Therapeutic effects of chimeric antigen receptor T cells (CAR-T) on relapse/refractory diffuse large B-cell lymphoma (R/R DLBCL): a meta-analysis.

OBJECTIVE: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). This study aimed to systematically evaluate the efficacy of chimeric antigen receptor T cells (CAR-T) in treating relapse/refractory DLBCL (R/R DLBCL) and associated complete-remission rate (CR). MATERIALS AND METHODS: PubMed, Cochrane Library, CNKI, VIP, CBM, and Wanfang databases were searched, and literature was collected up to January 2019. According to inclusion criteria and exclusion criteria, two researchers independently reviewed and screened literature, extracted required data and crossly checked them. This meta-analysis was conducted using RevMan 5.3 software. RESULTS: This study finally included 13 English literatures and 263 cases. There was no heterogeneity among all these studies, therefore, fixed effect model was used. Meta-analysis findings showed that total CR rate of R/R DLBCL treated with CAR-T was 46.8% (95% CI: 0.408-0.533). Subgroup analysis showed that CR rate of CD28 group was slightly higher [52.5%, with 95% confidence interval (CI): 0.441-0.602] compared to that of 4-1BB group (41.5%, with 95% CI: 0.324-0.510). CR rate of CD19 group was slightly higher (49.2%, with 95% CI: 0.429-0.556) compared to that of CD20 group (42.2%, with 95% CI: 0.231-0.639). Funnel chart of total CR rate, co-stimulatory factor, and target antigen demonstrated fundamental symmetry. Moreover, age, HSCT administration, CAR-T cell counts, and drug pre-treatment also affected immunotherapy on CAR-T on R/R DLBCL. CONCLUSIONS: CAR-T treatment for R/R DLBCL demonstrated evident curative effect and high complete remission rate. CAR-T cell immunotherapy would be expected to become mainstream therapy for hematolymph system tumors.

MicroRNA-338-3p inhibits the progression of bladder cancer through regulating ETS1 expression.

OBJECTIVE: MicroRNA-338-3p (miR-338-3p) was reported to influence the metastasis and development of several human cancers. However, in bladder cancer (BC), the special function of miR-338-3p remains unknown. Here, we aimed at exploring the miR-338-3p function in the progression of BC. PATIENTS AND METHODS: miR-338-3p and ETS1 expressions were examined by quantitative Real-time polymerase chain reaction (qRT-PCR) in BC samples. Following that, transwell assays for cell migration and invasion were performed. And MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay for cell proliferation was conducted as well. Western blot was employed to examine the epithelial-mesenchymal transition (EMT) marker expressions. Finally, the relationship between miR-338-3p and E26 transformation specific-1 (ETS1) was verified by luciferase reporter assay. RESULTS: The decreased miR-338-3p expression was examined in BC cells. Moreover, miR-338-3p upregulation repressed cell proliferation ability in BC. Next, miR-338-3p upregulation also depressed cell metastasis and EMT in BC cells. Furthermore, ETS1 was a direct target of miR-338-3p and inversely associated with its expression. And upregulation of ETS1 partially rescued the suppression of miR-338-3p for cell proliferation and metastasis in BC. CONCLUSIONS: Upregulation of miR-338-3p inhibited the proliferation, metastasis and EMT in BC by suppressing ETS, showing that miR-338-3p might block the development of BC through regulating ETS1 expression.

[Analysis of internal quality control data of complete blood count from laboratories participating in national external quality assessment].

Objective: To investigate current status and problems of internal quality control (IQC) of complete blood count in China so as to perform IQC normally. Methods: The IQC data of complete blood count for five parameters were collected from laboratories participating in national external quality assessment during 2012-2017 (totally 12 times), including WBC, RBC, Hb, Hct and PLT. After confirmation of all data, data for the 12 times were analyzed as follows.The proportions of using different levels of quality control materials were calculated.The 25th, 50th, 75th, 90th percentiles CV of data collected for the 12 times were calculated respectively and the trends of CV were observed over time.The difference of CV among laboratories running three control levels was compared.The CV of each parameter in 2017 was compared with precision requirements based on biological variation, health standards and German Medical Association Directive; The proportions of laboratories using different control rules were calculated. Results: After invalid data was excluded from those IQC data of laboratories for the 12 times external quality assessment (up to 2 402, as low as 1 449) from 2012 to 2017, the residual data (up to 2 332, as low as 1 431, accounting for 96.0%-99.2%) was used for analysis. 61.9%-66.1%, 18.2%-23.6% and 14.3%-17.3% of laboratories ran one, two and three control levels respectively, and the proportions of laboratories running more than two control levels increased from 33.9% to 38.1%. The decrease trend of the 75th, 90th percentiles CV of WBC, RBC, Hb, Hct for three levels, PLT for normal level and the 90th percentiles CV of PLT low level had statistically significance over time (P<0.05); the decrease trend of the 75th percentiles CV of PLT low level and 75th, 90th percentiles CV of PLT high level had no statistically significance over time. The CV had significant difference between low and normal, low and high control level for WBC and PLT, while there were no difference between normal and high control levels. There were no significant difference of CV among three control levels for RBC, Hb, and Hct. Except for the CV of Hct low, normal level and PLT low level, 85% of laboratories for the other parameters could meet the minimum precision requirements based on biological variation; more than 85% laboratories met the requirements of health standards; except for the CV of PLT low level, more than 80% laboratories met the requirements of German Medical Association Directive. The proportion of laboratories using 1(3s)/2(2s) quality control rules increased from 59.2% to 76.0%. Conclusions: During the past 6 years, the CV for IQC has shown a decrease trend over time. However, the control level and quality control rules used by some laboratories do not meet management requirements. The CV of Hct and PLT in a few laboratories do not meet the minimum requirements of the health standards, and need to implement quality improvements fatherly.

Interleukin-10 polymorphisms associated with susceptibility to acute myeloid leukemia.

We investigated the association between polymorphisms in interleukin-10 (IL-10) -1082G/A (rs1800896), -819T/C (rs1800871), and -592A/C (rs1800872) and the risk of acute myeloid leukemia (AML) in a Chinese population. A total of 167 primary AML cases and 328 healthy control subjects were recruited at the First People's Hospital of Yunnan Province between March 2009 and January 2012. The polymorphisms rs1800896, rs1800871, and rs1800872 were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Multivariate regression analyses showed that subjects carrying the rs1800871 CC genotype and C allele had a significantly increased risk of AML, with adjusted odds ratios (95% confidence intervals) of 1.72 (1.01-2.97) and 1.38 (1.04-1.81), respectively. Those carrying the rs1800872 G allele had a slightly increased risk of AML, with an adjusted odds ratio (95% confidence interval) of 1.30 (1.01-1.72). Moreover, genotyping results demonstrated that subjects carrying both the rs1800871 C allele and rs1800872 G allele had a moderately increased risk of AML, indicating that the 2 genotypes had a synergistic effect on AML risk (odds ratio = 2.03, 95% confidence interval = 1.24- 3.15). Our results demonstrated that polymorphisms in rs1800871 and rs1800872 enhance the risk of AML, and these 2 single nucleotide polymorphisms have a synergistic effect on AML risk.

Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients.

PURPOSE: An attempt was made to define the role of radiotherapy before operation for AGC. METHODS AND MATERIALS: From January 1978 to May 1989, a prospective randomized trial on preoperative radiotherapy (R+S) vs. surgery alone (S) for AGC was carried out in 370 patients. Patients were randomized into a combined group (R+S, 171 patients) or a surgery alone group (S, 199 patients) by the envelope method. 8-MV photon or telecobalt was used for the preoperative radiation therapy, using anterior-posterior opposing parallel fields to deliver 40 Gy to the cardia, lower segment of the esophagus, fundus, lesser curvature, and hepatogastric ligament. Surgery was performed after 2 to 4 weeks rest. RESULTS: The 5- and 10-year survival rates of the R+S Group and the S Alone Group were 30.10% and 19.75%, 20.26% and 13.30%, respectively. The survival curves of these two groups diverged right from the beginning after the operation over the ninth year. Statistics by Kaplan-Meier log rank test proves that the difference is significant (chi2 = 6.74, p = 0.0094). The immediate results were: resection rate 89.5% and 79.4% (p < 0.01); pathologic stage after resection T2 12.9% and 4.5% (p < 0.01), T4 40.3% and 51.3% (p < 0.05), lymph node metastasis rates 64.3% and 84.9% (p < 0.001); operative mortality rates 0.6% and 2.5%; intrathoracic leak rates 1.8% and 4.0%, respectively. The causes of failure were: local uncontrol and recurrence 38.6% vs. 51.7% (p < 0.025), regional lymph node metastasis 38.6% vs. 54.6% (p < 0.005), distant metastasis 24.3% vs. 24.7%. CONCLUSION: Preoperative radiation therapy is able to improve the results of surgery for adenocarcinoma of the gastric cardia.

An immunohistochemical study of TNF-alpha in optic nerves from AIDS patients.

PURPOSE: Both in vitro and in vivo studies have implicated a role for tumor necrosis factor (TNF-alpha) in the pathology of demyelinating diseases. The purpose of this study was to address the hypothesis that TNF-alpha is a mediator of AIDS-related optic nerve injury and to determine the cell types involved in the proliferation of TNF-alpha in the AIDS optic nerve. METHODS: Ten optic nerves from seven patients with AIDS, and three from persons who were HIV negative were stained, using the indirect immunoperoxidase method. Six of the ten AIDS optic nerves were positive for cytomegalovirus (CMV), but the remainder did not have abnormal fundus findings. RESULTS: In all the optic nerves from AIDS patients with or without CMV retinitis, the vast majority of astrocytes stained strongly for TNF-alpha. Microglial cells (MPS-derived macrophages) varied from not staining to staining strongly positive for TNF-alpha. However, oligodendrocytes were not labeled positively for TNF-alpha. Some endothelial cells also stained for TNF-alpha. Examination of normal optic nerves and controls did not reveal any cell type that stained positively for TNF-alpha. CONCLUSIONS: The present study supports the contention that TNF-alpha is a major mediator of AIDS-associated optic neuropathy. HIV infection induces the production of TNF-alpha in macrophages and astrocytes, which probably causes demyelination and other neuronal damage.

Pattern of axonal loss in longstanding papilledema due to idiopathic intracranial hypertension.

There is both clinical and histopathologic evidence for peripheral visual field loss and optic nerve degeneration in longstanding papilledema due to idiopathic intracranial hypertension (IIH). The purpose of this study was to look at the extent and distribution of axonal dropout in secondary optic atrophy due to IIH. Both optic nerves from a 29-year-old man with a two year history of IIH were examined histologically and morphometrically. A high-contrast lipid (myelin) stain, paraphenylenediamine (PPD), and a semiautomated image analysis system were employed to resolve sufficiently the optic nerve fiber images for counts and for measurement. There were 80% and 90% losses of axons, respectively, in the right and left optic nerves consequent to IIH. The axonal loss in the peripheral area of each optic nerve was much more severe than that in inner sectors (= 0.001 for the right optic nerve and = 0.005 for the left). This pattern of axonal dropout is consistent with the preservation of good central visual acuity despite devastating optic nerve atrophy, and with the severe peripheral visual field loss noted in this patient.

[Compensation and adaptation to hypoxia in clinical hypoxyradiotherapy].

During the whole course of clinical hypoxyradiotherapy, patients may experience with 25-35 sessions of the sustained hypoxic disciplines. It is quite possible for them to develop some compensation or adaptation to hypoxia. In the present study, analysis of parameters, derived from both hypoxic oxygen tolerance tests before and after the course, showed the evidence of the compensatory mechanism to transient systemic hypoxia induced by breathing hypoxic gas. The conclusion may be different from what is generally believed. Its physiologic basis, development and clinical tactics for counteraction were investigated.

Preliminary experience in HDR brachytherapy for 72 nasopharyngeal carcinoma patients.

From April 1989 to July 1991, 72 patients with residual or recurrent nasopharyngeal carcinoma (NPC) were treated by MSH Ir-192 brachytherapy or combined external radiation therapy. All were proven histologically. 39 patients with residual disease and 6 with recurrent lesion at the primary site were identified after one or more courses of radical external radiation. Eleven patients had received brachytherapy for boost therapy after one or more courses of external radiation. Sixteen were treated with a planned protocol of external irradiation combined with intracavitary brachytherapy. The overall local control rate was 93.3%; the local control rate for residual and recurrent disease was 100% and 50%, respectively. Soft palate perforation was observed in 3 patients. Brachytherapy is believed to be a useful treatment for residual or recurrent NPC following radical external radiation.

Non-cancerous ulcer in the esophagus after radiotherapy for esophageal carcinoma--a report of 27 patients.

Twenty-seven patients with non-cancerous ulcers (NCU) (radiation ulcer) after radiotherapy for esophageal carcinoma are presented. Two-thirds of them had been misdiagnosed as uncontrolled or recurrent cancers, leading to improper management. Patients with NCU in the esophagus are characterized by having severe pain in the chest or back, especially on swallowing. On X-ray films, the lesions appear as superficial ulcerations with a line of demarcation above and below the ulcer margin. The wall opposite the ulcer is not usually involved and the ulcer infrequently invades the nearby organs. On conservative treatment, they usually heal and the symptoms are relieved. Seven out of 27 patients have survived from 20 months to 13 years without any evidence of disease.

Management of local residual primary lesion of nasopharyngeal carcinoma: II. Results of prospective randomized trial on booster dose.

Although the question of booster dose for residual primary lesion arises in only 5% of nasopharyngeal carcinoma patients receiving radiotherapy, it poses a difficult problem for clinicians and should be followed. Hence, to test the validity of booster dose for residual primary lesion of nasopharyngeal carcinoma, a prospective randomized trial has been designed and carried out since January 1980. All patients who had a residual lesion in the nasopharynx at 70 Gy were biopsied. Those pathologically positive for cancer were randomized into two groups: (a) positive radiation group (PRG): patients were given further irradiation to a total dose of 90 Gy by the cone-down and assault technique, and (b) positive observation group (POG): patients were given no more irradiation but were followed periodically together with those who were pathology negative (NOG). A total of 78 patients were entered. The validity of booster dose was shown by the 5-year survival rates of the PRG, POG and NOG groups: 75% (3/4), 33% (1/3), and 58% (14/24), respectively. The total local recurrence rates of these groups were 6% (1/16), 36% (5/14), and 4% (2/48), respectively. The authors believe that booster dose for pathology positive residual lesion in the nasopharynx is necessary. The four factors leading to the development of a local recurrence are: (a) residual primary lesion proved positive by pathology but left unboosted, (b) well differentiated squamous cell carcinoma in the original primary lesion, (c) mild radio-response in the cancer parenchyma, and (d) mild radio-response in the interstitial tissue.

In situ benign growth after radical radiation therapy of head and neck cancers--report of eight patients.

Eight patients who developed benign growth at the primary site after radical radiotherapy of head and neck cancers (two laryngeal cancers, six nasopharyngeal carcinoma, NPC) are reported. Most of the lesions appeared as spheral or nodular growth with few symptoms. All were properly diagnosed and treated, but two of them had been wrongly diagnosed and treated as local malignant recurrence. The authors point out that repeated biopsies, before treatment, are very important for differentiating a malignant recurrence from a benign growth. Conservative treatment can cure these lesions.

Management of local residual primary lesion of nasopharyngeal carcinoma (NPC): are higher doses beneficial?

One hundred and eighty-two nasopharyngeal carcinoma (NPC) patients, treated from March 1958 through 1978, received 70 Gy or more and were left with gross residual lesion in the nasopharynx, were retrospectively analyzed. Ninety-two patients were given a boost by reduced portals to a total of 90-120 Gy (boost group) whereas for the other non-randomized 90 patients, the treatment was stopped at 70 Gy (observation group). The local recurrence, distant metastasis and 5-year survival rates of the two groups are: 35% (32/92) vs. 58% (52/90), 20% (18/92) vs. 43% (39/90), and 54% (50/92) vs. 21% (19/90), respectively. The benefit of boost is more apparent in patients with T1-2 than T3-4 lesions (p less than 0.001), at increased risk of radiation encephalo-myelitis from 5.5% to 17%. The authors believe that boost be given to patients with early Stage T or small residual lesion at the primary site of NPC.

Curative radiotherapy of early operable non-small cell lung cancer.

The results of 44 patients with early operable non-small cell lung cancer treated from January 1975 through 1981 are retrospectively analysed. All were proven by pathology and/or cytology and denied surgery in our joint Chest Clinic for various reasons. 55-70 Gy/6-7 weeks was delivered by conventional fractionation through A-P portals by telecobalt and/or 25-35 MeV high energy electron beam or 8 MV X-ray. 40 Gy/4 weeks was given prophylactically to the mediastinum. The 1-, 3-, and 5-year survival rates, 93, 55, and 32%, are superior to what is reported in the literature. In the present series, the favorable factors are: (1) patients without any intercurrent disease but refused operation; (2) T1 lesions; (3) complete regression of the lesion at the conclusion of radiotherapy; (4) doses ranging from 69 to 70 Gy. It is shown that early non-small cell lung cancer can be cured by radiotherapy alone giving survival rates comparable to surgery. Prospective randomized clinical trials are warranted.

Chinese herb "destagnation" series I: Combination of radiation with destagnation in the treatment of nasopharyngeal carcinoma (NPC): a prospective randomized trial on 188 cases.

The results of a prospective randomized trial on 188 patients with NPC is reported to evaluate the validity of Chinese herbal medicine-Destagnation combined with radiotherapy. Ninety patients were allotted to the Destagnation group (radiation plus Destagnation) and 98, to the control group (radiation only). The 5-year success rate (number surviving minus number recurred but salvaged by re-treatment) of the Destagnation group is 53% (48/90) in comparison to 37% (36/98) of the control group (p less than 0.05). Minor complications of Destagnation included occasional anorexia and frequency of bowel movement. The reduced rate of local recurrence at the primary site in the Destagnation group (14%-13/90) as compared to that of the control group (29%-28/98) (p less than 0.05) suggests that Destagnation may be a radiosensitizer. The similar metastatic rates in both groups; 21% (19/90) in the Destagnation group and 21% (21/98) in the control group may refute the belief that Destagnation enhances hematogenous spread.

Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of esophageal carcinoma: report on 206 patients.

From June 1977 to May 1985, a prospective randomized clinical trial on pre-operative radiation for esophageal carcinoma was carried out in 206 patients. Lesions under 8 cm in length and patients younger than 65 years, at least on semi-liquid diet and not contra-indicated for surgery were randomized into a combined group (104 patients) or a surgery alone group (102 patients). Eight MV X ray units were used for the pre-operative radiation using A-P portals to deliver 4,000 cGy to the whole mediastinum and the left gastroepiploic lymphatic chain. Surgery was carried out after 2 to 4 week's rest. The immediate results of the combined group and the surgery alone group were: resection rate 93% and 85%, operative mortality 5% and 6%, intra-thoracic anastomotic leak 0% and 1%, positive pathology at the esophageal stump 0% and 2%, and lymph nodes metastasis 27% and 35% respectively. The 5-year survival rates of the combined group and the surgery alone group were 35% and 30%. We have noticed that those patients with lesions showing radiation reaction of grade III gave a 5-year survival of 50% (12/24). Because intra- and extra-thoracic lymphnode metastasis caused failures (41% and 34% of these two groups), increasing the preoperative tumor dose to 60 Gy or designing post-operative irradiation to cover the bilateral supraclavicular areas was necessary. The whole mediastinum and the left gastroepiploic lymphatics could further improve the results of surgery. Further studies are needed.

Establishment, characteristics, and utilization of a new in vivo-in vitro system.

Radiotherapy and chemotherapy are two important methods for malignant tumor treatment. To research radiobiological response in therapy, we have established a better experimental method in contrast to the traditional ones such as TCD50, regrowth delay, cell survival curve, etc, all with their limitations. A new mouse tumor in vivo-in vitro system LA795 Vv-Vt has been developed for studies on radiobiology. Such a system could be used to study the in vivo response of a solid tumor by the in vitro cloning assay. For the purpose of increasing the PE in vitro, LA795 Vv-Vt tumor line was purified through culturing the cells as a clonogenic spheroid. The spheroids were then injected into the flank of mouse subcutaneously for tumor growth. The in vivo-in vitro system LA795 Vv-Vt is an excellent model dissecting and analyzing the various factors which affect tumor development and determine the response of tumor to specific agent and regimens.

Long-term survival of 1035 cases of nasopharyngeal carcinoma.

Long-term results of 1035 previously untreated patients with nasopharyngeal carcinoma seen at Cancer Hospital, Chinese Academy of Medical Sciences, between March 14, 1958 and March 15, 1968 are presented. Of the 1035 patients, 715 were treated with radiation therapy; 281 patients did not receive radiation therapy; and 39 patients whose records were lost. The patients were further subdivided according to the dose of radiation therapy (greater than 4000 rad versus less than 4000 rad), the presence or absence of pathologic confirmation of diagnosis, whether or not follow-up was complete, and whether or not distant metastases developed during treatment. All patients are included in the analysis. The 5-year and 10-year absolute survival rates for the entire group of 1035 patients are 19.6% and 14.5%, respectively. The 5-year and 10-year relative survival rates for the 715 patients who received radiation therapy are 28.4% and 21.0%, respectively. The 5-year and 10-year relative survival rates of the 464 with a pathologically confirmed diagnosis, who were without evidence of distant metastases and who received at least 4000 rad were 34.7% and 25.4%, respectively. Details regarding our statistical methods as well as an exact breakdown of the patient population are presented.

[Radiotherapy of nasopharyngeal carcinoma--analysis of 1379 patients].

This paper presents 1379 patients with nasopharyngeal carcinoma treated in our hospital from March 1958 to December 1978. The stage I and II lesions comprised 22% and stage III and IV lesions, 78%. 220 KV X-ray was used before 1960 and 60Co was predominant from 1961 through 1978. The overall 5 year survival rate was 41.4% (571/1379). Young adults and female patients gave better results. The 5 year survival rate was, according to pathological type, 45.1% for poorly differentiated squamous cell carcinoma and 13% for adenocarcinoma; according to clinical stage, 85.7% for stage I lesion, 59.5% for stage II, 45.8% and 29.2% for stages III and IV; according to period of treatment, 31.3% in the sixties and 48.6% in the seventies; according to tumor dose at the primary focus, 48.2% for 40-49 Gy, 55.6% for 60-69 Gy and 67.3% for 90 Gy or more; according to with or without prophylactic radiation in the neck region, 53.8% for the former and 23% for the latter. It implies that prophylactic radiation of the neck is necessary regardless of the presence of cervical lymph node metastasis or not. For those who had residual tumor at 70 Gy, the total dose may be boosted to more than 90 Gy with the cone down technic or the dose, at which the primary lesion disappears grossly, is added with 20 Gy. The common complications are radiation myelitis, trismus and otitis media. As in certain patients, the lesion would still recur 5 years after radiotherapy, the authors believe that the nasopharyngeal cancer patients should be followed for ten years at least.