Phase I study of gemcitabine given weekly as a short infusion for non-small cell lung cancer: results and possible immune system-related mechanisms.

PURPOSE: To define the maximum tolerated dose (MTD) and the nature of the toxicities associated with gemcitabine given as a short infusion to patients with non-small cell lung cancer (NSCLC). Secondary objectives were to monitor immunologic response, clinical response, and survival. PATIENTS AND METHODS: Thirty-two patients diagnosed with advanced inoperable NSCLC and performance status of 0 or 1 participated in this study. Patients consisted of 22 males and 10 females whose median age was 62 years (range 32-79). Gemcitabine was administered as a 30 min infusion once weekly for 3 weeks followed by 1 week of rest. Patients were enrolled at six gemcitabine dose levels ranging from 1000 to 3500 mg/m2. Patients completed a median of four cycles (range 1-17). Responses were evaluated after every two cycles. RESULTS: Toxicity was evaluated in all 32 patients. The MTD was not reached as gemcitabine was well tolerated at all dose levels. Grade 4 toxicity occurred in three (9%) patients: pulmonary and lymphocytopenia in one patient each, and both neurocortical and cardiac in one patient. Grade 3 toxicity was found in a total of 20 (63%) patients: pulmonary in 10 (31%) patients; pain in 6 (19%) patients; liver toxicity in 6 (19%) patients; leukopenia and lymphocytopenia in 5 (16%) patients each; anemia, nausea, and cardiac toxicity in 3 (9%) patients each; proteinuria and infection in 2 (6%) patients each; and hemorrhage in 1 (3%) patient. Of the 29 patients evaluable for response, seven objective responses were achieved: six at the 2200 mg/m2 dose level and one at the 2800 mg/m2 dose level. The distribution of responses differed significantly by dose (P = 0.0124 by the exact chi-square test for independence). The overall response rate was 24.1% (95% CI, 10.3-43.5%). At 6 h post-infusion, there was a significant increase in spontaneous tumor necrosis factor (TNF) release and stimulated interleukin (IL)-2 production, and significant decreases in total white blood cell and lymphocyte counts (CD3+, CD8+, and CD16+ lymphocytes) and resting and stimulated superoxide production by formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol myristate acetate, and opsonized zymosan (OPS-Z). At 24 h post-infusion, there were significant decreases in total lymphocyte count, lymphocyte subsets (CD3+, CD4-, CD8+, CD56+, CD19+), and in resting and stimulated superoxide production by fMLP and OPS-Z. There also appeared to be an association between the levels of spontaneous TNF release and the severity of both gastrointestinal (GI) and pulmonary toxicities. CONCLUSION: Gemcitabine given as a short infusion was well tolerated at the dose levels of 1000-3500 mg/m2. The MTD was not reached. Toxicities appeared to be cumulative with multiple cycles. Gemcitabine appears to have activity against NSCLC. Although there was a differential dose-response rate among dose levels, increasing the gemcitabine dose beyond 2200mg/m2 did not show increased clinical response. Gemcitabine appears to modulate the immune response, which may in turn mediate both response and toxicity, although no statistically significant correlation between immune and clinical response was detected.

Inflammatory cell infiltrate in a responding metastatic nodule after vaccine-based immunotherapy.

A patient with von Hippel Lindau disease, bilateral symmetric renal cell carcinoma and pulmonary metastases treated with immunotherapy is the subject of this study. A left kidney and tumour mass were removed and the tumour cells used to make an autologous tumour/bacille Calmette-Guérin (BCG) vaccine as part of the treatment protocol. The patient's pulmonary nodules responded, but the remaining renal nodule subsequently grew. Samples of both tumours were obtained allowing for an internally controlled evaluation of the histological and immunohistologic differences between a responding and non-responding tumour nodule after therapy. The immunotherapy protocol is designed to promote a T cell response to autologous tumour. Cellular infiltrates were demonstrated in both responding and non-responding nodules compared with the pretreatment tumour specimen, but the responding nodule contained proportionately more T cells as well as markedly increased numbers of plasma cells and granulocytes. This suggested that several arms of the immune system may have been operative in the responding nodule.

Biologic response modulation by tumor necrosis factor alpha (TNF alpha) in a phase Ib trial in cancer patients.

During a phase I study of recombinant human tumor necrosis factor (TNF) in cancer patients, serial immune studies were performed and analyzed for effects of TNF. The TNF (specific activity 9.6 x 10(6) U/mg protein, < 5.0 endotoxin units/mg protein) was given over 2 h intravenously on days 1, 8-12, 29-33, 50-54, and 71-75 at doses of 40, 80, 160, 200, and 240 micrograms/m2. Immunologic testing was performed before therapy three times and subsequently on days 2, 8, 10, 12, 29, 33, 50, 54, 71, 75, and off-study two times. Immune parameters evaluated included cytotoxicity [natural killer (NK), spontaneous lymphokine activated killer cells (LAK), LAK, and monocyte], cytokine production [spontaneous and stimulated interferon (IFN)-gamma and interleukin (IL)-2], superoxide production [resting and stimulated polymorphonuclear (PMN) and mononuclear cells (MNC)], and phenotype of peripheral blood lymphocyte subsets (CD3, CD4, CD8, CD16, CD56, CD19). Data were analyzed for long-term effects, the effect after 1 day of treatment (day 1), and for weekly effect (change from day 1 to day 5 of a given treatment week). Significant decreases were seen in the spontaneous cytotoxicity of peripheral blood NK cells and IL-2-inducible LAK cells, whereas increases in spontaneous peripheral blood LAK activity were seen with TNF treatment. Consistent increases in superoxide production of resting PMN and MNC were demonstrated, with late increases in superoxide production by opsonized, zymosan-treated PMN. No spontaneous IFN-gamma or IL-2 were noted in sera with treatment, but production of IL-2 by MNCs rose with TNF treatment. During 5 days of TNF treatment, the percentages of circulating CD8+ and CD56+ cells decreased, whereas that of CD4+ and CD19+ cells increased significantly and consistently, as determined by a multivariate analysis. Significant changes in several independently measured parameters were observed, including a dose-related diminished production of IFN-gamma by MNC stimulated by phytohemagglutinin and increased in vitro-generated LAK activity. Because there was no clinical response in this trial, no association of immunologic change with clinical response can be made. No biologically optimal dose of TNF was evident. The data suggest that TNF may act as a trigger cytokine, initiating a broad immune/inflammatory response.

Diagnostic reading session: temporal patterns and case-order effects.

The authors analyzed receiver-operating-characteristic studies to determine temporal patterns and performance as a function of the elapsed time in a reading session. Nineteen radiologists each read as many as 300 chest images with use of seven different display modalities, including conventional and laser-printed film and high-resolution soft display. With a computerized reporting system, the ratio of observers' interpretation rates (time to diagnosis) were recorded for the last five and 10 compared with the first five and 10 of 30-40 cases seen in sessions lasting 45-110 minutes. Observers tended to accelerate their interpretation as the sessions progressed by an average of 15% (P < .001). The acceleration was consistent for all readers (both fast and slow) with a variety of display modes under the nonrestricted time environment.

Cutaneous T-cell lymphoma: value of CT in staging and determining prognosis.

OBJECTIVE: The usefulness of CT in diagnosing, staging, and establishing the prognosis in cutaneous T-cell lymphoma was assessed. CT abnormalities indicative of the disease, diffuse peripheral adenopathy and skin lesions, as well as less specific signs of generalized lymphoma, were correlated with clinical findings. MATERIALS AND METHODS: The study group comprised 33 patients from a total of 87 with pathologically proved cutaneous T-cell lymphoma who were seen at the University of Pittsburgh Medical Center between 1986 and 1991 and who had CT scans. All patients had body CT imaging with contiguous axial sections no thicker than 10 mm of the chest, abdomen, and pelvis; other CT studies were performed as clinically indicated. Because of the cutaneous nature of this lymphoma, collimation included the skin surface. RESULTS: In 10 of the 33 patients, all of whom had stage II or higher disease, abnormalities indicative of cutaneous T-cell lymphoma were seen on CT scans. All 10 had multiple areas of focal skin thickening or plaques several centimeters or more in diameter and 5 mm or greater in thickness affecting the dermal tissues while leaving the subcutaneous fat intact. Extension of individual lesions below the dermis was associated with the development of squamous cell cancers in two patients, both of whom had previous topical therapy. Seven of the 10 also had an unusual pattern of lymphadenopathy: the mediastinum or paraaortic regions were spared while enlarged peripheral nodes were seen in both the axillary and inguinal areas. Skin abnormalities were seen on CT scans of all patients with lymphadenopathy. CONCLUSION: CT findings in cutaneous T-cell lymphoma are related to the pathophysiology of the disease: cutaneous plaques and diffuse peripheral adenopathy that spare the mediastinal and paraaortic lymph nodes. Although the skin lesions can be easily evaluated clinically, secondary malignant neoplasms arising in treated skin lesions can be found with CT by their extension into the subcutaneous fat.

Immunological effects of treatment with sequential administration of recombinant interferon gamma and alpha in patients with metastatic renal cell carcinoma during a phase I trial.

Many anticancer mechanisms of the interferons have been proposed but none have been associated with clinical response to date. The biological activities of the interferons in vivo have included effects upon the natural killer cell, T- and B-lymphocytes, and macrophages. This report details a prospective study of the immunological effects on peripheral blood mononuclear cells of sequentially administered recombinant (r) interferon (IFN) gamma and rIFN alpha in 28 patients with metastatic renal cell carcinoma. Natural killer cell activity, T-cell phenotype (CD4, CD8, CD56, CD16, CD4/HLA-DR, CD8/HLA-DR, CD56/HLA-DR) and 2',5'-oligoadenylate synthetase were measured prior to therapy, during therapy, and following completion of treatment. Statistical analysis of all parameters was performed for the entire group, by individual patient, by dosage, by time, and by clinical response. An overall significant depression in natural killer cell activity and in the percentage of circulating CD56, CD16, and CD8+ cells were noted. Significant increases in 2',5'-oligoadenylate synthetase and in the percentage of circulating CD4 cells were also noted. Although an association between the magnitude of change in percentage of CD16+ cells and 2',5'-oligoadenylate synthetase and dosage of rIFN gamma and rIFN alpha, respectively, was observed, optimal biological dose of this sequence of rIFNs could not be determined due to the limited number of patients. A decrease in the percentage of circulating CD8+ cells was observed among patients with objective clinical response (partial and complete). Sequentially administered rIFN gamma and rIFN alpha can modulate immunological parameters in vivo in patients with metastatic renal cell carcinoma. A fall in percentage of circulating CD8+ cell is associated with response and suggests that this sequence of rIFN alpha and rIFN gamma might influence T-cell mediated antitumor activity.

A phase IA trial of sequential administration recombinant DNA-produced interferons: combination recombinant interferon gamma and recombinant interferon alfa in patients with metastatic renal cell carcinoma.

This study investigated the effects of sequentially administered recombinant interferon gamma (rIFN gamma) and recombinant interferon alfa (rIFN alpha) in 36 patients with metastatic renal cell carcinoma (RCC). rIFN alpha was subcutaneously administered daily for 70 days at dosages that varied (2.5, 5, 10, and 20 x 10(6) U/m2) across four cohorts of patients. Within each cohort of patients receiving a given dose of rIFN alpha, three subsets of patients received either 30, 300, or 1,000 micrograms/m2 rIFN gamma. rIFN gamma was administered intravenously for 5 days every third week, 6 hours prior to administration of rIFN alpha. Dose-limiting toxicity (DLT) included constitutional symptoms, leukopenia, nephrotic syndrome with acute renal failure, hypotension associated with death, and congestive heart failure. DLT was related more often to the rIFN alpha dose level than to rIFN gamma dose level. Maximum-tolerated dose (MTD) was 10 x 10(6) U/m2 rIFN alpha and 1,000 micrograms/m2 rIFN gamma. Six patients failed to complete a minimum of 21 days of therapy due to toxicity or rapid progression of disease. Clinical responses were seen in eight of 30 assessable patients. Two patients experienced complete remission and have remained in complete remission 20+ and 22+ months. An additional six patients have shown partial responses for 4 to 18+ months. One patient in partial remission continues to show slow regression of pulmonary and liver lesions off therapy with rIFNs. Clinical responses have remained durable for patients with complete remissions and patients with partial remissions. The results of this study suggest that toxicities associated with combination rIFN therapy can be reduced by administering these agents sequentially as opposed to simultaneously.

Proton magnetic resonance spectroscopy of small regions (1 mL) localized inside superficial human tumors. A clinical feasibility study.

It is demonstrated that the stimulated echo technique for proton magnetic resonance spectroscopy (MRS) can be used to study metabolites in volumes of interest (VOIs) as small as 1 mL localized within superficial human tumors. Access to these small VOIs is important for characterization of tissue regions within a tumor, before, during and after treatment. Spectral appearance resembles that from studies on extracts, and cell suspensions and perfused cells of several tumor types. For the first time proton MRS was used to study cancer treatment in vivo in humans, for a case of radiation treatment of squamous cell carcinoma. No spectral evidence of changed metabolism prior to reduction in tumor size was found. However, after the first period of radiation (39 Gy, 4 weeks), complete disappearance of the metabolite resonances from the spectrum was observed, while a considerable mass still remained, suggesting effective cell destruction upon treatment. Needle aspiration cytology of this mass showed absence of malignant cells, supporting this result.

The effect of image processing on chest radiograph interpretations in a PACS environment.

The question of whether image processing affects a radiologist's diagnostic performance is becoming more important as the digital modalities proliferate. In the multi-observer study reported, the performance of radiologists who interpret a series of posteroanterior digitized chest images displayed on a high-resolution workstation, with and without a set of image processing options, is determined. These include brightness, contrast, reverse look-up tables (black-bone), and two edge enhancement options. Three hundred images were evaluated twice (once in each mode) by each of seven board-certified radiologists, who recorded their confidence ratings for the presence or absence of one or more of the following abnormalities: interstitial disease, nodule, and pneumothorax. The original, unprocessed digital image was available for reference for those sessions in which the processing options were available. With the exception of one reader, receiver operating characteristic (ROC) analysis showed no statistically significant difference between the two modes (with and without processing) for the detection of any of the different abnormalities by individual readers. Likewise, the group as a whole showed no significant difference (P less than .05) for detection of any of the three abnormalities between the two reading modes.

Does knowledge of the clinical history affect the accuracy of chest radiograph interpretation?

To examine the effect that a concise, objective, and potentially computer-extractable history would have on diagnostic accuracy in the interpretation of chest radiographs, we designed and tested a computerized patient-history form that could be integrated realistically into the clinical environment. We performed a series of studies in which 247 posteroanterior normal (79) and abnormal (168) chest radiographs were interpreted by four board-certified radiologists, both with and without accompanying clinical histories. The radiologists recorded their confidence rating of the presence or absence of one or more of the following abnormalities: interstitial disease, nodule, and pneumothorax. Analysis of receiver operating characteristics showed that, with the exception of interpretation of one abnormality by one radiologist, there were no statistically significant differences (p less than .05) between cases interpreted with and without the history form for any of the radiologists. The results of our study suggest that knowledge of clinical history does not affect the accuracy of chest radiograph interpretations for the detection of interstitial disease, nodules, and pneumothoraces. These results may not be applicable to other clinical situations.

Mediastinal large cell lymphoma. An uncommon subset of adult lymphoma curable with combined modality therapy.

Thirty adults with large cell lymphoma predominantly localized to the mediastinum diagnosed at the Massachusetts General Hospital between 1976 and 1985 were identified. The median age of the 20 females and 10 males was 34 years. All but one presented with symptoms due to an enlarging mediastinal mass, which was localized in 22 patients (73%) and exceeded 10 cm in maximal diameter in 65%. Superior vena cava syndrome and large pleural and pericardial effusions were common. Employing CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) and consolidation radiation therapy in most cases, 80% achieved a complete remission and 59% survive failure-free at 5 years by actuarial calculation. The size of the mediastinal mass adversely affected failure-free survival (89% vs. 40%, P less than 0.05). No other pretreatment risk factor predicted outcome, but more intense chemotherapy was associated with improved survival (P = 0.035). Large cell mediastinal lymphoma is a locally invasive, often bulky malignancy with a predilection for young women; disease of low or moderate bulk is curable with full dose CHOP chemotherapy and consolidation radiation, but bulky disease requires more aggressive treatment.

Severe acute pancreatitis after percutaneous biopsy of the pancreas.

A retrospective review of 184 pancreatic biopsies in 178 patients was performed to assess the prevalence of severe postbiopsy pancreatitis. The size, contour, and pathology of the lesions biopsied; the course of the needle (i.e., through bowel or other viscera); the size of the needle; the number of needle passes made; and the guidance technique used were analyzed. Severe pancreatitis developed in five cases (five patients) 5/184 or 3% of the biopsies), usually within 24-48 hr. Three of the five patients who developed pancreatitis had true-negative biopsies (normal pancreas) proved either at surgery (two) or at clinical follow-up (one). The diagnoses for the two remaining patients were adenocarcinomas. In four of the five patients, the diagnosis of severe pancreatitis was made by inspection at surgery. The fifth case was diagnosed by CT. Three patients who underwent surgery and one patient who had percutaneous drainage recovered from the pancreatitis. The fifth patient died despite surgical intervention. All five patients with pancreatitis had masses 3 cm or smaller as compared with the overall group, in which 71 (39%) of the 184 biopsies performed had masses smaller than 3 cm. Overall, 18% of the biopsies were true negative, compared with the 60% true-negative rate in the pancreatitis group. The bowel was transgressed in 21% of all 178 patients, including three of the five pancreatitis patients. We conclude that although the risk of pancreatitis is exceedingly small in percutaneous needle biopsies, it may occur, and at a higher rate than previously reported.

Three-dimensional volumetric assessment of response to treatment: stage I and II diffuse large cell lymphoma of the mediastinum.

From 1981 to 1986, 12 patients with Stage I and II diffuse large cell lymphoma of the mediastinum were treated with 4 or more cycles of multiagent chemotherapy and for nine patients this was followed by mediastinal irradiation. The response to treatment was assessed by three-dimensional volumetric analysis utilizing thoracic CT scans. The initial mean tumor volume of the five patients relapsing was 540 ml in contrast to an initial mean tumor volume of 360 ml for the seven patients remaining in remission. Of the eight patients in whom mediastinal lymphoma volumes could be assessed 1-2 months after chemotherapy prior to mediastinal irradiation, the three patients who have relapsed had volumes of 292, 92, and 50 ml (mean volume 145 ml) in contrast to five patients who have remained in remission with residual volume abnormalities of 4-87 ml (mean volume 32 ml). Four patients in prolonged remission with CT scans taken one year after treatment have been noted to have mediastinal tumor volumes of 0-28 ml with a mean value of 10 ml. This volumetric technique to assess the extent of mediastinal large cell lymphoma from thoracic CT scans appears to be a useful method to quantitate the amount of disease at presentation as well as objectively monitor response to treatment.

Stage IA to IIB mediastinal Hodgkin's disease: three-dimensional volumetric assessment of response to treatment.

From 1979 to 1986, the response to treatment of 53 patients with stage IA to IIB mediastinal Hodgkin's disease was evaluated by three-dimensional volumetric analysis using thoracic computed tomographic (CT) scans. The mean initial volume of mediastinal disease in 34 patients treated with mantle and para-aortic irradiation was 166 mL, whereas for 19 patients treated with two to six cycles of multiagent chemotherapy and mantle and para-aortic irradiation the mean initial volume was 446 mL. Preliminary data suggested that patients with mediastinal volumes of less than 200 mL had a lower mediastinal relapse rate (13%) than patients with volumes greater than 200 mL (32%). For 12 patients receiving six cycles of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP), those with a greater than 85% reduction in volume 1 to 2 months after chemotherapy had a lower incidence of mediastinal relapse (zero of six, 0%) compared with patients having 85% or less reduction in volume (four of six, 67%). The primary value of this technique is that it provides a sensitive assessment of response to treatment and may aid in monitoring the effectiveness of a given treatment.

Computed tomography in the evaluation of lymphoma of the uterine cervix.

Primary involvement of the uterine cervix is a rare presentation of extranodal lymphoma. The clinical and computed tomography findings are described in four patients ranging from 23 to 74 years of age. All presented with vaginal bleeding. Computed tomography findings were similar to those of other primary pelvic neoplasms, with diffuse uterine enlargement and lobular contour alteration often mimicking fibroids. Lymphadenopathy was not observed in comparison to secondary lymphoma of the female genitalia. All patients had excisional biopsies. One patient had an initial TAH and BSO. Histology was varied with one case of large cell lymphoma, one of diffuse histiocytic, one of unclassifiable poorly differentiated lymphoma, and one of nodular poorly differentiated lymphocytic lymphoma that was finally classified as granulocytic sarcoma. Disease extent could be assessed by computed tomography and aided treatment planning. In conclusion, computed tomography was found to be useful in the evaluation of uterine lymphoma. Although the findings are not specific, the local tumor extent can be evaluated at the same time as other sites of potential involvement.