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PubMed2026

A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death.

Developing cancer therapies that induce specific death of malignant cells is critical for preventing relapse. Highly effective strategies, such as immunotherapy, exemplify this principle. Here, we provide the mechanistic basis for a small-molecule approach that leverages chemically induced proximity (CIP) to kill diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma. We developed lysine acetyltransferase (KAT)-based TCIPs (transcriptional/epigenetic chemical inducers of proximity), or KAT-TCIPs, which redirect p300/CREB-binding protein (CBP) to activate cell-death networks repressed by the oncogenic driver BCL6. Our lead KAT-TCIP reprograms the epigenome to initiate apoptosis. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance protein-protein interactions may be exploited to confer the potency and selectivity of KAT-TCIPs. Thus, oncogenic drivers can be co-opted to activate robust cell death. Consistent with their gain-of-function mechanism, TCIPs recruiting different transcriptional activators-p300, BRD4, or CDK9-produce distinct genomic responses, suggesting specialized therapeutic uses.

Humans↗
PubMed2026

Cell-free DNA genomic and fragmentomic features for early outcome prediction in large B cell lymphoma.

Curative-intent immunochemotherapy fails in ∼30% of patients with large B cell lymphoma (LBCL), yet no validated molecular tool enables early identification of high-risk individuals to guide treatment intensification. Using shallow whole-genome sequencing (sWGS) of plasma cell-free DNA from 190 LBCL patients, we develop and validate the ACT score (aberrations, composition of fragments, and terminal motif analyses), a composite classifier integrating genomic and fragmentomic features from a single post-cycle-1 sample. ACT-positive patients have worse 2-year outcomes versus ACT-negative patients: time-to-progression 29% vs. 83% (hazard ratio [HR]: 4.4, 95% confidence interval [CI]: 1.9-10.0; p = 1.5 × 10-4) and overall survival 47% vs. 93% (HR: 8.7, 95% CI: 3.0-25.4; p = 1.8 × 10-6). The ACT score is independently prognostic of the International Prognostic Index, and their combination identifies the highest risk patients. Unlike mutation-based approaches, this assay requires neither tumor tissue, germline control, nor a baseline plasma sample. Built on open-source tools and sWGS, the ACT score offers a feasible, scalable strategy for early risk stratification in aggressive LBCL.

Humans↗
PubMed1975

Advanced diffuse histiocytic lymphoma, a potentially curable disease.

Twenty-seven patients with advanced diffuse histiocytic lymphoma (reticulum-cell sarcoma) were treated with combination chemotherapy utilising nitrogen mustard (or cyclophosphamide), procarbazine, vincristine, and prednisone. Elven (41%) achieved a complete remission and only one of these has had a recurrence of tumour. The remaining ten complete responders were free of all evidence of tumour when last seen 26-105 months from the end of treatment. In contrast, all non-responders or partial responders have died. An interpretation of published survival data suggests that this virulent disease evolves quickly and is usally rapidly fatal if treatment is unsuccessful. Survival free of disease beyond 2 years from the end of treatment may be considered tantamount to cure. This definition of cure, previously applied only to patients treated with radiotherapy, seems applicable to patients who acheive complete remissions with modern drug treatment.

Administration, Oral↗
PubMed1975

Increased incidence of malignancy during chronic renal failure.

The incidence of cancer in 646 dialysis/transplant patients before uraemia developed, during the period of progressive uraemia, and post-transplantation was compared. 10 tumours (3 breast, 2 kidney, 1 leukaemia, 1 lung, 1 insulinoma, 1 thyroid, 1 cervix in situ) developed in 9 patients during the period of progressive uraemia, a significant increase over the expected number in the age-matched general population. 6 of these patients have received transplants and have no evidence of recurrent disease 6 months to 4 years post-transplantation. 11 de-novo tumours have developed in 530 transplant recipients (4 cervix in situ, 2 skin, 2 reticulum-cell sarcoma, 1 lip, 1 dysgerminoma, 1 colon)--a significant increase over the age-matched general population. The cancers in the uraemic patients are relatively common types of mesenchymal tumours while the cancers in the transplant recipients are epithelial and lymphoproliferative. This difference may reflect the presence of the graft in the transplant patient or may be due to different patterns of immunosuppression in these two populations.

Adolescent↗
PubMed1975

Chronic antigenic stimulation, herpesvirus infection, and cancer in transplant recipients.

An increased incidence of malignancy has been reported in transplant recipients. The pathogenesis of this increase was originally attributed to immunosuppressive therapy. However, not all tumours are increased in proportion to their occurrence in the general population-75% of reported tumours are lymphorproliferative or carcinoma of the skin, lip, or cervix. This cannot be explained by impaired immunosurveillance, and alternative hypotheses must be considered. 90% of transplant recipients develop clinical or serological evidence of herpesvirus infection. Herpesviruses have been implicated in the pathogenesis of lymphorproliferative tumours and carcinoma of the skin and cervix. They can remain in latent form and be reactivated by allogeneic stimulation and/or immunosuppression. These viruses localise to skin, cervix, and neural tissue-i.e., exactly those sites where cancer develops in transplant patients. Herpesvirus infections in association with the presence of an allogeneic graft in an immunosuppressed patient may be responsible for the increased incidence of both lymphoproliferative tumours and carcinoma of the skin, lip, and cervix in the transplant recipient.

Antibodies, Viral↗
PubMed1976

Pituitary function in patients receiving intermittent cytotoxic and corticosteroid therapy for malignant lymphoma.

Diurnal variation in plasma-cortisol was studied immediately before and after intermittent steroid therapy in seven patients receiving monthly courses of quadruple chemotherapy for Hodgkin's or non-Hodgkins lymphoma over a period of 6 months. The serum-thyroid-stimulating-hormone (T.S.H.) response to intravenous T.S.H.-releasing factor was also measured before and during the first course and before the second and fourth courses. The morning plasma-cortisol concentration fell significantly over 6 months when measured immediately before the start of each course. The mean evening cortisol concentration also fell over this period. In most patients the T.S.H. response showed a downward trend during treatment, although in two patients the response returned to normal whilst they were still undergoing therapy.

Adult↗
PubMed1975

Temperature-dependent rosette formation by mouse lymphoma cells as a result of viral hemadsorption.

Cells from several mouse lymphomas formed rosettes with nonsensitized foreign erythrocytes through C-type virus particles clustered on the cell surface in serum-free medium held at 4 degrees C. This type of rosetting was found most typically in a lymphoma induced by Rauscher leukemia virus in tissue culture (RD-12), but it also occurred in 23 of 61 spontaneous thymic lymphomas in AKR mice. Chemically or X-ray-induced leukemias and spontaneous reticulum cell sarcomas did not form rosettes. The nature of the rosette formation may be interpreted as viral hemadsorption, with a possible relationship to hemagglutination by murine leukemia viruses. The receptor on virus particles was trypsin sensitive and showed high affinity to serum inhibitors (RIF). Serum rosette-inhibiting activity was assessed by a quantitative rosette inhibition test; rosette inhibition proved widely distributed among species. Physicochemical properties of serum RIF and their function both in vivo and in vitro were described. Rosette formation with similar temperature requirements, previously reported in a mouse lymphoma carrying membrane-bound heterophile cold hemagglutinin, was readily distinguished from viral hemadsorption by its insensitivity to mouse serum RIF.

Animals↗
PubMed2026

A Patient-Derived Xenograft Repository Capturing Clinical and Molecular Heterogeneity of Large B-cell Lymphoma.

UNLABELLED: Large B-cell lymphomas (LBCL) are a clinically and molecularly diverse group of malignancies with a rapidly evolving therapeutic landscape that has introduced new areas of clinical need, such as post-CD19 chimeric antigen receptor T (CART19) progression. Patient-derived xenograft (PDX) models are an important tool for mechanistic studies and preclinical evaluation of new therapies and can be generated from a variety of clinical contexts that capture tumor-intrinsic resistance mechanisms. We therefore undertook a comprehensive effort to generate PDX models that encompass the molecular landscape of LBCLs and include important clinical scenarios for new drug development. Here, we describe the first 48 models within this publicly available repository, capturing the transcriptional and genetic subsets of LBCL. These models also include 23 generated from post-CART19 progression patient biopsies, which reproduce patterns of progression driven by CD19 mutation or expression loss, as well as tumor cell-intrinsic CART19 resistance that we validated in vivo. SIGNIFICANCE: Here, we describe X-LYMPH (Xenografts of Lymphoma), a publicly available and molecularly annotated PDX repository that captures the heterogeneity of LBCL. X-LYMPH includes models of CAR T-cell resistance, providing a shared foundation for mechanistic research and therapeutic development for lymphomas. See related commentary by Evgin and Steidl, p. 655.

Humans↗
PubMed1975

Reversible interstitial pneumonitis associated with low dose bleomycin.

A patient with nodular histiocytic lymphoma was treated with bleomycin; she later developed interstitial pneumonitis documented by lung biopsy. The dose of bleomycin producing this complication was lower than previously reported, and the pulmonary toxicity was apparently completely reversible.

Abdominal Neoplasms↗
PubMed1976

Cancer of the undescended or maldescended testis.

An analysis of 45 cryptorchids (by history or examination) with a testicular cancer treated at Memorial Hospital, between 1934 and 1973, is presented. Twenty-five patients had the cryptorchid state repaired at ages four to 27 years, either spontaneously or by orchiopexy or hormonal therapy. Ipsilateral (24) or contralateral (one) intrascrotal testis tumors developed four to 47 years later. Twenty cryptorchid patients presented with ipsilateral inguinal (eleven), abdominal (seven), or contralateral intrascrotal (two) tumors. There were 18 pure seminomas, 17 embryonal carcinomas, nine teratocarcinomas, and one reticulum cell sarcoma. Five year survival rates as estimated by the product-limit method were 60% for the unrepaired cases and 41% for the repaired cases. The survival seems to follow histologic type and anatomical stage, whether the testis is within the scrotum or not. Five year survival similarly estimated was 78% in the seminomas and 29% in the other tumors. Twelve of thirteen survivors (including nine with seminoma) received postoperative irradiation to the regional lymphatics and eleven were without recurrent tumor for periods ranging from six to 28 years.

Adolescent↗
PubMed1979

Immunoblastic lymphadenopathy, systemic lupus erythematosus, and related disorders. Possible pathogenetic pathways.

The authors discuss the hypothesis that the spontaneously developing (angio-) immunoblastic lymphadenopathy of man as well as the various autoantibodies and constitutional symptoms accompanying this disease may be mediated by different reactions of T lymphocytes toward adjacent lymphocytes and macrophages, whose membranes were rendered incompatible by certain viruses or sensitizing drugs such as the antiepileptic compound diphenylhydantoin. This concept is based on two different lines of experimental evidence: (1) results obtained with animal graft-versus-host reactions, in which immunoblastic lymphadenopathy, angiogenesis, dermatitis and multiple autoantibody formation are known to be induced by reactions of parental T lymphocytes toward genetically foreign structures of the major histocompatibility complex; (2) experiments pointing to an essential similarity in T-cell reactions toward genetically foreign major histocompatibility structures on the one hand and self-major histocompatibility structures that were rendered "foreign" by viruses or chemicals on the other hand; (3) recent findings in mice that demonstrate a T-cell-dependent lymphoproliferation after the administration of diphenylhydantoin.

Animals↗
PubMed1975

Radiation therapy of the liver metastatic disease.

Eight patients with symptomatic liver metastasis from different primary tumours received palliative radiation therapy. Daily doses of 150-200 r calculated in the mid-liver plane were delivered. The total dose employed was 2,500 r given in 3 weeks. Six patients responded good, one reasonable and one patient failed to respond to radiation. Liver function tests and liver scans also reflected the treatment response. All eight patients tolerated the treatment and no mortality due to treatment was recorded.

Adenocarcinoma↗
PubMed1975

Lymphocytotoxins and immunologic unresponsiveness.

A 14-year-old boy with a lifelong history of recurrnet infections and debilitating bronchiectasis was found to lack any evidence of humoral or cellular immunity. His serum contained a high titer of IgM antibody to the heavy chain of IgG and this antibody was also cytotoxic for peripheral lymphocytes. Complement-dependent lymphocytotoxicity could be blocked by IgG or Fc fragment. In this patient, immunosuppression may have been due to an autoantibody against both autologous IgG and lymphocyte plasma membrane.

Adolescent↗