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PubMed2026

Oncogenic Mutations and Tumor Microenvironment Alterations in Diffuse Large B-Cell Lymphoma With Bulky Disease.

BACKGROUND: Bulky disease represents a clinically aggressive subset of diffuse large B-cell lymphoma (DLBCL) associated with adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on bulky disease in DLBCL. METHODS: We analyzed a cohort of 939 patients with newly diagnosed DLBCL. Using DNA (n = 934) and RNA (n = 524) sequencing, we compared oncogenic mutations and tumor microenvironment (TME) alterations based on tumor diameter, with cutoff values at 5.0 cm and 10.0 cm. Further stratification by mutations in key genes (CD58, STAT6, EBF1) correlated with tumor diameter revealed distinct transcriptomic and immunologic profiles. Subsequent single-cell RNA sequencing, guided by these mutational signatures, resolved the cellular heterogeneity within the TME. RESULTS: Integrative analysis revealed that tumor diameter correlated with increased incidence of mutations in CD58, STAT6, and EBF1; adverse genetic subtypes such as EZB-like MYC+ and TP53Mut; activation of oncogenic pathways (JAK/STAT, BCR, PI3K, and MYC); and an immunosuppressive tumor microenvironment. Notably, immune checkpoint molecules varied across the bulky stages, with CTLA-4, TIGIT, ICOS, and CD28 expression inversely correlated with tumor diameter, while CD70 and 4-1BBL expression positively correlated. Single-cell RNA sequencing further revealed mutation-specific tumor microenvironment insights. CD58-mutated tumor exhibited a profoundly immune-deserted microenvironment dominated by malignant B cells with minimal immune infiltration, whereas STAT6-mutated tumor was associated with increased fibroblasts and CD4 + T cells, particularly regulatory T cells (Treg) and Th1-like cells; EBF1-mutated tumor was characterized by increased proportions of malignant B cells. CONCLUSIONS: Collectively, our findings highlight the biological complexity of bulky disease, identifying candidate molecular targets and providing a biological framework for future therapeutic hypothesis generation in this clinically aggressive subset of DLBCL.

Humans↗

PubMed1978

A review of the role of radiation therapy in the treatment of non-hodgkin lymphomas.

Until recently, non-Hodgkin lymphoma has been difficult to understand. This was due to a lack of appreciation for histologic types, their sub-classifications, modes of spread, and sites of recurrence.The treatment of choice for stage I-II disease is radiation therapy. The value of irradiating adjacent uninvolved node areas or the more extensive Hodgkin-type mantle or inverted "Y" fields is uncertain.Most patients already have reached stage III or IV when first seen. Stage III cases should be treated by a combination of radiation therapy and chemotherapy. There are protocol studies evaluating the role of chemotherapy alone in stage III disease. The primary treatment of stage IV disease probably should be chemotherapy followed by radiation therapy to involved areas or to residual bulky disease.

Dose-Response Relationship, Radiation↗

PubMed1976

Eight-drug combination chemotherapy (MOPP and ABDV) and local radiotherapy for advanced Hodgkin's Disease.

Thirty-seven patients with advanced Hodgkin's disease have been treated for greater than or equal to 3 months with a protocol consisting of alternate monthly courses of MOPP (mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone) and ABDV (adriamycin, bleomycin, DTIC, and vinblastine) with local radiotherapy (RT) to areas of originally bulky disease. This therapy produced CR in 19 of 19 previously untreated patients (100%), eight of nine previously treated with RT (89%), and six of nine previously treated with RT and MOPP (67%). The remaining patients are all PRs tending toward CR status. The median time to CR was 3.0 months. The median time in remission to date for the previously untreated patients is 8+ months (2+-14+). After an induction period of eight cycles of chemotherapy patients are maintained on alternate-month treatment continuing the alternating sequence. During this phase three patients have experienced reappearance of disease (one recurrence, one possible second primary lymphoma, and one recurrence in a patient whose original diagnosis is in doubt). The regimen has been well tolerated. All patients were treated as outpatients. Alopecia and neurotoxicity were mild and myelosuppression was moderate. Clinically significant cardiopulmonary toxicity has been limited to mild radiation pneumonitis in one patient and bleomycin pneumonitis which cleared during prednisone in a second patient.

Adolescent↗

PubMedDate not supplied

Chemotherapy for testicular cancer: current status of the National Cancer Institute Combined Modality Trial.

Twenty-five previously untreated patients with advanced testicular carcinoma were treated with a five-drug combination chemotherapy program containing cis-dichlorodiammineplatinum(II). This drug regimen was used as part of a trial testing the efficacy of cytoreductive surgery (15 patients) and in ten additional patients not eligible for the combined modality study. Eleven of 25 (44%) patients had a complete response and 11 of 25 (44%) patients had a partial response. Nine of 11 (82%) patients with minimal tumor burden upon initiation of chemotherapy had a complete response. With a median followup of 12+ months, none have relapsed. Complete remissions in patients with very advanced bulky disease were rare (two of 14 [14%] patients) and of short duration, with both patients relapsing. In addition to the usual hematologic toxicity, 14 of 25 (56%) patients developed hypomagnesemia and five of 25 (20%) patients developed systemic reactions to cis-dichlorodiammineplatinum(II) which prevented further drug administration.

Adolescent↗

PubMed1979

Normal anatomy and limitations in CT interpretation of lymph node disease.

The CT appearance of normal retroperitoneal lymph nodes has been described. In many instances the structures are too small to be identified. other retroperitoneal structures, such as collapsed bowel loops, vessels, and other perirenal structures, may simulate the presence of nodes. CT is of great benefit in disease with bulky tumors, such as non-Hodgkin's lymphoma, testicular tumors, etc. Its usefulness is much more limited in disease that may have extensive nodal involvement but no significant enlargement of the nodes. The accuracy of CT scanning in Hodgkin's disease and in many instances of genitourinary tumors is questioned, and we submit that further studies are needed to establish the reliability of this mode of examination.

Adult↗

PubMed1979

Chemotherapy of advanced non-Hodgkin's lymphoma.

From the therapuetic point of view, non-Hodgkin's lymphomas can be classified into two groups: favourable prognosis histology (DWDL, NWDL, NPDL, and NM) and unfavourable prognosis histology (DPDL, DM, DH, NH, DU). The latter group also includes lymphoblastic lymphoma (T cell) and Burkitt's lymphoma (B cell). Further classification by immunological markers (T, B, monocyte, null cell) and functional categories (T-cell subsets) may reveal prognostic groups which require separate consideration. Intensive chemotherapy of unfavourable histoligies can result in long-term disease-free survival as reported in several series. It would appear that the 10 year survival rates will not differ greatly between several multi-drug regimens. At the present time, the histopathological subtype permits selection of patients for a trial of intensive chemotherapy. The progress in the future will be made with improved techniques for the management of bulky abdominal disease and central nervous system invasion. Although the above may result in some statistical improvement in survival of the unfavourable group, the vast majority of patients with favourable histology lymphoma require new approaches. These may take the form of treatment with immunological manoeuvres such as idiotypic-specific antibodies and/or the use of intensive chemotherapy, especially when there is convincing evidence of a change in the biology of the disease.

Drug Therapy, Combination↗

PubMed1979

Non-Hodgkin's lymphoma in children: a progress report on the original patients treated with the LSA2-L2 protocol.

This report is a follow-up of the initial group of 39 children with non-Hodgkin's lymphoma treated with the LSA2-L2 protocol as previously reported in Cancer (37:123--134, 1976). The disease-free actuarial survival is 73%. All surviving patients are off therapy and have shown no evidence of recurrence with a median observation time of 70+ months. Their survival times range from 56+ to 88+ months from diagnosis. An analysis of successes and failures is discussed and modifications in the role of radiation therapy and surgery in the multidisciplinary management of children with non-Hodgkin's lymphoma are advocated. The results in the present series indicate that the LSA2-L2 protocol has substantially improved the prognosis for children with non-Hodgkin's lymphoma. We have concluded that age, sex, primary site (perhaps with the exception of primary skeletal), and histology are not of prognostic significance. The amount of bulky widespread disease at initial presentation, early and aggressive therapy, and the achievement of a complete remission status within 1--2 months from onset of therapy are the most important prognostic factors.

Abdominal Neoplasms↗

PubMed1977

Malignant tumors of the testis: analysis of treatment results and sites and causes of failure.

A total of 150 patients with germinal testicular neoplasms treated at the University of California, San Francisco, were reviewed. The 5-year actuarial survival rate was 95% for 57 patients with seminoma and 56% for 75 patients with carcinoma. Treatment modalities were compared with respect to sites and causes of failure and complications. The most common sites of failure in the carcinoma patients were lung, and supraclavicular or mediastinal lymph nodes. Scrotal orchiectomy, elevated gonadotropins, elements of choriocarcinoma, and bulky abdominal disease were all correlated with high treatment failure rate.

Carcinoma↗

PubMed1975

Testicular tumours.

With modern methods of diagnosis, staging and treatment, seminoma is a highly curable tumour. The worse results for the treatment of teratomas are likely to improve particularly as methods for detection of the tumour improve and as types of treatment are increasingly combined in a way which takes account of the biology of the tumour and the strength and limitation of each treatment modality. Stage I and II teratoma should receive irradiation after orchidectomy although when bulky retroperitoneal disease is present irradiation alone is rarely capable of securing local tumour control. In these cases chemotherapy may achieve nodal regression preparatory to irradiation. Excision of residual masses after irradiation should be considered in teratoma. Chemotherapy is the treatment of choice for disseminated teratoma but maintaining tumour control poses problems. Whole lung irradiation following chemotherapy is being assessed in selected patients.

Adult↗

PubMed1979

cis-Platinum combination chemotherapy of bladder cancer: an update.

The combination of cis-platinum (DDP), adriamycin, and 5-fluorouracil was evaluated in 44 patients with advanced urothelial cancer, 39 of whom were evaluable for response. There were 18 partial remissions (46.2%) and no complete responses. Remissions were clinically meaningful, but of short duration. Four patients had bulky pelvic disease that was made resectable by chemotherapy, but none of these patients remained disease-free. These results are not superior to that expected from DDP as a single agent. In addition, there appears to be little or no survival benefit associated with chemotherapy. DDP represents an advance in the treatment of bladder cancer, but additional active agents and innovative approaches are needed.

Adult↗

PubMed1979

Ultrasound evaluation of American Burkitt's lymphoma.

Burkitt's lymphoma is a childhood disease that characteristically produces large, bulky abdominal tumors. Although these are potentially curable, chemotherapy can produce rapid tumor lysis, with subsequent life-threatening metabolic abnormalities, especially in those patients with large tumors or those who have compromised renal function. Twenty-two patients with proven Burkitt's lymphoma were evaluated by ultrasound. Thirteen patients had abdominal masses. These masses tended to be large, solitary, and acoustically homogeneous. Although most of these tumors were found in the pelvis, upper abdominal and retroperitoneal tumors were also encountered. None of the patients had the typical paravertebral mantle of enlarged nodes seen in other types of lymphoma. In 11 patients with abnormal intravenous pyelograms, ultrasound successfully distinguished between renal lymphoma, hydronephrosis, and, by exclusion, metabolic renal disease. The absence of lymph node disease and the presence of bulky homogeneous extranodal tumor are characteristic ultrasound findings in Burkitt's lymphoma. By locating and quantifying tumor mass and distinguishing between renal lymphoma and hydronephrosis, ultrasound proved to be clinically useful in the management of this disease.

Abdominal Neoplasms↗

PubMed1979

Combined management of malignant teratoma of the testis.

Intensive chemotherapy with bleomycin and vinblastine was used as initial treatment in patients with advanced testicular teratoma and after relapse following lymph-node irradiation in patients with early-stage disease. Between January, 1976, and March, 1978, 84 patients, 28 with early disease and 56 with advanced disease, were treated. All 28 men with early-stage disease are alive and disease-free. Patients with advanced disease were divided into two groups. Patients with bulky multiple lung metastases and those with liver involvement did poorly, only 4 of 23 (17.4%) being disease-free. Conversely, patients with bulky abdominal nodes and those with limited lung disease did well, 17 of 21 previously untreated patients (80.9%) being alive and disease-free. Within the latter group, 16 patients were managed with chemotherapy and radiotherapy and/or surgery. Of these, 15 (93.4%) are disease-free.

Abdominal Neoplasms↗

PubMed1976

Locally recurrent carcinoma of the breast. Results of radiation therapy.

Local and regional recurrences are frequent problems in breast cancer management. Radiation therapy is effective in producing long term remission. This study evaluates the results of radiation therapy of 215 patients with recurrent disease limited to the chest wall and/or regional lymph node areas. The local results showed complete control in 67% of cases (mean and median durations 32 months and 22 months, respectively), partial control in 24% of cases (mean and median 11 and 8 months, respectively) and no control in the remaining 9%. The radiation dose recommended for the treatment of recurrent mammary carcinoma is 5000 rads in 5 weeks for relatively small lesions. Supplementary local doses of 500-1000 rads in 1 week may be given to bulky lesions as necessary for residual disease. Although local relapse indicates a poor prognosis, it is by no means totally hopeless. Of 215 patients treated 44 (21%) survived 5 years and 10 (5%) survived 10 years following radiation therapy of recurrent disease. There were seven patients, or 3%, who were free of cancer at 5 to 15 years. Radiation therapy was valuable in controlling local lesions, and thus, in improving quality of survival, even in those patients who eventually died of metastatic disease.

Breast Neoplasms↗

PubMed1976

Radiographic distribution of intrathoracic disease in previously untreated patients with Hodgkin's disease and non-Hodgkin's lymphoma.

An analysis was made of the incidence of various intrathoracic abnormalities noted on plain chest radiographs and tomograms in a consecutive series of 300 patients with untreated Hodgkin's disease and nonHodgkin's lymphoma. Those with Hodgkin's disease have a higher incidence of intrathoracic disease at presentation than those with non-Hodgkin's lymphoma (67% vs. 43%). Bulky superior mediastinal lymphadenopathy is the hallmark of Hodgkin's disease. Lung involvement was more common in Hodgkin's disease (11.6% vs. 3.7%) and was always accompanied by mediastinal and/or hilar lymphadenopathy.

Bone Neoplasms↗

PubMed1977

[Histomorphometric studies on the influence of long-term calcitonin therapy on osteodystrophia deformans Paget].

Bone alterations in Paget's disease, have been studied by histomorphometrical evaluation iliac creat bone biopsies before and after long-term treatment with human ans salmon calcitonin. Therapeutic effect was controlled from 12, up to 48 months. All-together 28 bone biopsies were taken from 9 patients (aged 46 to 71 years) with Paget's disease of their os ileum. The biopsies were prepared for histological examination without previous decalcification, cut, stained and quantitatively analysed at the light microscopic level. By means of a point counting method we determined the parameters of bone structure, bone formation and bone resorption. Before therapy was started, trabecular bone alterations could be observed which were typical for Paget's disease of bone as there were bulky trabeculare, increased remodelling surfaces and giant osteoclasts. Following treatment with calcitonin a dramatic reduction of bone remodelling surfaces and a normalization of bone structure occurs. Considering our previous electon microscopy findings, a reduction of the number of osteoclasts as well as their nuclear content, might be explained by an inhibitory effect of calcitonin on cell fusion of osteoclastic precursor cells. In 2 cases, an interruption or hormonal treatment of 5 to 12 months, presented no risk of losing the therapeutic effect.

Aged↗

PubMed1977

Hyperbaric oxygen as a radiotherapeutic adjuvant in advanced cancer of the uterine cervix: preliminary results of a randomized trial.

From September 1968 to March 1974, a randomized clinical trial was carried out, using conventional fractionation, i.e., five treatments per week, in 233 patients with advanced cancers of the uterine cervix--Stages IIB, IIA, IIIB and IVA. The age limit was 70 years and all patients had medical clearance. Lymphangiography and, in some patients, an exploratory laparotomy with selective lymphadenectomy, were done prior to treatment to determine the extent of nodal disease. The staging has not been changed either by lymphangiogram or lymphadenectomy findings. A few patients with bulky Stage I and IIA lesions were entered into the trial because of extensive nodal disease demonstrated either by lymphangiogram and/or lymphadenectomy. First, the patients were grouped according to the clinical stage. The secondary stratification was according to the lymphangiogram and/or selective lymphadenectomy findings. The patients were then randomized to air or hyperbaric oxygen within each group. The patients were pressurized in a Vickers chamber at 3 atmosphere absolute, using a 20-minute soak time prior to the irradition. The size of the external beam portal was determined by the status of the nodes. The difference in absolute NED (no evidence of disease) survival rates for both groups as a whole and by stages is not statistically significant. There is no difference in the incidence of failures in the irradiated area between the HPO and air patients. There is no increase in distant metastases in the HP group. It does not seem that the HPO has had an effect on the major complications. However, there was an increase in the incidence of complications with extended fields. The addition of lymphadenectomy had increased the incidence of fatal complications, even with routine pelvic portals. The negative results of this trial with conventional fractioantion should not lead to the conclusion that HPO could not be useful with schemes using a few high dose fractions.

Adult↗

PubMed1978

Condyloma. A new epidemic.

Condyloma acuminatum of the anus is an increasingly frequent disease that may require a combination of therapies. Large bulky lesions can be reduced with topical freezing, cautery, or the scapel. Topical chemotherapy with podophyllum resin can be supplemented with cancer chemotherapeutic agents. Many of these drugs probably act, at least in part, by stimulating a strong local cellular immune reaction. Dinitrochlorobenzene was used to eradicate lesions that had been resistant to treatment with podophyllum resin. 5-Flourouracil was used as a control. All 23 patients studied were initially skin tested with both agents and randomized to either treatment group. All but one of the dinitrochlorobenzene-treated patients had excellent regressions. Immunotherapeutic agents, such as dinitrochlorobenzene, warrant further study as adjuvant therapeutic agents for this disease.

Antineoplastic Agents↗

PubMed1976

Re-exploration for retroperitoneal lymph node metastases from testis tumors.

Prognosis has been poor for patients with retroperitoneal metastases from non-seminomatous testis tumors that are initially unresectable and persist after chemotherapy and irradiation or those that recur after initial lymphadenectomy. Eleven such patients have had re-explorations at our center and are described herein. In 4 patients only histologically benign teratoma and/or fibrosis was found. Therefore, the presence of a retroperitoneal mass in these circumstances does not necessarily mean that malignant tissue was present. The procedure provided an accurate diagnosis in all patients and permitted the elimination or reduction of subsequent chemotherapy or radiation in 4 patients who had no tumor. In addition, 5 of 7 patients with symptoms caused by bulky masses were improved and 3 patients with unresectable disease had radiopaque markers placed to facilitate subsequent radiotherapy. The operation was often difficult because of retroperitoneal adhesions from previous treatment but there was no significant morbidity and no mortality. Nine patients have survived from 6 months to 4 years and 7 have no evidence of disease. Two patients died of recurrent tumor 2 and 9 months after re-exploration. A good prognosis was indicated if the mass found at re-exploration was completely resectable and contained only histologically benign teratoma and/or fibrous tissue. We believe that re-exploration should be considered for selected patients with testis tumors who have 1) a retroperitoneal mass that appears after initial lymphadenectomy and persists after interval chemotherapy or radiation therapy and 2) retroperitoneal metastases that are initially unresectable and persist after subsequent chemotherapy or radiation therapy.

Adult↗