune evasion and therapeutic opportunities based on natural killer cells

Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.

Designing a risk prognosis model based on natural killer cell-linked genes to accurately evaluate the prognosis of gastric cancer

Background:This study was aimed at identifying natural killer(NK)cell-related genes to design a risk prognosis model for the accurate evaluation of gastric cancer(GC)prognosis.Methods:We obtained NK cell-related genes from various databases,followed by Cox regression analysis and molecular typing to identify prognostic genes.Various immune algorithms and enrichment analyses were used to investigate the mutations,immune status,and pathway variations among different genotypes.The key prognostic genes were assessed using the least absolute shrinkage and selection operator(Lasso)regression analysis and univariate Cox regression analysis.Thereafter,the risk score(RS)prognosis model was constructed based on the selected important prognostic genes.A Receiver Operating Characteristics(ROC)curve was plotted for analyzing the robustness of the model.Subsequently,the decision and calibration curves were used for assessing the reliability and prediction accuracy of the proposed model.The‘pRRophetic’R software package was utilized for predicting the half-maximal inhibitory concentration(IC50)of immunotherapy and chemotherapy drugs.Results:We screened 21 prognostic genes and three molecular subtypes and found that the C1 subtype had the worst prognosis.Further,the pathways promoting tumor proliferation,such as epithelial-mesenchymal transition were significantly up-regulated.The results also showed that the macrophages in the M2 stage were significantly infiltrated in the C1 subtype,and there was significant overexpression in the C1 subtype,accompanied by a severe inflammatory reaction.The C1 was highly sensitive to drugs like 5-fluorouracil and paclitaxel.The ROC,calibration curve,and decision curve showed that the risk model was robust and strongly reliable.Conclusion:Overall,our proposed NK cell-related RS model can be used as a more accurate prediction index for GC patients,providing a valuable contribution to personalized medicine.

Establishment of a prognostic model related to tregs and natural killer cells infiltration in bladder cancer

BACKGROUND Regulatory T cells(Tregs)and natural killer(NK)cells play an essential role in the development of bladder urothelial carcinoma(BUC).AIM To construct a prognosis-related model to judge the prognosis of patients with bladder cancer,meanwhile,predict the sensitivity of patients to chemotherapy and immunotherapy.METHODS Bladder cancer information data was obtained from The Cancer Genome Atlas and GSE32894.The CIBERSORT was used to calculate the immune score of each sample.Weighted gene co-expression network analysis was used to find genes that will have the same or similar expression patterns.Subsequently,multivariate cox regression and lasso regression was used to further screen prognosis-related genes.The prrophetic package was used to predict phenotype from gene expression data,drug sensitivity of external cell line and predict clinical data.RESULTS The stage and risk scores are independent prognostic factors in patients with BUC.Mutations in FGFR3 lead to an increase in Tregs percolation and affect the prognosis of the tumor,and additionally,EMP1,TCHH and CNTNAP3B in the model are mainly positively correlated with the expression of immune checkpoints,while CMTM8,SORT1 and IQSEC1 are negatively correlated with immune checkpoints and the high-risk group had higher sensitivity to chemotherapy drugs.CONCLUSION Prognosis-related models of bladder tumor patients,based on Treg and NK cell percolation in tumor tissue.In addition to judging the prognosis of patients with bladder cancer,it can also predict the sensitivity of patients to chemotherapy and immunotherapy.At the same time,patients were divided into high and low risk groups based on this model,and differences in genetic mutations were found between the high and low risk groups.

Diffuse large B-cell lymphoma successfully treated with amplified natural killer therapy alone: A case report

BACKGROUND The prognosis of patients with advanced diffuse large B-cell lymphoma(DLBCL)is poor,with a 5-year survival rate of approximately 50%.The mainstay of treatment is multidrug combination chemotherapy,which has been associated with serious side effects.Amplified natural killer(ANK)cell therapy amplifies and activates natural killer(NK)cells to attack only malignant tumors.As ANK cells attack programmed death ligand 1(PD-L1)-positive tumor cells,ANK therapy is considered effective against adult T-cell lymphoma and malignant lymphoma.CASE SUMMARY Herein,we report a case of an older patient with advanced DLBCL who was successfully treated with ANK immunotherapy.A 91-year-old female visited our hospital with sudden swelling of the right axillary lymph node in April 2022.The patient was diagnosed with stage II disease,given the absence of splenic involvement or contralateral lymphadenopathy.ANK therapy was administered.Six rounds of lymphocyte sampling were performed on July 28,2022.To reduce the occurrence of side effects,the six samples were diluted by half to obtain 12 samples.Cultured NK cells were administered twice weekly.The treatment efficacy was evaluated by performing computed tomography and serological tests every 1 or 2 mo.The treatment suppressed lesion growth,and the antitumor effect persisted for several months.The patient experienced mild side effects.PD-L1 immunostaining was positive,indicating that the treatment was highly effective.CONCLUSION ANK therapy can be used as a first-line treatment for malignant lymphoma;the PD-L1 positivity rate can predict treatment efficacy.

Synchronous adenocarcinoma and extranodal natural killer/T-cell lymphoma of the colon:A case report and literature review

Extranodal natural killer/T-cell lymphoma(ENKTL) is a distinct subtype of non-Hodgkin's lymphoma and is rare in the colon.Synchronous adenocarcinoma and ENKTL of the colon has not been reported in the literature.In the present study,we report a 63-year-old male who suffered from intermittent bloody stools for 2 mo.He did not have fever,body weight loss or night sweat.Endoscopic and imaging studies revealed a 4.5-cm ulcerative mass in the ascending colon and a 3.0-cm polypoid,easy bleeding mass in the sigmoid colon,respectively.Thought to have double carcinoma of the colon,he received simultaneous right hemicolectomy and sigmoidectomy.The pathological diagnosis was a synchronous ENKTL(ascending colon) and adenocarcinoma(sigmoid colon).The literature on synchronous adenocarcinoma and malignant lymphoma of the colon was also reviewed.

Outcomes of patients treated with SVILE vs.P-GemOx for extranodal natural killer/T-cell lymphoma,nasal type:a prospective,randomized controlled study

Objective:To compare the efficacy and safety of the novel SVILE regimen with the P-GemOx regimen in patients with newly diagnosed extranodal natural killer/T-cell lymphoma,nasal type(ND-ENKTL).Methods:From April 2015 to July 2018,103 patients with ND-ENKTL were randomly assigned to SVILE(experimental group)or P-GemOx(control group)chemotherapy followed by radiotherapy and consolidation chemotherapy.The primary endpoint was the overall response rate after 3 cycles of chemotherapy,and secondary study endpoints were complete response(CR),progression-free survival(PFS),and overall survival(OS).Safety was also evaluated.Results:There were no significant differences in baseline characteristics in the experimentalvs.control groups.In experimental and control groups,respectively,the overall response rates were 91.7%vs.97.0%for stageI/II and 75.0%vs.72.2%for stage III/IV.The CR rates were 83.4%vs.97.0%for stage I/II and 68.8%vs.61.1%for stage III/IV.None of those differences were significant.There was no significant difference in PFS and OS between groups and between patients in stage I/II and stage III/IV.The 3-year PFS and OS in stage I/II were 88.3%vs.93.3%and 88.8%vs.97.0%,respectively.The 3-year PFS and OS in stage III/IV were 46.2%vs.65.7%and 68.8%vs.72.2%,respectively.The common adverse events were hematological toxicity,hepatotoxicity,and coagulation abnormalities,which were found to be reversible with supportive therapy.Conclusions:The novel SVILE regimen has comparable effects to those of P-GemOx in patients with ND-ENKTL and is well tolerated.SVILE is a therapeutic option for ND-ENKTL.

The combined prognostic value of pretreatment neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and platelet-to-lymphocyte ratio in stage IE/IIE extranodal natural killer/T-cell lymphoma

Objective This study aimed to explore the combined prognostic value of pretreatment neutrophil-tolymphocyte ratio(NLR), lymphocyte-to-monocyte ratio(LMR), and platelet-to-lymphocyte ratio(PLR) in newly diagnosed IE/IIE extranodal natural killer/T-cell lymphoma(ENKTL) treated with a P-Gemox regimen combined with radiotherapy or radiotherapy alone.Methods A total of 132 patients from 2009 to 2017 at the Sichuan Cancer Hospital were enrolled in the study. The cutoff values of NLR, LMR, and PLR using overall survival(OS) rate as an endpoint were obtained by the receiver operating curve. Results The cutoff value of NLR was 3.5. Patients with high NLR had significantly shorter progressionfree survival(PFS)(P < 0.001) and OS(P < 0.001) than those with low NLR. Similarly, the cutoff value of LMR was 3.0. The high LMR group had significantly longer PFS(P=0.001) and OS(P < 0.001) than the low LMR group. Similarly, the cutoff value of PLR was 191.7. The high PLR group was significantly associated with poor PFS(P < 0.001) and OS(P < 0.001) than the low PLR group. Furthermore, combining NLR, LMR, and PLR to build a new model to stratify patients into low-, intermediate-, intermediate-high-, and high-risk groups, there were also significant differences in PFS(P < 0.001) and OS(P < 0.001). The univariate analysis showed that presenting B symptoms, stage IIE, local tumor invasion, Eastern Cooperative Oncology Group score ≥ 2, elevated lactate dehydrogenase level, elevated NLR, decreased LMR, and elevated PLR were significantly associated with poor survival. The multivariate analysis demonstrated that PLR was an independent prognostic factor for both PFS(hazard ratio [HR]= 2.073, 95% confidence interval [CI]= 1.080–3.981, P = 0.028) and OS(HR = 2.127, 95% CI = 1.102–4.107, P = 0.025).Conclusion Elevated pretreatment PLR was a novel simple predictor of poor survival in patients with stage IE/IIE ENKTL. Combining NLR, LMR, and PLR could provide additional stratification.

Updating targets for natural killer/T-cell lymphoma immunotherapy

Natural killer/T-cell lymphoma(NKTCL)is a highly invasive subtype of non-Hodgkin lymphoma,typically positive for cytoplasmic CD3,CD56,cytotoxic markers,including granzyme B and TIA1,and Epstein-Barr virus(EBV).The current treatment methods for NKTCL are associated with several drawbacks.For example,chemotherapy can lead to drug resistance,while treatment with radiotherapy alone is inadequate and results in frequent relapses.Moreover,hematopoietic stem cell transplantation exhibits limited efficacy and is not well recognized by domestic and foreign experts.In recent years,immunotherapy has shown good clinical results and has become a hot spot in cancer research.Clinical activity of targeted antibodies,such as daratumumab(anti-CD38 antibody)and brentuximab vedotin(anti-CD30 antibody),have been reported in NKTCL.Additionally,dacetuzumab and Campath-1 H have demonstrated promising results.Further encouraging data have been obtained using checkpoint inhibitors.The success of these immunotherapy agents is attributed to high expression levels of programmed death-ligand 1 in NKTCL.Furthermore,anti-CCR4 monoclonal antibodies(m Abs)exert cytotoxic actions on both CCR4+tumor cells and regulatory T cells.Depletion of these cells and the long half-life of anti-CCR4 m Abs result in enhanced induction of antitumor effector T cells.The role of IL10 in NKTCL has also been investigated.It has been proposed that exploitation of this cytokine might provide potential novel therapeutic strategies.Cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 has shown promising results and sustained remission.Cellular immunotherapy may be used either as maintenance therapy following initial induction chemotherapy or in cases of relapsed/refractory disease.The present review outlines the known immunotherapy targets for the treatment of NKTCL.

Extranodal natural killer/T-cell lymphoma(nasal type) presenting as a perianal abscess: A case report

BACKGROUND Extranodal natural killer(NK) T-cell lymphoma(ENKTL), nasal type is a rare subtype of extranodal non-Hodgkin lymphoma characterized by vascular damage and necrosis. The lesions usually present in the nasal cavity and adjacent tissues, however, the disease originates from the gastrointestinal or genitourinary tract in 25% of cases. Since rectal involvement in ENKTL is rare, rectal symptoms in the course of ENKTL are often misdiagnosed and considered to be related to benign diseases such as rectal fistula or perianal abscess.CASE SUMMARY We report the case of a 24-year-old Han Chinese female who initially presented with a perianal abscess that was subsequently diagnosed as nasal type ENKTL.Due to typical perianal pain, perianal abscess was diagnosed and surgical incision and drainage were performed. After recurrent, severe anal hemorrhages leading to hypovolemic shock and multiple surgeries, a diagnosis of ENKTL was made. The patient's condition gradually deteriorated, and she died shortly after initiation of chemotherapy.CONCLUSION Systemic and neoplastic diseases should be included in the differential diagnosis of any potentially benign perianal abscess complicated with recurrent hemorrhages.

CD30 expression in extranodal natural killer/T-cell lymphoma,nasal type among 622 cases of mature T-cell and natural killer-cell lymphoma at a single institution in South China

Background:Mature T-cell and natural killer(NK)-cell lymphomas compose a heterogeneous group of non-Hodgkin lymphomas,and extranodal NK/T-cell lymphoma,nasal type(ENKTL) is an aggressive subtype with sporadic CD30 expression.However,the significance of CD30 expression in ENKTL is controversial.We aimed to classify a large cohort of patients with mature T-cell and NK-cell lymphomas according to the 2016 World Health Organization(WHO) classification guidelines and to study the association between CD30 expression and prognosis of patients with ENKTL.Methods:We selected consecutive patients with mature T-cell and NK-cell lymphomas who attended our institution between September 1,2009 and August 31,2013.We classified the lymphomas according to the 2016 revision of the WHO classification of lymphoid neoplasms,analyzed the associations between CD30 expression and clinicopathologic features of ENKTL patients,and evaluated the prognostic implications of CD30 expression.Results:We identified 622 consecutive patients with mature T-cell and NK-cell lymphomas,including 317(51.0%)patients with ENKTL.In addition,CD30 expression was detected in 43(47.3%) of a subset of 91 patients with ENKTL.No clinicopathologic features were associated with CD30 expression,and CD30 positivity showed no prognostic significance in patients with ENKTL.Conclusions:ENKTL is the most common type of mature T-cell and NK-cell lymphoma diagnosed at our institution.CD30 is frequently expressed in ENKTL and represents a therapeutic target;however,it may not be a prognostic marker.

Natural killer/T-cell lymphoma with intracranial infiltration and Epstein-Barr virus infection: A case report

BACKGROUND Because of atypical clinical symptoms,lymphoma is easily confused with infectious diseases.Extranodal nasal-type natural killer/T-cell lymphoma(NKTL)is more common,and there are few cases of eyelid site onset and intracranial infiltration,which increases the difficulty of diagnosis.This disease usually has a very poor prognosis and there are few reports of recovery.CASE SUMMARY A 3-year-old boy was admitted to our hospital due to an initial misdiagnosis of"eyelid cellulitis"and failed antibiotic treatment.He was characterized by fever,right eyeball bulging,convulsions,and abnormal liver function.His blood Epstein-Barr virus(EBV)DNA was positive(8.798×10^4 copies/mL),and remained positive for about half a year.The cranial imaging examination suggested a space-occupying lesion in the right eyelid,with the right temporal lobe and meninges involved.The boy underwent ocular mass resection.The pathological diagnosis was NKTL.He was diagnosed as having NKTL with intracranial infiltration,combined with chronic active EBV infection(CAEBV).Then he underwent systemic chemotherapy and intrathecal injection.The boy suffered from abnormal blood coagulation,oral mucositis,diarrhea,liver damage,and severe bone marrow suppression but survived.Finally,the tumor was completely relieved and his blood EBV-DNA level turned negative.The current follow-up has been more than 2 years and his condition is stable.CONCLUSION This case suggests that chemotherapy combined with intrathecal injection may have a good effect on intracranial infiltrating lymphoma and CAEBV,which deserves further study and discussion.

Combination of atezolizumab and chidamide to maintain long-term remission in refractory metastatic extranodal natural killer/T-cell lymphoma:A case report

BACKGROUND The prognosis of refractory extranodal natural killer/T-cell lymphoma(ENKTL)is poor.Recent data have indicated that immune checkpoint blockade with a programmed cell death protein-1(PD-1)antibody in combination with administration of histone deacetylase inhibitors represents a potentially effective treatment strategy.Compared with PD-1 antibodies,programmed death-ligand 1 antibodies have fewer side effects.Here,we present a rare case of a patient with refractory metastatic ENKTL who achieved sustained remission of approximately 10 mo with minor adverse effects after combination therapy with atezolizumab,chidamide,and radiotherapy.CASE SUMMARY A 56-year-old woman underwent resection of a tumour in her left nasal cavity and was diagnosed with ENKTL(nasal type).Medical examination revealed tumours observed in the bilateral nasal mucosa,the subcutaneous soft tissue of the inner side of the left eye,the soft tissue of the nasopharynx,the bilateral tonsils,and the left preauricular,right hilar,bilateral neck lymph nodes and bone marrow.However,tomography/computed tomography showed increased metabolism of the bilateral nasal mucosa and subcutaneous soft tissue of the inner side of the left eye and newly increased metabolism of the left cervical lymph node after chemotherapy.Therefore,combination therapy with chidamide,atezolizumab,and radiotherapy was performed.Fortunately,the patient achieved a complete response following 10 mo of combination therapy.CONCLUSION The outcome in this case suggests that the combination of atezolizumab,chidamide,and radiotherapy is a promising regimen for treating refractory metastatic ENKTL following chemotherapy treatment failure.

Primary intestinal extranodal natural killer/T-cell lymphoma, nasal type: A case report

BACKGROUND Primary intestinal extranodal natural killer/T-cell lymphoma,nasal type(PIENKTCL)is a rare non-Hodgkin’s lymphoma(NHL)subtype,and its prognosis is extremely poor.Clinical characteristics of the disease are not obvious and easily misdiagnosed.In this case report,we describe a patient with PI-ENKTCL who presented with intermittent hematochezia.The advantages of positron emission tomography/computed tomography(PET-CT)as a useful diagnostic tool and the role of surgery as an important therapy are highlighted.CASE SUMMARY A 45-year-old man,hospitalized due to intermittent hematochezia,underwent gastroscopy,colonoscopy,biopsy and CT,but no cause was found.Hence,we carried out a multidisciplinary team(MDT)discussion on the causes and treatment of this patient,and it was decided to perform PET-CT imaging with a MDT discussion of the results.PET-CT demonstrated a diagnosis of lymphoma and it was decided to surgically resect the lesion,and a R0 resection was successfully performed.Postoperative pathology showed negative resection margins,and examination of the lesion confirmed the diagnosis of PI-ENKTCL.After surgery,the patient underwent a follow-up period of 6 mo and received 6 cycles of gemcitabine,oxaliplatin and L-asparaginase.No recurrence or metastasis occurred.CONCLUSION PI-ENKTCL is rare,and MDT discussion is required during diagnosis.PET-CT can be performed for imaging diagnosis.Treatment is based on surgical resection,and the best treatment regimen is determined according to postoperative pathological results to improve prognosis and to extend survival in patients.

Natural killer/T-cell lymphoma with concomitant syndrome of inappropriate antidiuretic hormone secretion: A case report and review of literature

We report a case of natural killer(NK)/T-cell lymphoma with concomitant syndrome of inappropriate antidiuretic hormone secretion(SIADH).The patient was a 64-yearold woman with a history of nasopharyngeal carcinoma of over 30 years.She was admitted with a chief complaint of intermittent fever for 2 mo.Palpation after admission indicated a swollen lymph node below the left jaw.Multiple imaging examinations on admission indicated multiple enlarged lymph nodes throughout the body.We performed a left submandibular lymph node biopsy,and the results revealed NK/T-cell lymphoma.A biochemical examination indicated Epstein-Barr virus positivity.At the same time,the patient developed hyponatremia.Based on her laboratory examination and clinical manifestation,decreased plasma osmolality,urine osmolality greater than plasma osmolality,lack of skin swelling,normal blood pressure,normal renal function,no adrenal function detected on serology,and no abnormalities in imaging examination of the adrenal glands,the likelihood of SIADH in the patient was high.After fluid restriction and administration of sodium chloride,the patient’s blood sodium level gradually increased.Subsequently,the immune function of the patient declined,there were severe symptoms of infection,and she died of respiratory failure.NK/T-cell lymphoma associated with SIADH has not,to our knowledge,been previously reported in PubMed.This case emphasizes the importance of monitoring serum ion levels,especially serum sodium,in patients with NK/T-cell lymphoma.

Analysis of clinical efficacy of P-Gemox regimen sandwich radiotherapy,P-Gemox regimen sequential radiotherapy,and radiotherapy alone treatment for extranodal natural killer/T-cell lymphoma

Objective The study aimed to explore the clinical efficacy of P-Gemox regimen sandwich radiotherapy, P-Gemox regimen sequential radiotherapy, and radiotherapy alone in early-stage extranodal natural killer/T-cell lymphoma(ENKTL).Methods In total, 124 patients with early-stage ENKTL, from June 2009 to January 2016, were retrospectively analyzed to compare the clinical efficacy of the three regimens. Results A total of 46 patients were treated with P-Gemox regimen sandwich radiotherapy, with complete remission(CR) of 91.3%, objective response rate(ORR) of 97.8%, 2-year progression-free survival(PFS) of 76.1%, and 2-year overall survival(OS) of 80.4%. Then, 37 patients received P-Gemox regimen sequential radiotherapy, with CR of 86.5%, ORR of 94.6%, 2-year PFS of 75.7%, and 2-year OS of 81.1%. Finally, 41 patients received radiotherapy alone, with CR of 61.0%, ORR of 80.5%, 2-year PFS of 51.2%, and 2-year OS of 65.9%. When the two groups were compared, significant differences in CR, PFS, and OS were observed among the sandwich radiotherapy, sequential radiotherapy, and radiotherapy alone groups(P < 0.05), respectively. However, no significant difference in CR, ORR, PFS, and OS was observed between the sandwich radiotherapy and sequential radiotherapy groups(P > 0.05). Multivariate analysis revealed that Eastern Cooperative Oncology Group(ECOG), serum lactate dehydrogenase(LDH), plateletto-lymphocyte ratio(PLR), local tumor invasion, and treatment modalities were independent prognostic factors for PFS(P < 0.05). ECOG, LDH, PLR, local tumor invasion, underlying disease, and treatment modalities were independent prognostic factors for OS(P < 0.05).Conclusion P-Gemox regimen combination radiotherapy for patients with early-stage ENKTL was better than the radiotherapy alone.

Natural killer reprogramming in cutaneous T-cell lymphomas: Facts and hypotheses

To better understand the pathogenesis of Sézary cells, distinguish them from reactive skin-infiltrating T-cells and improve disease treatment, efforts have been made to identify molecular targets deregulated by the malignant process. From immunophenotypic analysis and subtractive differential expression experiments to pan-genomic studies, many approaches have been used to identify markers of the disease. During the last decade several natural killer(NK) cell markers have been found aberrantly expressed at the surface of Sézary cells. In particular, KIR3DL2/CD158 k, expressed by less than 2% of healthy individuals CD4+ T-cells, is an excellent marker to identify and follow the tumor burden in the blood of Sézary syndrome patients. It may also represent a valuable target for specific immunotherapy. Other products of the NK cluster on chromosome 19q13 have been detected on Sézary cells, raising the hypothesis of an NK reprogramming process associated with the malignant transformation that may induce survival functions.

Primary site and regional lymph nodeinvolvement are independent prognosticfactors for early？stage extranodal nasal？typenatural killer/T cell lymphoma

Background:Nasal-type extranodal natural killer/T-cell lymphoma(ENKTCL) originates primarily in the nasal cavity or extra-nasal sites within the upper aerodigestive tract.However,it is unclear whether the primary site can serve as an independent prognostic factor or whether the varying clinical outcomes observed with different primary sites can be attributed merely to their propensities of regional lymph node involvement.The aim of this study was to investigate the prognostic implications of the primary site and regional lymph node involvement in patients with early-stage nasal-type ENKTCL.Methods:To develop a nomogram,we reviewed the clinical data of 215 consecutively diagnosed patients with early-stage nasal-type ENKTCL who were treated in Sun Yat-sen University Cancer Center with chemotherapy and radiotherapy between 2000 and 2011.The predictive accuracy and discriminative ability of the nomogram were determined using a concordance index(C-index) and calibration curve.Results:The 5-year overall survival(OS) and progression-free survival(PFS) rates of patients with nasal ENKTCL were higher than those of patients with extra-nasal ENKTCL(OS:68.2%vs.46.0%,P = 0.030;PFS:53.4%vs.26.6%,P = 0.010).The 5-year OS and PFS rates of patients with Ann Arbor stage IE ENKTCL were higher than those of patients with Ann Arbor stage HE ENKTCL(OS:66.3%vs.59.2%,P = 0.003;PFS:51.4%vs.40.3%,P = 0.009).Multivariate analysis showed that age >60 years,ECOG performance status score >2,elevated lactate dehydrogenase(LDH) level,extranasal primary site,and regional lymph node involvement were significantly associated with lower 5-year OS rate;age >60 years,elevated LDH level,extra-nasal primary site,and regional lymph node involvement were significantly associated with lower 5-year PFS rate.The nomogram included the primary site and regional lymph node involvement based on multivariate analysis.The calibration curve showed good agreement between the predicted and actual 5-year OS and PFS rates,and the C-indexes of the nomogram for the OS and PFS rates were 0.697 and 0.634,respectively.Conclusions:The primary site and regional lymph node involvement are independent prognostic factors for earlystage ENKTCL treated with chemotherapy followed by definitive radiotherapy.

Natural Killer Cell-Based Immunotherapy for Cancer: Advances and Prospects

Natural killer (NK) cells are key innate immune cells that provide the first line of defense against viral infection and cancer. Although NK cells can discriminate between "self" and "non-self," recognize abnormal cells, and eliminate transformed cells and malignancies in real time, tumors develop several strategies to escape from NK cell attack. These strategies include upregulating ligands for the inhibitory receptors of NK cells and producing soluble molecules or immunosuppressive factors. Various types of NK cells are currently being applied in clinical trials, including autologous or allogeneic NK cells, umbilical cord blood (UCB) or induced pluripotent stem cell (iPSC)-derived NK cells, memory-like NK cells, and NK cell line NK-92 cells, for the treatment of different types of tumors. Chimeric antigen receptors (CARs)-NK cells have recently shown great potential due to their redirect specificity and effective antitumor activity. In this review, we summarize the mechanisms of tumor escape from NK cell recognition, the current status and advanced progress of NK cell-based immunotherapy, ways of enhancing the antitumor capacity of NK cells in vivo, and major challenges for clinical practice in this field.

Tumor immunotherapy: New aspects of natural killer cells

A group of impressive immunotherapies for cancer treatment, including immune checkpoint-blocking antibodies,gene therapy and immune cell adoptive cellular immunotherapy, have been established, providing new weapons to fight cancer. Natural killer（NK） cells are a component of the first line of defense against tumors and virus infections. Studies have shown dysfunctional NK cells in patients with cancer. Thus, restoring NK cell antitumor functionality could be a promising therapeutic strategy. NK cells that are activated and expanded ex vivo can supplement malfunctional NK cells in tumor patients. Therapeutic antibodies, chimeric antigen receptor（CAR）, or bispecific proteins can all retarget NK cells precisely to tumor cells. Therapeutic antibody blockade of the immune checkpoints of NK cells has been suggested to overcome the immunosuppressive signals delivered to NK cells.Oncolytic virotherapy provokes antitumor activity of NK cells by triggering antiviral immune responses. Herein,we review the current immunotherapeutic approaches employed to restore NK cell antitumor functionality for the treatment of cancer.