In vitro assessment of antineoplastic therapy. New indication for thoracotomy?

Selection and determination of the efficacy of antineoplastic agents has been dependent upon the trial and error method of observing measurable disease. Such methods subject the patient not only to loss of precious time but to needless toxicity if the drug is ineffective. The clonogenic assay, an in vitro assessment of tumor cell sensitivity to antineoplastic agents, has the potential for individualizing therapy. In this assay, tumor cells exposed to various drugs are cloned in soft agar. In the 16 primary and 24 metastatic pulmonary tumors tested with this technique, a growth rate of 80% was achieved. Fifty-five percent of the primary tumors and 60% of the metastatic lesions responded in vitro to one or more of the test drugs. There were twelve possible correlations between in vitro and in vivo results. In four of 12 assays, in vivo sensitivity was predicted and three of four patients demonstrated a clinical response. No drug that was inactive in vitro had activity in vivo. Prior knowledge of in vitro sensitivity may dictate a more aggressive surgical approach to pulmonary metastatic disease, whereas in vitro resistance would call for more conservative treatment. Just as with estrogen receptor status in breast cancer, data derived from the clonogenic assay may ultimately be of such import that thoracotomy would be warranted solely for the purpose of obtaining tissue for the assay.

Definition of human melanoma-associated cell surface antigens by hybridoma monoclonal antibodies.

Many human melanoma cell lines express HLA-D antigens in addition to HLA-A, -B, and -C specificities. Hybridoma antibodies produced after sensitization with melanoma cells are directed not only against tumor-associated antigens but against HLA and Ia-like specificities. Paired human melanoma cell lines and autologous lymphoblast lines were used to identify those monoclonal hybridoma antibodies that define human melanoma-associated antigens. Autologous lymphoblast lines were used to exclude hybridoma antibodies directed against HLA and Ia-like specificities. Using this method, we have identified several cell surface antigens that are expressed on the majority of human melanoma cell lines tested.

Delayed diagnosis of breast cancer as a result of normal mammograms.

Review of the effects of a normal mammogram on the treatment of 36 women with palpable breast carcinomas during a two-year period showed that 17 patients had biopsies performed within two months of their normal mammograms and 19 patients had biopsies delayed for three to 24 months. Of the 17 who had biopsies within one month of a normal mammogram, three (17.6%) had extension of disease to axillary nodes. Of 19 patients whose biopsy was delayed, cancer was found in axillary nodes of 11 (57.9%). Normal mammograms should not preclude biopsy of a breast mass.

Biopsy of thoracic neoplasms for assay of chemosensitivity. New indication for thoracotomy.

Eighty-six thoracic neoplasms, both primary and metastatic, were removed at thoracotomy from 86 patients and were tested for chemosensitivity in the clonogenic assay. Substantial tumor growth was achieved in 79% (67/86). Fifty-two percent (16/31) of the primary lung tumors and 45% (15/33) of the metastatic tumors were sensitive to at least one tested drug. Clinical correlations between in vitro chemosensitivity and in vivo response were possible in 20 patients. The assay was 83% accurate for predicting in vivo sensitivity and 86% accurate for predicting in vivo resistance. The value of the assay as it pertains to lung cancer has been demonstrated. On the basis of the results, thoracotomy is indicated in selected patients as a diagnostic procedure to obtain tissue for chemosensitivity testing.

Clinical correlations with drug sensitivities in the clonogenic assay: a retrospective study.

We tested the ability of the in vitro clonogenic assay (CLAS) to predict clinical response for patients with solid tumors. Patients had objectively measurable disease and received at least one course of chemotherapy. The correlation between clinical responses and in vitro sensitivity was evaluated retrospectively. Tumor types included melanoma (19), sarcoma (five), hepatoma (one), and carcinoma of the stomach (two), colon (three), lung (one), and breast (one). Five patients received two separate courses of chemotherapy with different drugs or drug regimens. In nine of 11 (82%) instances, tumors were sensitive to a particular drug, and the patient had at least 50% regression of tumor following treatment with the tested drug. Two patients whose tumors were sensitive in vitro had no evidence of clinical response. In 25 of 26 assays, the CLAS accurately predicted tumor resistance, and only one patient had evidence of clinical response (96%). Associations of in vitro results with clinical responses were highly significant. The CLAS can accurately predict the chemosensitivity of a variety of solid tumors.

Chromosomal abnormalities of a mediastinal embryonal cell carcinoma in a patient with 47,XXY Klinefelter syndrome: evidence for the premeiotic origin of a germ cell tumor.

Trypsin-Giemsa banding studies were performed on 30 tumor cells from an embryonal cell carcinoma originating in the mediastinum of an 18-year-old male with the Klinefelter syndrome (47,XXY). All tumor cells revealed an XXY chromosomal pattern with the addition of extra chromosomes. Electrophoretic patterns of the patient's red blood cells and tumor cells were identical. These data suggest that this germ cell tumor originated from a primordial germ cell in which oncogenesis had occurred prior to meiotic division.

Teaching three-dimensional surgical concepts of inguinal hernia in a time-effective manner using a two-dimensional paper-cut.

BACKGROUND: Because inguinal hernia repair is difficult for third-year students to comprehend, a 2-dimensional paper-cut was developed to teach the concepts of inguinal hernia in a time-effective manner before students' observation of herniorrhaphy in the operating room. METHODS: Using Adobe Illustrator 5.5 for MacIntosh, a 2-dimensional inexpensively printed paper-cut was created to allow students to perform their own simulated hernia repair before observing surgery. The exercise was performed using a no.15 scalpel or an iris scissors and was evaluated by comparing 10-question pre-tests and post-tests. RESULTS: Seventy-five students performed the exercise, most completing it within 15 minutes. The mean pre-test score was 7.4/10 and the mean post-test score was 9.1/10. Students performing the paper-cut reported better understanding when observing actual herniorrhaphy. CONCLUSIONS: A 2-dimensional paper-cut ("surgical origami") may be a time-effective method to prepare students for the observation of hernia repair.

Teaching a multidisciplinary approach to cancer treatment during surgical clerkship via an interactive board game.

BACKGROUND: Although educators agree that the approach to cancer management must be multidisciplinary, medical students usually observe cancer patients through the eyes of a single specialist at any given time. METHODS: In order to teach third-year medical students that cancer management is multidisciplinary, we developed the Oncology Game, an interactive, computer-assisted board game built on the principles of self-directed learning and student-student interaction. Eight "patients" with different histologic types of cancer are distributed randomly to 4 students, who play in teams of 2. The object is for the team to obtain the best treatment for its patients by advancing them via a roll of dice through surgical, medical, and radiation oncology clinics in the order most logical for the patient's particular cancer type. To test improvement in cognitive skills as a function of play, 16 students participated in a tournament taking parallel pretest and posttests before and after each round of play. RESULTS: Students demonstrated a statistically significant change in the total number of questions answered correctly each time they played the Oncology Game (F = 4.16, P = 0.018; Pretest Round 1: 8.88 +/- 0.58; Posttest Round 1: 9.63 +/- 0.42; Pretest Round 2: 10.75 +/- 0.62; Posttest Round 2: 11.5 +/- 0.85). Post hoc pairwise comparison revealed a significant improvement in student performance after playing two rounds of the Oncology Game. Based on the postgame survey, students felt they improved their understanding of oncologic principles (4.56 +/- 0.13), knowledge of malignancies (4.50 +/- 0.13), and appreciation for the multidisciplinary nature of cancer management (4.56 +/- 0.13). CONCLUSIONS: Improved test scores and postgame survey results demonstrate that third-year medical student students can learn about basic oncology principles and gain an appreciation for oncology as a multidisciplinary field of medicine through an interactive, computer-assisted board game.

Use of a paper-cut as an adjunct to teaching the Whipple procedure by video.

BACKGROUND: Medical students often experience difficulty comprehending anatomic relationships of complex operations to which they are exposed during surgical clerkship. Pancreaticoduodenectomy, the Whipple procedure, is one such operation. Although video recordings are available to facilitate the learning of the Whipple procedure, commercially available tapes are not self-explanatory to the uninitiated. Since we have previously demonstrated that third-year medical students could learn the operative steps of inguinal herniorraphy by a paper-cutting exercise, we set out to determine whether an exercise of similar design could enhance a student's comprehension of the Whipple procedure. METHODS: Using Adobe Illustrator 5.5 for MacIntosh, an exercise was developed on a 8.5 x 11-inch paper that could be distributed to students for self-administration. The exercise was performed using a #15 scalpel or an iris scissors. Thirty-seven students were randomized into two groups. Each student received a pretest of questions focusing on the Whipple procedure. Group I was shown an 18-minute commercially available teaching video on the Whipple procedure. Group II was given the Whipple origami exercise, which required 20 minutes to complete. A first posttest was administered to each group. Next, the groups switched exercises, and a second posttest was administered. RESULTS: There was no significant difference between the groups' pretest scores (two-tailed t test, P = 0.290). Group I improved its score from an average of 64.21 (SD 14.27) to 67.89 (SD 13.16) after watching the video, and further to 77.89 (SD 14.37) after completing the paper-cut exercise. Group II improved from 60.00 (SD 9.43) to 78.95 (SD 11.00) after performing the paper-cut, but derived no additional measurable benefit from watching the video, average score 74.74 (SD 18.37). After the first exercise, students who performed the paper-cut showed a significantly greater improvement in test scores compared with students who saw the video (P = 0.0035 by Mann-Whitney U). After both groups had completed the exercises, the mean changes from baseline were no longer significantly different (P = 0.58 by Mann-Whitney U). CONCLUSION: As a single educational intervention, the paper-cut exercise was a more effective teaching device than the video in the given time frame. The origami model may be generalized to a variety of surgical procedures and appears to be a valuable adjunct to traditional teaching.

Modification of a choledochoscope for extraction of difficult biliary stones.

Cholelithiasis is a common problem in the United States, affecting 10 to 15 per cent of the population. Although only one per cent of these patients have intrahepatic gallstones their discovery intraoperatively may present a technical challenge for the surgeon. This paper describes a simple method for dislodging difficult intrahepatic biliary stones: modification of a rigid choledochoscope to permit use of a biliary Fogarty catheter and Segura basket under direct visualization.

Clinical application of the clonogenic assay.

Simple methods were developed for cloning human solid tumors; 68 percent of the tumors processed formed at least 30 colonies within two to four weeks. The accuracy of the clonogenic assay for predicting clinical response was determined in a prospective, correlative study. Eight-four patients had objectively measurable disease and had at least one course of chemotherapy. Tumor types included melanoma (33), lung (12), colon (7), breast (7), stomach (4), ovarian (12), sarcoma (7), and hepatoma (2). For patients whose tumors were sensitive in vitro to a particular drug, clinical response was seen in 21/25 cases (84 percent). Tumor resistance was found in 59 instances, and 54 patients (92 percent) had no clinical response to the same drugs. Associations between in vitro chemosensitivities and clinical course were highly significant.

Monoclonal antibodies to 125 kd and 95 kd proteins on human melanoma cells: comparison with other monoclonal-defined melanoma antigens.

Two monoclonal antibodies produced by hybridomas were identified by an indirect 125I-protein A binding assay that define cell surface antigens expressed on cultured human melanoma cells but not on autologous lymphoblastoid cells. The first antibody, 705F6 (an IgG2b immunoglobulin), bound to 14/14 melanoma lines, 6/9 carcinomas and sarcomas, 7/7 gliomas and neuroblastomas, 2/2 fetal cell lines, 0/8 lymphoblastoid cell lines, and weakly to 2/4 leukemia lines. The second monoclonal antibody, 436G10 (IgG1), reacted with 10/14 melanomas 5/13 carcinomas and sarcomas, 2/7 gliomas and neuroblastomas, and weakly with the fetal cells, but not with the leukemic or lymphoblastoid cell lines. Comparison of 705F6 and 436G10 with 28 other monoclonal antibodies from different laboratories identified several with similar binding patterns to a panel of tumor and nontumor cell lines. Crossblocking of 125I-labeled 436G10 was not observed by R23, I12 or L10 antibodies. However, 705F6 was completely blocked by monoclonal 376.96S, showing that these two antibodies bind to the same antigenic determinant. The 705F6 antibody immunoprecipitated a 95 kd (kilodalton) membrane protein and the 436G10 antibody bound a 125 kd protein from 125I-labeled melanoma cells. The broad distribution of these two proteins on melanomas and other solid tumors suggests that they define common oncodevelopmental antigens expressed on proliferating cells.

Results of ilioinguinal dissection for stage II melanoma.

Eighty-two Stage II melanoma patients with inguinal lymph node metastases have undergone ilioinguinal node dissections at UCLA during the past 10 years. Twenty-four (29.3%) patients had involvement of both inguinal and iliac nodes, whereas 58 (70.7%) patients had only inguinal metastases. The frequency of iliac metastases did not relate to location, Clark's level or thickness of the primary tumor or interval from diagnosis of primary tumor to lymphadenectomy, but was related to the number of inguinal nodes involved with metastases, rising from 14.6% with one positive inguinal node to 50% with four or more inguinal node metastases. Twenty of 24 (83.3%) patients with inguinal and iliac node metastases developed recurrent disease, whereas 32/58 (55.2%) patients with only inguinal node metastases and no tumor in the iliac nodes recurred. The time to recurrence was much shorter if iliac nodes were diseased (median disease-free interval 5.8 months versus 25.6 months). Three of five patients with clinically negative but histologically positive inguinal and iliac nodes survived 5 years, while only 1/18 patients with clinically positive inguinal nodes and diseased iliac nodes lived 5 years. Those with clinically negative but histologically positive inguinal nodes and iliac metastases had recurrence and survival rates similar to those with clinically negative but histologically positive inguinal nodes and no iliac metastases. Ilioinguinal lymphadenectomy provides significant prognostic information for Stage II patients with inguinal metastases and may be therapeutic for those with iliac metastases. Therefore, ilioinguinal dissection is the operation of choice for melanoma patients with regional metastases to the inguinal area.

Melanoma metastatic to "lipomata".

Three patients presented with solitary melanoma metastases that mimicked a simple "lipomata." On further investigation each patient had a discrete fatty tissue tumor mass surrounding a melanoma metastasis. The presence of an enlarging mass in patients with a history of melanoma should be viewed with suspicion and a biopsy should be performed.

Teaching medical students by role playing: a model for integrating psychosocial issues with disease management.

BACKGROUND: Medical students on third-year rotations seem to be focused more on the particulars of disease management than on patient management. They often pay too little attention to the psychological and social needs of the patient and to the importance of working in a multidisciplinary team. The authors postulated that a model for teaching breast cancer management that included role playing, self-study, and active student involvement would facilitate the integration of psychosocial and affective issues into scientific content and would demonstrate the importance of the team approach in managing patients with breast cancer. METHODS: One month following a problem-oriented, case-based, interactive session focusing on clinical management of breast disease, each student was assigned the role of either "patient" or one of four "specialists"-1) a general surgeon, 2) a medical oncologist, 3) a radiation oncologist, or 4) a plastic surgeon. A packet of readings containing discipline-specific information was distributed to each "specialist" and a similar preparation packet was distributed to each "patient." One week later students from each specialty met in "multidisciplinary groups" and five "patients" with written scenarios of recently diagnosed primary breast cancer rotated among them. Important decision-making choices were discussed in each consultation. Following their consultations in the "multidisciplinary" groups, the "patients" met with the entire group of 20-25 students and with physician faculty to discuss differences in the information obtained. They compared "specialists'" styles of presentation and attitudes. Specific issues involving coordination of care among "specialists" were carefully highlighted. RESULTS: All students participated and the teaching sessions were well received. CONCLUSIONS: Role playing facilitates the discussion of psychosocial issues and aptly demonstrates to students the need for a multidisciplinary approach to breast cancer treatment. This model is applicable to other types of cancer and to other groups of cancer educators.

Breast cancers: estrogen and progesterone receptor status as a predictor of in vitro chemotherapeutic response.

Although clinical observations have shown that estrogen receptor-positive (ER+) breast tumors are more responsive to hormonal therapy than ER-negative (ER-) tumors, it remains controversial whether ER status can predict chemotherapeutic response. To determine if there was any correlation between estrogen and progesterone values and in vitro chemosensitivity to various anticancer drugs, clonogenic (CA), estrogen (ERA), and progesterone (PRA) assays on breast cancers were performed on 100 patients. Clonogenic assays were performed using the double-layer soft agar technique with continuous drug exposures. ERAs and PRAs were performed using the charcoal-coated dextran method. Chemosensitivity was defined as 50% inhibition of colony formation. ERA was considered positive if greater than or equal to 5 fmole/mg cytosol and PRA positive if greater than or equal to 10 fmole/mg cytosol. Significant tumor growth (greater than 30 colonies/plate) was achieved in 81/100 assays. ERA and PRA values were not predictive of colony formation in vitro. Of all agents or combinations of agents tested (L-PAM, 5-FU, MTX, adriamycin, vinblastine, cis-plat, FAC, CMF), only the response to 5-FU correlated significantly with ERA. Eight of 11 (73%) of the ER- tumors were sensitive to 5-FU, whereas only 6/20 (30%) of ER+ tumors were sensitive (P less than 0.05). ER- tumors were also more likely to be sensitive to CMF (P = 0.09) and adriamycin (P = 0.07) than ER+ tumors. PRA values were not predictive of chemosensitivity, nor did combining PRA and ERA enhance the predictive value of ERA alone.

Chemosensitivity testing of human solid tumors. A review of 1582 assays with 258 clinical correlations.

To improve clinical interpretation and use of in vitro clonogenic assay results, the authors reviewed their experience to date with chemosensitivity testing of over 1500 solid tumors. All clonogenic assays were performed using a double-layer-soft-agar system with continuous exposure of cells to one concentration of standard anticancer drugs. Significant growth was defined as greater than or equal to 30 colonies/control plate. Clinical responses were determined according to standard criteria. Data were analyzed using two different criteria of in vitro sensitivity (greater than or equal to 50% and greater than or equal to 75% inhibition of colony formation) and independently for each histologic type of tumor. Overall, 68% of specimens plated produced significant growth in vitro. Cloning ability varied from 57% to 82% depending on tumor histology. The assay was 57% reliable for predicting in vivo sensitivity, and 92% reliable for in vivo resistance. Predictive accuracy for sensitivity varied from 30% to 86%, depending on the tumor histology. Use of greater than or equal to 50% ICF (inhibition of colony formation) as criteria for differentiating sensitivity from resistance proved most reliable, although criteria should be individualized for each tumor type to maximize predictive accuracy.

Screening to the converted: an educational intervention in African American churches.

BACKGROUND: African American women have higher incidences of breast and cervical cancers and African American men present with more advanced stages of colon and prostate cancers than do their non-African American counterparts. Since the church is central to the organization of the African American community, the authors set out to determine whether a church-directed educational project could influence parishioners to obtain cancer screening. METHODS: Three African American churches having memberships of 250, 500, and 1,500, respectively, were selected for their different socioeconomic strata: one congregation was composed mostly of working poor, the second was more affluent, and the third consisted primarily of retirees. During a five-week summer period, appropriate literature, health fairs, testimonials by cancer survivors, and visits by representatives of the medical community were used to increase awareness of cancer screening. Surveys regarding cancer-screening behaviors were distributed at the end of church services. Using the guidelines established by the American Cancer Society, individual recommendations for screening examinations were developed and sent to parishioners based on their survey responses. RESULTS: Of 437 parishioners surveyed (73% female, 27% male), 75% were 40 years old or older. Many reported up-to-date screening for breast (84%), cervical (78%), colon (62%), and prostate (89%) cancers. The results were remarkably similar in all three churches. Telephone follow-up seven months after the survey directed at the 120 parishioners identified as noncompliant for at least one cancer screening revealed that 49% had obtained the appropriate screenings. CONCLUSIONS: These African American churchgoers were well screened compared with estimated national averages, possibly due to previous efforts of the activist ministers in the churches selected. The message for cancer screening is heeded when delivered through the African American church.