Unleashing Natural IL18 Activity Using an Anti-IL18BP Blocker Induces Potent Immune Stimulation and Antitumor Effects.

Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer.

Salivary Gland Secretory Carcinoma; Review of 13 Years World-Wide Experience and Meta-Analysis.

OBJECTIVES: Secretory Carcinoma is a malignant salivary gland tumor, initially described in 2010. This rare tumor is associated with the translocation t(12;15) (p13;q25), resulting in the fusion gene ETV6-NTRK3. Since this tumor is quite rare, most publications describe only small cohorts of patients. We aimed to investigate the clinical, pathological, and prognostic features of this newly defined malignant entity. DATA SOURCES: Pubmed, Google Scholar, and Web of Science databases. REVIEW METHODS: All published articles between 2010 and 2023 were reviewed. Search terms included the terms "Mammary Analogue Secretory Carcinoma" and "Secretory Carcinoma". All articles published in English reporting on Secretory Carcinoma of salivary glands were retrieved. RESULTS: One-hundred and 12 retrospective articles reporting a total of 674 patients were included, with 52% males and a mean age of 44.9 ± 18.9. The event rate for patients with advanced-stage disease (Stage 3/4) at presentation was 24.1% (95% CI 17.6%-31.9%, I2 = 9.2%), 14.6% for regional metastases (95% CI 10.5%-20%, I2 = 12%), and the event rate of distant metastasis was 8.4% (95% CI 5.5%-12.7%, I2 = 4.2%). Adjuvant radiotherapy was administered for 30.3% of patients (95% CI 24.1%-37.2%, I2 = 21.5%). The recurrence rate was 19% (95% CI 15.1%-23.8%, I2 = 5%). Survival outcomes showed a 17.2% death of disease rate for Secretory Carcinoma patients (95% CI 13.5%-21.8%, I2 = 7.3%). CONCLUSIONS: Secretory Carcinoma is a rare and relatively newly defined entity arising in the parotid gland most commonly. Characterized as a low-grade tumor, the majority of patients are diagnosed at an early stage, without regional or distant disease, and the prognosis is relatively good. LEVEL OF EVIDENCE: NA Laryngoscope, 134:1716-1724, 2024.

Tumor Satellites Are Associated With Poor Outcome in Patients With Oral Cancer.

OBJECTIVES: Tumor satellites are defined as islands of tumor cells completely separated from the border of the main tumor. They are believed to be a sign of aggressive disease. Our goal was to investigate the association between tumor satellites and outcome in patients with oral squamous cell carcinoma. MATERIALS AND METHODS: A retrospective analysis of all patients treated for oral squamous cell carcinoma at a university-affiliated tertiary care center between 2010 and 2018 was performed. Data collected included demographics, clinical and pathological features including tumor satellites, staging, treatment modalities, and outcomes. RESULTS: A total of 144 patients were included. The mean age of all patients was 63.5 and 50.7% were males. The mean follow-up time was 40.5 months. Seventeen patients (11.8%) had tumor satellites. These patients had a higher rate of involved margins, peri-neural invasion, lympho-vascular invasion, and extra-nodal extension. Tumor, nodal and overall classification were significantly more advanced in patients with satellites. Disease-specific and overall survival rates were significantly lower among satellites patients (28.7% vs. 59.7% and 28.7% vs. 54.9%, respectively). CONCLUSIONS: Tumor satellites are associated with several adverse features and advanced locoregional disease. Patients with satellites should be treated aggressively with a combination of surgery aimed at achieving free surgical margins and adjuvant treatment, as they have a worse prognosis compared with patients without satellites. Further prospective studies are mandatory to consolidate the importance of adjuvant treatment in these patients. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:336-343, 2023.

Skull base chordomas review of current treatment paradigms.

BACKGROUND: Chordomas are locally invasive neoplasms, arising from notochordal remnants and can appear anywhere along the axial skeleton. Local recurrences are common, and distant metastases may occur years after the initial presentation. METHODS: Literature review of current treatment strategies for chordomas of the skull base. RESULTS: Surgery is the mainstay of treatment and complete resection has paramount importance for prognosis.When complete resection is not achieved recurrent disease is common. The anatomical complexity of the skull base makes resection complex. Endonasal endoscopic approaches to the clivus has become increasingly favored in recent years although addressing reconstruction of the skull base to prevent CSF leak may be challenging.Evidence suggests that radiotherapy should not be considered as a primary single modality when trying to achieve cure of the disease. Nonetheless, immediate post-operative radiotherapy improves survival. Many strategies have been suggested to preserve sensitive vital structures in the skull base during treatment but as for survival there is no evidence of advantage when comparing adjuvant therapy with photon radiotherapy, gamma knife surgery, proton beam therapy, and carbon ion radiation therapy.There is no evidence to support cytotoxic chemotherapy in the treatment of chordomas but targeted therapies have started to show promise. Several optional molecular targets exist. Brachyury is overexpressed in 95% of chordomas but not in other mesenchymal neoplasms. However, its precise role in chordoma pathogenesis is currently unclear, and its cellular location in the nucleus makes it difficult to target. The inhibition of brachyury in chordoma cell lines induces growth arrest and apoptosis. This does not have clinical application to date. There are retrospective results with different molecular targeted therapies for advanced chordomas with some effectiveness. CONCLUSION: Despite improvements made in the past 10 years in our knowledge of chordoma biology, available therapies still offer a limited benefit. There is an unmet need for new therapeutic options for patients with advanced disease. Therefore, patients with advanced disease should be encouraged to participate in clinical trials when and where available.

Multicentre validation of a microRNA-based assay for diagnosing indeterminate thyroid nodules utilising fine needle aspirate smears.

AIMS: The distinction between benign and malignant thyroid nodules has important therapeutic implications. Our objective was to develop an assay that could classify indeterminate thyroid nodules as benign or suspicious, using routinely prepared fine needle aspirate (FNA) cytology smears. METHODS: A training set of 375 FNA smears was used to develop the microRNA-based assay, which was validated using a blinded, multicentre, retrospective cohort of 201 smears. Final diagnosis of the validation samples was determined based on corresponding surgical specimens, reviewed by the contributing institute pathologist and two independent pathologists. Validation samples were from adult patients (≥18 years) with nodule size >0.5 cm, and a final diagnosis confirmed by at least one of the two blinded, independent pathologists. The developed assay, RosettaGX Reveal, differentiates benign from malignant thyroid nodules, using quantitative RT-PCR. RESULTS: Test performance on the 189 samples that passed quality control: negative predictive value: 91% (95% CI 84% to 96%); sensitivity: 85% (CI 74% to 93%); specificity: 72% (CI 63% to 79%). Performance for cases in which all three reviewing pathologists were in agreement regarding the final diagnosis (n=150): negative predictive value: 99% (CI 94% to 100%); sensitivity: 98% (CI 87% to 100%); specificity: 78% (CI 69% to 85%). CONCLUSIONS: A novel assay utilising microRNA expression in cytology smears was developed. The assay distinguishes benign from malignant thyroid nodules using a single FNA stained smear, and does not require fresh tissue or special collection and shipment conditions. This assay offers a valuable tool for the preoperative classification of thyroid samples with indeterminate cytology.

The predictive value of dendritic cells in early squamous cell carcinoma of the tongue.

OBJECTIVES: The aim of this study was to evaluate the relationship between dendritic cell density in early squamous cell carcinoma (SCC) of the tongue and patients' clinical outcome. METHODS: Representative samples of low-risk SCC of the tongue (T1-2,N0,M0) from a homogeneous group of 18 patients following local complete excision and elective selective neck dissection, were immunostained with antibodies against S100 and CD1a. Dendritic cell density was analyzed by outcome. RESULTS: Mean dendritic cell densities were 17 cells/HPF for tumoral S100 and CD1a counts, and 10 cells/HPF for peritumoral S100 and CD1a counts. Better disease-free survival was associated with low peritumoral S100- and CD1a- positive cell counts (p=0.006 and p=0.004, respectively), and with low tumoral S100- and CD1a- positive cell counts (p=0.037 and p=0.04, respectively). Lymphocytic response was decreased in tumors with high dendritic cell density (p=NS). There was no association of dendritic cell density with patient age, tumor size and depth of invasion. CONCLUSIONS: These results may suggest an association between dendritic cell accumulation and functional immunologic impairment.

Distinctive pattern of let-7 family microRNAs in aggressive carcinoma of the oral tongue in young patients.

Oral cavity squamous cell carcinoma may be more aggressive at presentation and recurrence in young patients compared with older patients. Dysregulation of microRNAs (miRNAs or miRs) has been associated with the development and prognosis of oral cavity cancer. The present study investigated miRNA expression in carcinoma of the oral tongue in young patients. miRNA expression profiles were evaluated in formalin-fixed, paraffin-embedded samples of tumor and normal mucosa from 12 patients aged <30 years old with squamous cell carcinoma of the tongue. The levels of let-7f-5p, miR-30b-5p and let-7e-5p were upregulated in tumors (P<0.05). The expression of let-7f-5p was upregulated in non-aggressive tumors, while the expression of let-7e-5p was upregulated in aggressive tumors, compared with the corresponding normal tissue. Aggressive tumors had higher levels of let-7c, miR-130a-3p, miR-361-5p, miR-99a-5p, miR-29c-3p and let-7d-5p than non-aggressive tumors (P<0.05). The findings remained significant for let-7c upon false-discovery rate correction. An excellent correlation was noticed on validation of NanoString counts by quantitative polymerase chain reaction. The comparison with published findings in adults demonstrated a unique miRNA signature in young patients with aggressive disease. Aggressive oral cavity cancer in patients <30 years old is associated with a distinctive expression pattern of the let-7 family. Larger studies including direct comparison with older patients are warranted.

Pediatric Thyroid Cancer: Postoperative Classifications and Response to Initial Therapy as Prognostic Factors.

CONTEXT: Prognostic factors for pediatric differentiated thyroid cancer (DTC) are not well established. OBJECTIVE: The objective of the study was to retrospectively compare the postoperative risk-stratification systems: American Thyroid Association (ATA) risk categories, Schneider Children's Medical Center of Israel (SCMCI) score, and the response to initial therapy as predictors for disease outcome. PATIENTS AND METHODS: Fifty-four DTC patients, median age at diagnosis 13.9 years (range 1.9-17 y), followed up for a median of 8.8 years (range 2.6-20.5 y) were stratified into prepubertal (n = 9), pubertal (n = 25), and postpubertal (n = 20) groups. All patients underwent total/near-total thyroidectomy; 48 received radioiodine therapy. The extent of DTC was evaluated by applying the ATA risk categories and the novel SCMCI score. Postoperative risk stratifications (low/intermediate/high) were determined using histopathological, laboratory, and imaging findings. Response to initial therapy (complete/acceptable/incomplete) was based on stimulated thyroglobulin and imaging results during the first 2 years of follow-up. RESULTS: The risk for recurrent/persistent disease, as assessed by the postoperative ATA risk-stratification system and the SCMCI score and by the response to initial therapy, was higher in the prepubertal group (P < .001, P = .002, and P = .02, respectively). Outcome prediction by the risk-stratification systems was applicable: ATA risk categories, P = .014, R(2) = 0.247, predictive ability 80.4%; SCMCI score, P < .001, R(2) = 0.435, predictive ability 86.3%; and response to initial therapy stratification, P < .001, R(2) = 0.789, predictive ability 96.1%. The proportion of variance explained by the ATA risk categories (0.25), SCMCI score (0.44), and response to initial therapy (0.79) indicated that the latter was the most precise predictor and that the SCMCI score reflected the disease outcome better than ATA risk categories. CONCLUSIONS: Our data confirm that the postoperative pediatric ATA stratification system and the novel SCMCI score are suitable for predicting the risk of recurrent/persistent disease in this population. The response to initial therapy classification performed 1-2 years after the initial therapy may be more appropriate for guiding surveillance recommendations.

Effect of cell phone-like electromagnetic radiation on primary human thyroid cells.

PURPOSE: To evaluate the potential carcinogenic effects of radiofrequency energy (RFE) emitted by cell phones on human thyroid primary cells. MATERIALS AND METHODS: Primary thyroid cell culture was prepared from normal thyroid tissue obtained from patients who underwent surgery at our department. Subconfluent thyroid cells were irradiated under different conditions inside a cell incubator using a device that simulates cell phone-RFE. Proliferation of control and irradiated cells was assessed by the immunohistochemical staining of antigen Kiel clone-67 (Ki-67) and tumor suppressor p53 (p53) expression. DNA ploidy and the stress biomarkers heat shock protein 70 (HSP70) and reactive oxygen species (ROS) was evaluated by fluorescence-activated cell sorting (FACS). RESULTS: Our cells highly expressed thyroglobulin (Tg) and sodium-iodide symporter (NIS) confirming the origin of the tissue. None of the irradiation conditions evaluated here had an effect neither on the proliferation marker Ki-67 nor on p53 expression. DNA ploidy was also not affected by RFE, as well as the expression of the biomarkers HSP70 and ROS. CONCLUSION: Our conditions of RFE exposure seem to have no potential carcinogenic effect on human thyroid cells. Moreover, common biomarkers usually associated to environmental stress also remained unchanged. We failed to find an association between cell phone-RFE and thyroid cancer. Additional studies are recommended.

IgG4-related thyroiditis: a case report and review of literature.

UNLABELLED: A 55-year-old male, with a positive medical history for hypothyroidism, treated with stable doses for years was admitted with subacute thyroiditis and a feeling of pain and pressure in the neck. Laboratory tests showed decrease in TSH levels, elevated erythrocyte sedimentation rate, and very high antithyroid antibodies. Owing to enlarging goiter and exacerbation in the patient's complaints, he was operated with excision of a fibrotic and enlarged thyroid lobe. Elevated IgG4 plasma levels and high IgG4/IgG plasma cell ratio on immunohistochemistry led to the diagnosis of IgG4-mediated thyroiditis. We concluded that IgG4-thyroiditis and IgG4-related disease should be considered in all patients with an aggressive form of Hashimoto's thyroiditis. LEARNING POINTS: IgG4-related disease is a systemic disease that includes several syndromes; IgG4-related thyroiditis is one among them.IgG4-thyroiditis should be considered in all patients with an aggressive form of Hashimoto's thyroiditis.Patients with suspected IgG4-thyroiditis should have blood tested for IgG4/IgG ratio and appropriate immunohistochemical staining if possible.

Differentiated thyroid cancer is associated with less aggressive disease and better outcome in patients with coexisting Hashimotos thyroiditis.

BACKGROUND: Evaluation of surgical specimens suggests that patients with Hashimoto thyroiditis (HT) have a higher prevalence of differentiated thyroid cancer. Although patients with HT are reported to present with earlier stage disease, there is controversy as to whether these patients have better prognosis when adjusted for histology and stage at presentation. OBJECTIVES: To investigate differences between patients with differentiated thyroid cancer patients and without HT for aggressiveness of disease and clinical outcome, and the decline rate of antithyroglobulin antibodies titers over time. METHODS: A retrospective study using the Rabin Medical Center Thyroid Cancer Registry. Seven hundred fifty-three patients were included and divided into 2 groups of patients with and without HT at diagnosis. Disease severity at presentation was evaluated using the entire cohort, whereas a control group matched for age, gender, histology, and stage was used to evaluate disease course and outcome. RESULTS: HT was present in 14.2% (n = 107) of included patients and was associated with smaller primary tumor (17.9 vs 21.2 mm, P = .01) and less lymph node involvement (23% vs 34%, P = .02) at presentation. When matched groups were compared, patients with HT received less additional radioactive iodine (RAI) treatments (1.24 vs 1.45, P = .03) and showed lower rates of persistence at 1 year (13% vs 26%, P = .04) and higher rates of disease remission at the end of follow-up (90% vs 79%, P = .05). On multivariate analysis HT was predictive of a lower rate of lymph nodes involvement (odds ratio 0.34, 95% confidence interval 0.17-0.66) and persistent disease at the end of follow-up (odds ratio 0.48, 95% confidence interval 0.24-0.93). Antithyroglobulin antibodies slowly disappeared in most patients with no evidence of disease. CONCLUSION: Our study demonstrates that HT is associated with a less aggressive form of differentiated thyroid cancer and a better long-term outcome.

Thyroid gland involvement in advanced laryngeal cancer: association with clinical and pathologic characteristics.

BACKGROUND: Indications for thyroidectomy during laryngectomy are controversial. We examined whether clinicopathologic features can predict thyroid gland involvement, and the prognostic effect of thyroid gland involvement in patients undergoing total laryngectomy. METHODS: The study set out to review preoperative assessment, operation findings, pathologic findings, and follow-up data. RESULTS: Thyroid gland involvement was found in 11 of 53 patients (21%) undergoing total laryngectomy and thyroidectomy. Preoperative work-up failed to predict thyroid gland involvement. Thyroid gland involvement was associated with salvage procedures (p = .025), paratracheal metastases (p = .003), and poor overall survival (hazard ratio = 2.74, p = .008). CONCLUSIONS: Thyroid gland involvement in patients undergoing total laryngectomy is frequent and is associated with poor prognosis. Preoperative assessment failed to predict thyroid gland involvement. We believe that thyroidectomy should be considered in cases with paratracheal lymphatic spread irrespective of tumor location within the larynx.

Early tongue carcinoma: analysis of failure.

BACKGROUND: Failure rate of surgery for early tongue carcinoma remains high. We sought to identify patterns of failure and recurrence risk factors. METHODS: Data review was carried out on 50 patients treated for early tongue carcinoma (T1/2N0M0); surgery was unsuccessful in 11 of these patients. All patients underwent transoral resection of the tongue tumor and prophylactic neck dissection (supraomohyoid). RESULTS: Tumor recurred within 3 to 18 months. Nine died of disease. Four had failure in neck level 4, 6 in level 1, and 1 simultaneously in level 1 and locally. Most tumors were moderately differentiated. Average depth was 6.64 mm. CONCLUSIONS: We report 11 patients with early tongue carcinoma who failed local excision with neck dissection. Failures occurred in level 4 (4 patients) and level 1 (7 patients). This group may benefit from extended neck surgery. Sex, age, stage, and depth of tumor were not significantly different in the group with treatment failure. Tumors in the group with treatment failure were more poorly differentiated.

Early death from papillary thyroid carcinoma.

PURPOSE: The natural history of papillary thyroid carcinoma (PTC) is characterized by a slow growth rate and an excellent prognosis at 20 and 30 years. However, there is a small subset of patients with poorer outcome. METHODS: Twenty patients who died of PTC within 10 years of diagnosis were studied to identify prognostic indicators and biological markers of early death. Findings were statistically compared with a previous review of all patients with PTC treated in the same institute and studies in the literature. RESULTS: The study group included 6 men and 14 women with a mean age of 65 years at diagnosis. Average tumor size was 3.6 cm; 16 patients had extracapsular extension. All tumor samples studied histologically stained poorly for p53, Ki67, and CD34. Regional metastases were present in half the patients, and distal metastases in all. All patients had an advanced disease stage (Tumor, Node, Metastases classification), and only 4 had a low score on the Metastases, Age, Completeness of resection, local Invasion, tumor Size risk stratification. Analysis of the findings against data in the literature for the whole population of patients with PTC, who had a considerably better survival (<8% mortality within 8-15 years vs 100% within 10 years in our sample), yielded significant differences for rates of extrathyroidal extension (P = .0001), regional metastases (P = .016), and distant metastases (P = .0001). CONCLUSION: Extrathyroid extension, late regional metastases, and distant metastases may be risk factors for early death from PTC.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors: clinical experience with a rare entity.

BACKGROUND: Normal adult lungs contain pulmonary neuroendocrine cells (PNECs). PNEC hyperplasia may be either reactive or idiopathic, and the idiopathic type is defined as diffuse idiopathic PNEC hyperplasia (DIPNECH). It is believed that DIPNECH is a neuroendocrine proliferative process associated with carcinoid tumors. The available data regarding this rare condition are very limited. The objective of the current study was to describe the clinical, radiologic, and pathologic characteristics of patients with DIPNECH and the effect of various therapeutic modalities on patient well being. METHODS: The authors retrospectively studied 11 consecutive patients with DIPNECH who were followed at 2 referral centers in Israel between 2000 and 2010. RESULTS: All patients were women, and their median age was 62.8 years. Six patients presented with respiratory symptoms, such as prolonged dyspnea, wheezing, and cough. All patients had carcinoid tumor together with multiple, small pulmonary nodules observed on thoracic high-resolution computerized tomography images. The mean size of the dominant lesion was 19.4 ± 9.6 mm. Nine patients underwent thoracotomy and resection of the dominant lesion. The disease was stable in 5 of 11 patients; in 6 of 10 patients, it progressed, and the patients received treatment with somatostatin analogs, which induced disease stabilization in all patients. Metastatic disease was diagnosed in 3 of 11 patients (36%). All patients were alive at the end of follow-up (mean, 4.63 ± 2.04 years; ongoing). CONCLUSIONS: The association of lung neuroendocrine tumor with multiple nodules in women, together with complains of chronic cough and wheezing, should raise suspicion of DIPNECH. Whenever possible, these patients should undergo surgical excision of the dominant lesion, and somatostatin analogs may be considered for symptomatic or tumor control in patients with progressive disease.

Fulminant ectopic Cushing syndrome in a patient with metastatic neuroendocrine carcinoma and Crohn's disease.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have been rarely reported in patients with Crohn's disease, being usually small and incidentally detected in areas uninvolved by the inflammatory process. We describe the case of a young female patient with Crohn's disease and a fulminant Cushing's syndrome induced by the ectopic secretion of adrenocorticotropic hormone (ACTH) by an aggressive gastrointestinal neuroendocrine carcinoma (NEC). Despite a multi-therapeutic approach, including the administration of multiple courses of chemotherapy, hypo-cortisolemic agents, somatostatin analogues, as well as the performance of bilateral adrenal vein embolization followed by bilateral adrenalectomy, patient's condition progressively deteriorated and she died nine months after the diagnosis of NEC due to liver failure. The available literature addressing the possible connection between Crohn's disease and NEC is discussed in detail.

MicroRNA expression differentiates between primary lung tumors and metastases to the lung.

For surgical pathologists, distinguishing whether a pulmonary neoplasm is primary or metastatic can be challenging, and current biomarkers do not always aid lung tumor classification. The tissue-associated expression of microRNA likely explains the remarkable finding that many tumors can be classified based solely on their microRNA expression signature. Here we show that microRNAs can serve as biomarkers for lung tumor classification. Using microRNA microarray data generated from 76 formalin-fixed, paraffin-embedded (FFPE) samples of either primary lung cancer or metastatic tumors to the lung, we have identified a set of microRNAs expressed differentially between these two groups. This set includes hsa-miR-182, which was most strongly over-expressed in the lung primary tumors, and hsa-miR-126, which was over-expressed in the metastatic tumors. The differential expression of this set of microRNAs was confirmed using qRT-PCR on a set of 54 samples. In light of our data, microRNA expression should be considered as a potential clinical biomarker for surgical pathologists faced with discerning the tumor type of an inscrutable lung neoplasm.

Role and prognostic significance of the Ki-67 index in non-Hodgkin's lymphoma.

Expression of Ki-67, a nuclear antigen protein present in all cycling cells, is used to determine the growth fraction of tumors. The aim of this study was to evaluate the role and prognostic significance of the Ki-67 proliferation index (PI) in non-Hodgkin's lymphoma. Ki-67 was assayed immunohistochemically in tissue samples of 319 patients with newly-diagnosed non-Hodgkin's lymphoma. In 268 patients, the Ki-67 PI was correlated with clinical course and outcome. The mean Ki-67 PI ranged from 26.6% in indolent lymphomas to 97.6% in very aggressive lymphomas (P < 0.001). The index was <45% in 82.8% of indolent lymphomas and >45% in 85% of aggressive lymphomas (AUC = 0.877, P < 0.001). In patients with diffuse large B-cell lymphoma (n = 141), a Ki-67 PI of 70% was found to significantly discriminate patients with good or bad prognosis (AUC = 0.65, P = 0.004). Three-year survival was 75% +/- 5.6% in patients with a low Ki-67 index compared with 55.9% +/- 6% in patients with a high index (P = 0.015). In patients with a low IPI (10 cm), the corresponding 3-year survival by Ki-67 index was 100% and 25% +/- 12% (P = 0.012). Our results suggest that the mean Ki-67 PI differs by type of lymphoma. A cut-off value of 45% can help differentiate indolent from aggressive disease. In diffuse large B-cell lymphoma, a cut-off value of 70% can distinguish patients with a good and bad prognosis when combined with other prognostic factors of low IPI score and bulky disease.