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Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes.

Over several decades, studies have described the progression of autoimmune diabetes, from the first appearance of autoantibodies until, and after, the diagnosis of clinical disease with hyperglycaemia and insulin dependence. Despite the improved management of type 1 diabetes with exogenous insulin, most patients do not meet clinical glycaemic goals, and diabetes remains an important medical problem that affects children and adults. Clinical and preclinical studies have suggested strategies to prevent the diagnosis of type 1 diabetes in people at risk, but the outcomes of previous clinical trials have not met their primary endpoints of disease prevention or delay. The results from the TN-10 teplizumab prevention trial show that the diagnosis of type 1 diabetes can be delayed by treatment with a FcR non-binding monoclonal antibody to CD3 in people at high risk for disease. This Series paper discusses how this clinical achievement raises new questions about for whom, and when, immunological strategies might be developed to prevent type 1 diabetes, and how to achieve this goal.

Objective.The objective of this study was to evaluate the benefits and risk of adjuvant pelvic radiotherapy aimed at reducing recurrence in women with Stage IB cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy.

Since its inception in 1970, the Gynecologic Oncology Group (GOG) has pursued a series of Phase II and III cooperative clinical investigations of the combination of cytotoxic chemotherapy and radiation therapy for patients with locally advanced carcinoma of the cervix. After an initial randomized trial indicated that hydroxyurea was superior to placebo, subsequent studies have evaluated whether the hypoxic sensitizer, misonidazole, or the combination of cisplatin with infusional 5‐fluorouracil were superior to hydroxyurea. Other studies have evaluated concurrent chemotherapy with extended field radiation for patients with metastatic disease in their paraaortic nodes. The GOG will continue to attempt to identify and develop superior adjuncts to radiation therapy for this patient population.

Although cure rates are high, the morbidity of radical operation for carcinoma of the vulva is substantial. Between 1983-1989, member institutions of the Gynecologic Oncology Group entered 155 patients in a prospective evaluation of modified radical hemivulvectomy and ipsilateral inguinal lymphadenectomy for clinical stage I vulvar cancer. Only patients with neoplastic thickness of 5 mm or less, without vascular space invasion, and negative inguinal lymph nodes were eligible for this study. There have been 19 recurrences and seven deaths from disease among the 121 eligible and evaluable patients. Patients whose disease recurred on the vulva were frequently (eight of ten patients) salvaged by further operation. Five of the seven deaths due to cancer occurred among patients whose first recurrence was in the groin. Acute and long-term morbidity as well as hospital stay were each less than in the Group's previous experience in a comparable patient population treated with radical vulvectomy and bilateral inguinal-femoral lymphadenectomy. There was a significantly increased risk of recurrence but not death when compared with these same historic controls. Modified radical hemivulvectomy and ipsilateral inguinal lymphadenectomy is an alternative to traditional radical operation for these selected patients with stage I carcinoma of the vulva. The number of patients who experienced recurrence in the operated groin is of concern and may be attributable to the decision to leave the femoral nodes intact.

Background.In a previous study, the Gynecologic Oncology Group (GOG) compared hydroxyurea (HDXR) and the combination of cisplatin (C) and 5-fluorouracil (5-FU) infusion as potentiators of radiation therapy. This study was undertaken to determine whether these two regimens could be combined, concurrent with pelvic radiation therapy in patients with locally advanced cervical cancer.

The subjects of this study are 445 patients with advanced cervical cancer treated by standardized radiation therapy. Upon entry into one of two Gynecologic Oncology Group (GOG) protocols, original pathologic diagnoses and histologic tumor descriptions for each patient were compared with separate evaluations made by a consensus opinion of two GOG pathologists. A review diagnosis using grade, cell type, and the Stendahl scoring system was then made by the first author (R.J.S.) without knowledge of the prior diagnoses. Of the original pathologists' diagnoses, 21 did not include grade or cell type. There was little agreement among the different pathologists as to the use of either specific grade or cell type. Histologic grade, irrespective of the pathologists making the diagnosis, had no correlation to prognosis. The Reagan and Wentz large-cell keratinizing (LCK) cell type, when applied by the author to tumors with any form of squamous keratinization present, identified a group of patients with a poorer prognosis, although not independently of other prognostic factors. The Stendahl scoring system identified a number of patients with both a poorer and better prognosis. This was statistically significant and independent of other risk factors. A major limitation, however, was the number of patients evaluable because of inadequate biopsy material in 23.6 of the study group.

The pathologic grade of endometrial adenocarcinoma is widely recognized as an important prognostic and therapeutic indicator. However, disagreement persists about the optimal method of determining grade. The pathology committee of the Gynecologic Oncology Group employs a system based on the proportion of tumor in glandular array; this system is both reproducible and predictive of outcome. Others have suggested that grading based on nuclear pleomorphism and the size of nucleoli provides better prognostication. We compared the three-level architectural grading system (AG) with a two-level nuclear grading system (NG) to determine reproducibility and prognostic value in 88 cases of stage 1 endometrial adenocarcinoma. Three pathologists made independent assessments of grade by each method. The division of tumors by architectural arrangement was superior for predicting survival (83, 73, and 44, AG, p = 0.005; vs. 79 and 61, NG, p = 0.14) and equivalent to nuclear grading for prediction of recurrence. Both systems were moderately reproducible (k = 0.49, AG; k = 0.57, NG). Assessment of NG was more tedious than that of AG. Subdivision of architectural grade based on high nuclear atypia, as recommended in current, International Federation of Gynecology and Obstetrics guidelines, did not improve prognostication. Because grading based on nuclear pleomorphism does not provide prognostic information superior to that resulting from architectural grading, we do not advocate its use in routine surgical pathology practice.

Twenty-five evaluable patients with advanced non-squamous carcinoma of the uterine cervix were treated with mitoxantrone 12 mg/m2 every three weeks. All patients had good performance status and measurable disease and only 11 had received prior chemotherapy. One complete and one partial response were noted among 15 patients with no prior chemotherapy while no responses were seen in 11 previously treated patients. The major toxicity was myelosuppression; other toxicity was mild. The median progression-free interval was 2.1 months and median survival 4.3 months. Mitoxantrone displays minimal activity in patients with advanced non-squamous carcinoma of the cervix.

Objectives.The objectives of this study were to assess efficacy and toxicity of the combination of bleomycin, etoposide, and cisplatin (BEP) in this Phase II trial as first-line therapy for ovarian stromal malignancies.Methods.Patients with incompletely resected Stages II–IV or recurrent cancer underwent surgical debulking. There were two bleomycin-related deaths early in the trial; thus, the initial schedule of bleomycin (20 units/m2× 9 weeks for a maximum dose of ≤30 units × 9) was changed, without subsequent mortality. The final dose schedule was 20 units/m2bleomycin iv push day 1 every 3 weeks × 4, 75 mg/m2etoposide days 1–5 every 3 weeks × 4 and 20 mg/m2cisplatin days 1–5 every 3 weeks × 4. The frequency of negative second-look surgery was the primary outcome measure.Results.Seventy-five women were entered; 18 were excluded. Grade 4 myelotoxicity occurred in 61% of the patients. The end point used for response was negative second-look laparotomy. Thirty-seven percent (14/38) of the patients undergoing second-look laparotomy had negative findings. The six complete responders were of long median duration (24.4 months). Patients with measurable disease were at the highest risk of progression and death.Conclusions.BEP appears to be an active combination regimen for first-line chemotherapy of malignant tumors of the ovarian stroma. Myelotoxicity was tolerable.

From 1977 to 1984, 114 eligible patients with invasive squamous cell carcinoma of the vulva and positive groin nodes after radical vulvectomy and bilateral groin lymphadenectomy were randomized to receive either radiation therapy or pelvic node resection. Fifty-three of the 59 patients randomized to radiation therapy received a 4500− to 5000-rad tumor dose in five to 6.5 weeks bilaterally to the groins and to the midplane of the pelvis even if only unilateral positive groin nodes had been detected; no radiation was given to the central vulvar area. Fifty-three of the 55 patients randomized to further surgery had pelvic node resection performed on the side containing positive groin nodes either unilaterally or bilaterally. Acute and chronic morbidity was similar for both regimens. The two major poor prognostic factors were clinically suspicious or fixed ulcerated groin nodes and two or more positive groin nodes. The difference in survival for the 114 evaluable patients was significant, favoring the adjunctive radiation therapy group (P =.03). The estimated two-year survival rates were 68 for the radiation therapy group and 54 for pelvic node resection group. The most dramatic survival advantage for radiation therapy was in patients who had either of the two major poor prognostic factors present; at this time, the benefit of radiation therapy for the remaining patients is uncertain. In this randomized prospective study, the addition of adjunctive groin and pelvic irradiation therapy after radical vulvectomy and inguinal lymphadenectomy proved superior to pelvic node resection.

From 1977 to 1984 the Gynecologic Oncology Group (GOG) conducted a prospective clinical and surgical staging protocol of squamous cell carcinoma of the vulva (n= 637). The patients with superficial (5 mm or less invasion) lesions were the subject of a previous report (n= 272). The subject of this report is on factors that predict groin node metastasis based on all 588 evaluable patients. Comparisons between the two reports are made. Almost half of this group (49.3%) had minimal tumor thickness (⩽5 mm). Almost one-third of patients had small vulvar lesions (⩽2 cm). Groin node metastasis was 18.9% for the ⩽2-cm diameter tumors and 41.6% for the >2-cm diameter lesions. The inaccuracy of clinical palpation of the groin nodes (23.9% false negative) largely accounts for underestimation of extent of disease. Body weight was not related to the sensitivity of detecting positive groin nodes (P= 0.26). Using the logistic model, independent predictors of positive groin nodes were identified (in order of importance): less tumor differentiation by GOG criteria (P< 0.0001), suspicious or fixed/-ulcerated nodes (P< 0.0001), presence of capillary-lymphatic involvement (P< 0.0001), older age (P= 0.0002), and greater tumor thickness (invasion) (P= 0.03). Lesion size and location were not independent predictors of positive groin nodes.

Teplizumab treatment of nondiabetic relatives at high risk for T1D induces partially exhausted CD8+T cells and improves beta cell function.

This paper develops a methodology and defines a measure that can be used to separate subjects that received an experimental therapy into those that benefitted from those that did not in recent‐onset type 1 diabetes. Benefit means a slowing (or arresting) the decline in beta‐cell function over time. The measure can be applied to comparing treatment arms from a clinical trial or to response at the individual level. An analysis of covariance model was fitted to the 12‐month area under the curve C‐peptide following a 2‐hour mixed meal tolerance test from 492 individuals enrolled on five TrialNet studies of recent‐onset type 1 diabetes. Significant predictors in the model were age and C‐peptide at study entry. The observed minus the model‐based expected C‐peptide value (quantitative response, QR) is defined to reflect the effect of the therapy. A comparison of the primary hypothesis test for each study included and a t test of the QR value by treatment group were comparable. The results were also confirmed for a new TrialNet study, independent of the set of studies used to derive the model. With our proposed analytical method and using QR as the end‐point, we conducted simulation studies, to estimate statistical power in detecting a biomarker that expresses differential treatment effect. The QR in its continuous form provided the greatest statistical power when compared to several ways of defining responder/non‐responder using various QR thresholds. This paper illustrates the use of the QR, as a measure of the magnitude of treatment effect at the aggregate and subject‐level. We show that the QR distribution by treatment group provides a better sense of the treatment effect than simply giving the mean estimates. Using the QR in its continuous form is shown to have higher statistical power in comparison with dichotomized categorization. This paper proposes a quantitative end‐point in the study of recent‐onset type 1 diabetes that measures the effect of a treatment on the stimulated C‐peptide of an individual patient and, in the aggregate, discriminate those who benefited (responders) from those who did not (non‐responders). The quantitative response measure can be used to evaluate promising biomarkers or other prognostic characteristics and is defined by the difference between the observed and expected C‐peptide levels.

This study from the Gynecology Oncology Group investigated the use of postoperative whole abdominal radiation therapy in women with stage III and IV endometrial cancer. In the period between December 1986 and February 1994, 180 patients who met study criteria were enrolled in the study. Seventy-seven patients (mean age 63 years) had typical endometrial carcinoma (adenocarcinoma, endometrioid, glassy cell, mixed epithelial, adenosquamous, villoglandular, or undifferentiated) and 103 had papillary serous (median age 68.5 years) or clear cell carcinoma (median age 71 years) (P < .001 for age difference between typical and higher-risk tumors). Papillary serous tumors were more common in black women (78%) than in white women (53%), and grade 3 disease was more common in women with papillary serous/clear cell tumors (66%) than in those with typical endometrial cancer (44%).

Patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to or in relapse following induction chemotherapy have a poor prognosis, and inducing an immune response to autologous AML or ALL cells following chemotherapy is an attractive approach to improving outcome. Immune responses to autologous leukemia cells may be stimulated by dendritic cell presentation of leukemia cell antigens, dendritic cells may be deficient in acute leukemia, and administration of the recombinant hematopoietic growth factors granulocyte-monocyte colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) following chemotherapy may increase dendritic cell numbers. We compared the effects of GM-CSF and G-CSF administered following high-dose chemotherapy. Adult relapsed and refractory AML and ALL patients received salvage chemotherapy consisting of high-dose cytarabine 3 g/m2 (1.5 g/m2 for age =50 years) over one hour every 12 hours × 12 doses and mitoxantrone 12 mg/m2 daily × 3 (HiDAC/Mx), and at completion of chemotherapy were randomized to receive GM-CSF 250 mcg/m2 or G-CSF 5 mcg/kg daily beginning 12 hours after the last chemotherapy dose, until absolute neutrophil count =5 × 1091 year) and late (=1 year) first and subsequent relapse. Peripheral blood was collected when ANC reached 5 × 109/L for measurement of myeloid dendritic cell (lineage-negative, HLADr+, CD11c+) percentages by flow cytometry. Sixty patients were enrolled, ages 18 to 82 (median 66) years, 41 male and 19 female, 47 with AML and 13 with ALL, and 15 with primary refractory disease, 27 in early and 17 in late first relapse and one in subsequent relapse; 6 had relapsed following allogeneic transplantation. Overall, 22 of 60 patients (37%) achieved CR and 4 (7%) CR with incomplete count recovery (CRi), while 23 (38%) had resistant disease and 11 (18%) died. The regimen was generally well tolerated, the most frequent grade =4 toxicities pulmonary, infectious and cardiac, in 8, 7 and 6 patients, respectively, and 13 patients subsequently received transplant-based therapies (9 allogeneic, 4 autologous). 56 patients were randomized, as 4 died or stopped therapy before randomization, and randomization was to GM-CSF in 29 patients and G-CSF in 27. CR and CRi were achieved by 13 and 1 patients of 29 patients receiving GM-CSF and 9 and 3 of 27 receiving G-CSF (p NS, Fisher’s Exact Text). ANC =0.5 was achieved at 22 to 98 days (median 27) from start of chemotherapy in 25 GM-CSF patients and at 18 to 65 days (median 25) in 20 G-CSF patients (p=0.08, Wilcoxon Rank Sum Test). Toxicities did not differ significantly on the two arms. Only 17 patients (G-CSF: 7 and GM-CSF: 10) had blood samples submitted and successfully studied for myeloid dendritic cell percentages. Myeloid dendritic cell percentages were 0 to 40 (median 22), and the comparison by treatment group showed no evidence of a difference. In summary, HiDAC/Mx is an effective salvage regimen in this high-risk population and may serve as a bridge to transplant-based therapies or, possibly, a backbone for targeted therapies, myeloid dendritic cells are present at count recovery in patients receiving GM-CSF or G-CSF following HiDAC/Mx, and treatment outcome, toxicities, count recovery and myeloid dendritic cell percentages did not differ in patients receiving GM-CSF or G-CSF following HiDAC/Mx.

Patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to or in relapse following induction chemotherapy have a poor prognosis, and inducing an immune response to autologous AML or ALL cells following chemotherapy is an attractive approach to improving outcome. Immune responses to autologous leukemia cells may be stimulated by dendritic cell presentation of leukemia cell antigens, dendritic cells may be deficient in acute leukemia, and administration of the recombinant hematopoietic growth factors granulocyte-monocyte colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) following chemotherapy may increase dendritic cell numbers. We compared the effects of GM-CSF and G-CSF administered following high-dose chemotherapy. Adult relapsed and refractory AML and ALL patients received salvage chemotherapy consisting of high-dose cytarabine 3 g/m2(1.5 g/m2for age ≥50 years) over one hour every 12 hours × 12 doses and mitoxantrone 12 mg/m2daily × 3 (HiDAC/Mx), and at completion of chemotherapy were randomized to receive GM-CSF 250 mcg/m2or G-CSF 5 mcg/kg daily beginning 12 hours after the last chemotherapy dose, until absolute neutrophil count ≥5 × 109〈1 year) and late (≥1 year) first and subsequent relapse. Peripheral blood was collected when ANC reached 5 × 109/L for measurement of myeloid dendritic cell (lineage-negative, HLADr+, CD11c+) percentages by flow cytometry. Sixty patients were enrolled, ages 18 to 82 (median 66) years, 41 male and 19 female, 47 with AML and 13 with ALL, and 15 with primary refractory disease, 27 in early and 17 in late first relapse and one in subsequent relapse; 6 had relapsed following allogeneic transplantation. Overall, 22 of 60 patients (37%) achieved CR and 4 (7%) CR with incomplete count recovery (CRi), while 23 (38%) had resistant disease and 11 (18%) died. The regimen was generally well tolerated, the most frequent grade ≥4 toxicities pulmonary, infectious and cardiac, in 8, 7 and 6 patients, respectively, and 13 patients subsequently received transplant-based therapies (9 allogeneic, 4 autologous). 56 patients were randomized, as 4 died or stopped therapy before randomization, and randomization was to GM-CSF in 29 patients and G-CSF in 27. CR and CRi were achieved by 13 and 1 patients of 29 patients receiving GM-CSF and 9 and 3 of 27 receiving G-CSF (p NS, Fisher's Exact Text). ANC ≥0.5 was achieved at 22 to 98 days (median 27) from start of chemotherapy in 25 GM-CSF patients and at 18 to 65 days (median 25) in 20 G-CSF patients (p=0.08, Wilcoxon Rank Sum Test). Toxicities did not differ significantly on the two arms. Only 17 patients (G-CSF: 7 and GM-CSF: 10) had blood samples submitted and successfully studied for myeloid dendritic cell percentages. Myeloid dendritic cell percentages were 0 to 40 (median 22), and the comparison by treatment group showed no evidence of a difference. In summary, HiDAC/Mx is an effective salvage regimen in this high-risk population and may serve as a bridge to transplant-based therapies or, possibly, a backbone for targeted therapies, myeloid dendritic cells are present at count recovery in patients receiving GM-CSF or G-CSF following HiDAC/Mx, and treatment outcome, toxicities, count recovery and myeloid dendritic cell percentages did not differ in patients receiving GM-CSF or G-CSF following HiDAC/Mx.