Surgical outcomes among inflammatory bowel disease patients undergoing colectomy : results from a national database.

INTRODUCTION: Colectomy is relatively common in inflammatory bowel diseases (IBD), occurring more in Ulcerative Colitis (UC) as compared to Crohn's disease (CD). The surgical outcomes among this mixed population of patients are not well understood. This study aims to determine the predictors of post colectomy surgical outcomes in this patient population. METHODS: Using the National Surgical Quality Improvement Project (NSQIP) demographics, preoperative and post-operative data were analyzed for all patients undergoing colectomy for either CD or UC. Multiple variables were linked to several outcomes including mortality, anastomotic leak, and reoperation post colectomy. RESULTS: A total of 5049 IBD patients that underwent colectomy were identified. Rate of reoperation and anastomotic leak were significantly increased with steroid intake with an Odds Ratio (OR) of 1.66 (95% Confidence Interval (CI) (1.26-2.19)) and 1.81 (95%CI (1.34-2.45)) respectively. As for 30-day mortality, it was significantly lower among patients on steroid (OR=0.41; 95%CI (0.19-0.86)). Comparing UC to CD, anastomotic leaks were less common among UC patients (OR=0.53; 95%CI (0.37-0.76)), but 30-day mortality was significantly more prevalent among UC patients (OR=8.11; 95%CI (4.22-15.6)). CONCLUSION: Among IBD patients undergoing colectomy, major surgical complications except 30-day mortality appear to increase with the use of preoperative steroids.

Analysis of the HLA population data (AHPD) submitted to the 15th International Histocompatibility/Immunogenetics Workshop by using the Gene[rate] computer tools accommodating ambiguous data (AHPD project report).

During the 15th International Histocompatibility and Immunogenetics Workshop (IHIWS), 14 human leukocyte antigen (HLA) laboratories participated in the Analysis of HLA Population Data (AHPD) project where 18 new population samples were analyzed statistically and compared with data available from previous workshops. To that aim, an original methodology was developed and used (i) to estimate frequencies by taking into account ambiguous genotypic data, (ii) to test for Hardy-Weinberg equilibrium (HWE) by using a nested likelihood ratio test involving a parameter accounting for HWE deviations, (iii) to test for selective neutrality by using a resampling algorithm, and (iv) to provide explicit graphical representations including allele frequencies and basic statistics for each series of data. A total of 66 data series (1-7 loci per population) were analyzed with this standard approach. Frequency estimates were compliant with HWE in all but one population of mixed stem cell donors. Neutrality testing confirmed the observation of heterozygote excess at all HLA loci, although a significant deviation was established in only a few cases. Population comparisons showed that HLA genetic patterns were mostly shaped by geographic and/or linguistic differentiations in Africa and Europe, but not in America where both genetic drift in isolated populations and gene flow in admixed populations led to a more complex genetic structure. Overall, a fruitful collaboration between HLA typing laboratories and population geneticists allowed finding useful solutions to the problem of estimating gene frequencies and testing basic population diversity statistics on highly complex HLA data (high numbers of alleles and ambiguities), with promising applications in either anthropological, epidemiological, or transplantation studies.

High-dose chemotherapy and autologous stem cell transplant in adolescent patients with relapsed or refractory Hodgkin's lymphoma.

Fifty-eight adolescent patients with relapsed or primary refractory Hodgkin's lymphoma underwent high-dose chemotherapy (HDC) and autologous SCT (ASCT). The median age at ASCT was 17 years (range 14-21). The disease had relapsed in 24 patients (41%) and was refractory to initial chemotherapy in 34 (59%). ESHAP salvage chemotherapy before ASCT resulted in 88% response. After ASCT, complete remission (CR; including CR-unconfirmed) was seen in 41 patients (71%) and partial remission in 7 (12%). The overall response rate was 83%. One patient did not respond and nine (15%) had progressive disease. Three more patients achieved CR after consolidative radiation post-ASCT. There was no transplant-related mortality. At a median follow-up of 43 months from ASCT, 31 patients (53%) are alive in CR, 5 (9%) are alive with disease and 22 (38%) have died (21 from disease and 1 unrelated). The actuarial probabilities of event-free and overall (OS) survival are 45 and 55% at 11 years. The only negative prognostic factor for OS was the presence of B symptom at relapse or progression (11-year OS 27 vs 60%, P=0.003).

High-dose chemotherapy and autologous stem cell transplantation for Hodgkin's lymphoma in the kingdom of Saudi Arabia: King Faisal specialist hospital and research center experience.

We report our experience with high-dose chemotherapy (HDC) and autologous SCT (ASCT) in 66 patients out of 113 (113 patients out of 153 had complete analysis) with primary refractory Hodgkin's lymphoma (PR-HL) who received salvage chemotherapy followed by BEAM as HDC. Median age at ASCT was 23 years. Before salvage chemotherapy, stages I:II:III:IV were 2:21:14:29, bulky disease 27%, involvement of mediastinum 79%, spleen 26% and extranodal site 47%; 92% had ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin) as salvage. Post-ASCT evaluation showed response in 50 patients (76%), complete response (CR) in 37 (56%), partial response in 14 (21%), no response or stable disease in three (5%) and progressive disease in 10 (15%) patients. Six patients achieved CR after XRT (5) or surgery (1), making a total with CR of 43 (65%). From diagnosis and HDC, median follow-up is 38.5 and 22.8 months and median overall survival 78 and 57 months, respectively. EFS and overall survival (OS) are 36 and 64%, respectively. In all 47% patients are in CR. Twenty-two (33%) patients died of the disease. Multivariate analysis showed elevated lactic dehydrogenase (LDH) for EFS (P=0.041) and mediastinal involvement for OS (P=0.038) as negative prognostic factors. In conclusion, EFS and OS are only 36 and 64%, respectively. Elevated LDH and mediastinal involvement are poor prognostic factors.

Primary refractory Hodgkin's lymphoma: outcome after high-dose chemotherapy and autologous SCT and impact of various prognostic factors on overall and event-free survival. A single institution result of 66 patients.

We report our experience with high-dose chemotherapy (HDC) and autologous SCT (ASCT) in 66 patients with primary refractory Hodgkin's lymphoma (PR-HL) who received salvage chemotherapy followed by BEAM as HDC. Median age at ASCT was 23 years. Before salvage chemotherapy, stages I:II:III:IV were 2:21:14:29, bulky disease 27%, involvement of mediastinum 79%, spleen 26% and extranodal site 47%, 92% had ESHAP as salvage. Post-ASCT evaluation showed response in 50 patients (76%); complete response (CR) 37 (56%), partial response 14 (21%), no response or stable disease 3 (5%) and progressive disease in 10 (15%). Another five patients achieved CR after radiation therapy and one after surgery, making total CR 43 (65%). From diagnosis and HDC, median follow-up is 38.5 and 22.8 months and median overall survival (OS) 78 and 57 months, respectively. Event-free survival (EFS) and OS are 36 and 64%, respectively. In all, 47% patients are in CR. Twenty-two patients (33%) died due to disease. Multivariate analysis showed elevated lactate dehydrogenase (LDH) for EFS (P=0.041) and mediastinal involvement for OS (P=0.038) as negative prognostic factors. In conclusion, EFS and OS are only 36 and 64%, respectively. Elevated LDH and mediastinal involvement are poor prognostic factors.

ESHAP + fixed dose G-CSF as autologous peripheral blood stem cell mobilization regimen in patients with relapsed or refractory diffuse large cell and Hodgkin's lymphoma: a single institution result of 127 patients.

From 1996 to November 2004, 131 consecutive patients with relapsed or refractory diffuse large cell lymphoma (DLCL) and Hodgkin's lymphoma (HD) received ESHAP as mobilization chemotherapy before autologous peripheral blood stem cell transplant (ASCT). Patients received fixed dose G-CSF 300 microg SC bid starting 24-36 h after finishing mobilizing ESHAP. In all, four patients failed mobilization and are excluded. Characteristics of 127 patients: 68 males: 59 females. DLCL 49: HD 78. Initial stage I:II:III:IV:unknown was 15:34:33:42:3. Median age at ASCT 26 years. Median prior chemotherapy cycles were six [<6 (17 patients), 6-8 (90 patients), >8 (20 patients)]. Median ESHAP cycle used as mobilizer was third. Patients required 1, 2, 3, 4 apheresis were 93:25:8:1. Median total CD34+ cells/kg collected were 6.9 x 10(6) (DLCL 5.17 x 10(6) and HD 7.6 x 10(6)), patients weighing < or = 70 kg (93 patients) 6.54 x 10(6) and >70 kg (34 patients) 7.44 x 10(6) (P = 0.59), one apheresis (93 patients) 8.6 x 10(6)/kg and >1 apheresis (34 patients) 4.5 x 10(6) (P = 0.001). We conclude that ESHAP and G-CSF 300 microg SC bid is an effective mobilizing regimen even in patients >70 kg and most patients require only 1-2 apheresis.

Phase II study of neoadjuvant paclitaxel and cisplatin for operable and locally advanced breast cancer: analysis of 126 patients.

In an earlier study, we have demonstrated a high clinical and pathologic response rate of neoadjuvant paclitaxel (P) and cisplatin (C) for patients with locally advanced breast cancer (LABC). The current phase II study includes larger number of patients who had longer follow-up. A total of 126 consecutive patients with noninflammatory LABC (T2 >4 cm, T3 or T4, N0-N3, M0) were included in the study. Patients were scheduled to receive three to four cycles of the neoadjuvant PC (paclitaxel 135 mg m(-2) and cisplatin 75 mg m(-2) on day 1) every 21 days. Patients were then subjected to surgery and subsequently received six cycles of FAC (5-fluorouracil 500 mg m(-2), doxorubicin 50 mg m(-2), and cyclophosphamide 500 mg m(-2)) or four cycles of AC (doxorubicin 60 mg m(-2) and cyclophosphamide 600 mg m(-2)); all drugs were administered intravenously on day 1 with cycles repeated every 21 days. Patients then received radiation therapy, and those with hormone receptor-positive tumours were given adjuvant tamoxifen intended for 5 years. The median age was 41 years. Clinically, 12, 52, and 37% of patients had T2 >4 cm, T3, and T4, respectively. The mean tumour size was 7 cm (95% CI, 7.3-8.5). The clinical nodal status was N0, N1, and N2-N3 in 32, 52, and 17% of patients, respectively. Disease stage at diagnosis was IIA (2%), IIB (32%), IIIA (28%), and IIIB (39%). Clinical assessment of the primary tumour and the axillary nodal status after primary chemotherapy showed that 35 patients (28%) achieved complete response (cCR), while 80 (63%) demonstrated partial response to PC. Of patients with evaluable pathologic data of the primary tumour (123 patients), complete pathologic response (pCR) was achieved in 29 patients (24%), and an additional nine (7%) only had a microinvasive disease. Moreover, 20 of the 122 patients (16%) had no residual disease in the primary tumour or in the axillary nodes. Failure to attain cCR predicted failure to achieve pCR. At a median follow-up of 37.5 months (95% CI, 31.5-43.3), 71% were alive with no recurrence, 16% were alive with evidence of disease, and 13% were dead. Of the 122 patients who had surgery, 36 (29%) developed recurrence including one of the patients who attained pCR. The median overall or disease-free survival has not been reached with a projected 5-year overall survival (OS) and disease-free survival (DFS) of 85% (+/-4%) and 63% (+/-5%), respectively. On multivariate analysis, clinical response of the primary tumour, pathological response of the primary tumour, and the pathological nodal status were identified as independent prognostic variables for DFS. No variable, however, was identified to prognosticate OS. PC was acceptably safe. Neoadjuvant PC as used in this phase II study in a multidisciplinary strategy was highly effective. Clinical and pathologic responses remain the most important variables that predict outcome.

High complete pathological response in locally advanced breast cancer using paclitaxel and cisplatin.

BACKGROUND: In an earlier study, we have demonstrated a high response rate in metastatic breast cancer using paclitaxel (P) and cisplatin (C). A phase II study using the same regimen (PC) has been conducted in locally advanced breast cancer (LABC). METHODS: A total of 72 consecutive patients with non-inflammatory LABC (T2 > or = 4 cm, T3 or T4, N0-N2, M0). Patients were scheduled to receive 3-4 cycles of the neoadjuvant PC (paclitaxel 135 mg/m2 and cisplatin 75 mg/m2 on day 1) every 21 days. Patients were then subjected to surgery and subsequently received 6 cycles of FAC (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2) or 4 cycles of AC (doxorubicin 60 mg/m2, and cyclophosphamide 600 mg/m2). Patients then received radiation therapy, and those with hormone receptor positive tumors were given adjuvant tamoxifen intended for 5 years. RESULTS: The median age was 39 years (range, 24-78). Clinically, 7%, 58%, and 35% of patients had T2 > or = 4 cm, T3, and T4, respectively. Disease stage at diagnosis was IIB (33%), IIIA (27%), and IIIB (40%). Complete and partial clinical response to PC was demonstrated in 13 (18%), and 52 (72%) patients, respectively. Of those patients with evaluable pathologic response (68 patients), complete pathologic response (pCR) was achieved in 15 (22%) patients. At a median follow-up of 22 (+/- 3.5) months, 58 (81%) were alive with no recurrence, nine (12%) were alive with evidence of disease, and five (7%) were dead. None of the patients achieving pCR has developed any relapse. The median overall survival has not been reached for all 72 patients with a projected 3-year survival (+/- SE) of 90% (+/- 4%). The median progression-free survival (PFS) was 42.1 (+/- 4.8) months with a projected PFS of 74% +/- 7% at 3-years (for 68 patients). CONCLUSIONS: PC regimen in LABC produced a high pCR. The contribution of the other added modalities to survival could not be assessed.

Myelointegration of titanium implants: B lymphopoiesis and hemopoietic cell proliferation in mouse bone marrow exposed to titanium implants.

Multinucleated giant cells have been observed at interfaces between bone marrow and titanium implants in mouse femurs. This raises concern that macrophage-derived factors might perturb local lymphohemopoiesis, possibly even predisposing to neoplasia in the B lymphocyte lineage. It has been found that an implant-marrow interface with associated giant cells persists for at least 1.5 years. Precursor B cells show early increases in number and proliferative activity. At later intervals, however, they do not differ significantly from controls, and there are no perturbations in spatial localization of either B lineage cells or DNA-synthesizing hemopoietic cells. The results of this investigation in mice demonstrate that, following initial marrow regeneration and fluctuating precursor B cell activity, and despite the presence of giant cells, titanium implants apparently become well-tolerated by directly apposed bone marrow cells in a lasting state of "myelointegration."

Adding high-dose tamoxifen to CHOP does not influence response or survival in aggressive non-Hodgkin's lymphoma: an interim analysis of a randomized phase III trial.

PURPOSE: CHOP is the standard regimen currently used in the management of the majority of patients with aggressive non-Hodgkin's lymphoma (NHL). However, CHOP only produces 30-35% long-term survival. We hypothesized that adding high-dose tamoxifen, which is known to have multiple drug resistance-modulatory effects, to the CHOP regimen could increase the response rate, and consequently enhance the survival of patients with NHL. PATIENTS AND METHODS: In a prospective, controlled, and randomized study, eligible adult patients with aggressive NHL were randomized between CHOP only (Group I), or CHOP plus high-dose tamoxifen (Group II). The primary aim was to assess the effect of tamoxifen on complete response (CR) rate, with the secondary evaluation of tamoxifen potential impact on survival. The interim analysis of this study is presented. RESULTS: Fifty-one and forty-seven evaluable patients were randomized to Group I and Group II, respectively. The median age of all patients was 53 y (range 18-78 y). The two groups had comparable distributions of the pretreatment prognostic variables. The CR for patients in Group I was 80% (41 patients) as compared with 74% (35 patients) in Group II (P=0.48). Likewise, there was no apparent difference in the partial remission rates between the two groups (6% vs 15%, respectively). Of patients who initially attained CR, 15 (37%) and 10 (29%) subsequently relapsed in Groups II and I respectively (P = 0.45). The NHL International Prognostic Index (IPI) was the only factor that predicted attaining CR. At the time of this interim analysis, the actuarial-estimated overall survival (OS) probability (+/-S.E.) for the entire population at 5 y was 58% (+/-6) with no survival difference between the two groups (P=0.51). Only attaining CR and the IPI predicted OS probability. The probability of remaining event-free at 5 y (+/-SE) for those achieving CR was 72% (+/-9), and there was no significant difference between the two treatment groups (P=0.68). Toxicity profile was similar in the two groups. CONCLUSION: Based on this interim analysis, combining high-dose tamoxifen, as used in this study, with the CHOP regimen has failed to have any favorable effect on the outcome of patients with aggressive NHL, and therefore cannot be recommended for future trials.

Primary gastric non-Hodgkin's lymphoma: clinical features, management, and prognosis of 185 patients with diffuse large B-cell lymphoma.

BACKGROUND: Primary gastric non-Hodgkin's lymphoma (PG-NHL) is common in Saudi Arabia. This has prompted the analysis of a large series of patients with PG-NHL having high-grade diffuse large B-cell lymphoma (DLCL) in order to define the clinical features and outcome of this disease. PATIENTS AND METHODS: The data of all adult patients in the series with PG-NHL having DLCL histology were retrospectively reviewed. Patients were eligible if they had biopsy-confirmed diagnoses obtained by endoscopy or following laparotomy. RESULTS: Over a 16-year period, 185 patients with DLCL PG-NHL were identified and their data were reviewed. Patients had a median age of 54 years. In 53% of them only one initial therapeutic modality was given, while 47% were managed by a multi-modality approach. One hundred forty patients (76%), 19 (10%), and 26 (14%) attained complete remission (CR), partial remission, and no response/progressive disease, respectively. Multivariate analysis showed that poor performance status and advanced stage were negatively associated with the likelihood of attaining CR. Over a median follow-up of 54 months, 118 (64%) of the patients were alive and disease-free, 17 (9%) were alive with evidence of disease, and the remaining 50 (27%) were dead. The projected 5-year and 10-year overall survivals (OS) (+/- SD) were 68% (+/- 4%) and 61% (+/- 6%), respectively. The Cox proportional hazards model identified the same variables of response as adverse prognostic factors of survival. Using the influence of performance status, and stage, a prognostic index was constructed to recognize three prognostically distinctive risk categories with overall survival proportions of 87%, 61%, and 45%, respectively. The unadjusted International Prognostic Index, however, failed to classify patients into prognostically meaningful risk strata. Of the 140 patients who achieved CR, the median disease-free survival (DFS) was not reached, but the predicted 5- and 10-year DFS were 82% and 75%, respectively. A multivariate analysis identified poor performance status as the only independent prognostic covariate that adversely influenced DFS. Our analysis showed that compared with single-modality management, multi-modality strategy attained significantly higher CR, and advantageous OS and DFS. CONCLUSIONS: This large series characterized the clinico-pathologic features and outcome of patients with DLCL PG-NHL. Performance status, and stage significantly influenced patient outcome. A prognostic index was developed and it identified three prognostically distinctive risk groups; however, prospective validation is warranted.

Primary pancreatic non-Hodgkin's lymphoma in a renal transplant recipient.

Primary pancreatic non-Hodgkin's lymphoma (NHL) is rare and accounts for less than 1% of all lymphomas. The development of NHL following transplant is well recognized. However, there are no previous reports on localized lymphomatous pancreatic involvement in a transplant patient. We report on the first case of primary pancreatic NHL developing in a renal transplant recipient. The patient was treated without reducing immunosuppression and received combination chemotherapy and radiation. The patient is in complete remission at 10-month follow-up.

A phase II trial of circadian-timed paclitaxel and cisplatin therapy in metastatic breast cancer.

PURPOSE: In a phase II study with combination paclitaxel and cisplatin in metastatic breast cancer using circadian timing, we attempted to maximise response and minimise toxicity. MATERIALS AND METHODS: Forty-one patients with histologically-proven metastatic breast cancer with or without previous chemotherapy were treated with Paclitaxel 135 mg/m2 administered as a three-hour infusion at 06.00 hours followed by cisplatin 75 mg/m2 as a one-hour infusion at 18.00 hours utilising circadian timing. Six cycles were planned once every 21 days. Response assessment was performed every two cycles, and toxicity was measured using WHO criteria. RESULTS: All patients were evaluable for response and toxicity. There were nine (22%) complete responses (CR), and 24 (59%) partial responses (PR), for an overall response rate of 80% (95% confidence interval (CI) 69-92). Responses were seen in patients previously treated with anthracyclines (75%) (95% CI 57-92), and in patients who had had no prior chemotherapy (90%) (95% CI 71-100). Responses were seen in all metastatic sites: liver 80%, lung 76%, bone 69%, and soft tissues 71%. The overall median response duration was seven months (range 3-26, 95% CI 5.0-9.8), and 14 of the responses (42%), (95% CI 28-62) were durable. A total of 212 cycles of chemotherapy were given. There were 15 episodes (7%) of grade 3-4 neutropenia, seven (3.2%) of grade 3-4 neurologic toxicity, and three (1.4%) of grade 3-4 nephrotoxicity. There were no toxic deaths. CONCLUSION: The combination of paclitaxel and cisplatin is very effective in metastatic breast cancer, and with application of circadian timing, toxicity has been acceptable. This combination is being tested as primary therapy in locally-advanced breast cancer at our institution.

Primary pancreatic non-Hodgkin's lymphomas.

Primary pancreatic lymphomas are rare. We reviewed our experience at King Faisal Specialist Hospital and Research Center; the hospital tumor registry identified five patients with primary pancreatic lymphoma among the 1,212 adult non-Hodgkin's (NHL) cases referred to this institute during 1987-1994. The histology was diffuse large cell in all cases. According to the Ann Arbor classification, four patients had stage IE and one patient stage IIE disease. The diagnosis was established by laparotomy in three and ultrasound or CT-guided biopsy in two patients. All patients received chemotherapy. Radiotherapy was used in two cases; in one patient the pancreatic bed was irradiated, whereas in the other radiation was given for obstructive jaundice. Four patients are alive with no evidence of disease at 84, 26, 24, and 21 months follow-up. One patient relapsed at 12 months following chemotherapy and is alive with disease at 23 months follow-up. The clinical and radiological findings in primary pancreatic NHL are not pathognomonic, and the diagnosis is only established on histopathological examination. The management should be nonsurgical as the response to chemotherapy and radiation appears to be no different from NHL at other sites.

Final report of a phase II study of chemotherapy with bleomycin, epirubicin, and cisplatin for locally advanced and metastatic/recurrent undifferentiated carcinoma of the nasopharyngeal type.

PURPOSE: This article presents an assessment of the combination of bleomycin, epirubicin, and cisplatin as induction chemotherapy before radiotherapy in the treatment of undifferentiated carcinoma of the nasopharyngeal type in patients with recurrent/metastatic disease (group A), and in previously untreated patients with locoregionally advanced disease (UICC-AJCC 87, N2-3, M0) (group B) in terms of toxicity, antitumoral activity, and therapeutic efficacy. PATIENTS AND METHODS: From January 1987 to September 1990, 111 consecutive patients with histologically proven UCNT were treated with six cycles of intravenous cisplatin (100 mg/m2 day 1) epirubicin (80 mg/m2 day 1), and bleomycin (15 mg bolus day 1), followed by 16 mg/m2/day continuous infusion for 5 days, repeated every 21 days for three cycles. Three further cycles without bleomycin were given to 44 patients in group A. In group B (67 patients), only three cycles of the same protocol were given, with a slightly lower dose of epirubicin (70 mg/m2), followed by conventional radiotherapy (70 Gy/7 weeks). RESULTS: Of 44 patients entered in group A, 38 were evaluable for response. We observed 9 (20%) complete responses and 11 (25%) partial responses, for a 45% overall response rate. In 12 patients not previously given chemotherapy, there were 4 complete responses, compared to 5 complete responses in 32 patients previously treated with chemotherapy. Four patients are alive with no evidence of disease after 53+, 60+, 61+, and 72+ months. In group B the overall response rate to chemotherapy was 98% with 42 complete (62%) and 24 partial responses (36%). Three months after the end of radiotherapy, the overall complete response rate was 94% (63 patients). After a median follow-up time of 77 months (range, 53-94), the 4-year overall survival and disease-free survival rates for this group are 66% and 60%, respectively. The median disease-free survival has not been reached at 90 months. CONCLUSION: The results of the BEC combination trial are very encouraging in metastatic and recurrrent UCNT, with durable remissions in this poor-prognosis population. The results in patients with locally advanced disease have motivated prospective phase III testing of the neoadjuvant chemotherapy approach to evaluate its impact on locoregionally advanced disease (> or =N2MO UICC-AJCC 87).

Response of bone marrow to titanium implants: osseointegration and the establishment of a bone marrow-titanium interface in mice.

A method has been developed to examine the relationships between titanium implants in bone and the immune and hemopoietic cell populations in the adjacent bone marrow; it involves the use of miniaturized implants in the diaphysis of mouse femurs. After surgical placement of the implants, mice were sacrificed and the femurs were either embedded directly in Epon for preparation of ground sections or were decalcified in EDTA, embedded in Epon, subjected to a fracture technique to remove the implant, and sectioned for light and electron microscopy. Scanning electron microscopy revealed that the surfaces of implants removed in this way were virtually free of tissue remnants. Ground sections showed bone in direct contact with the implant surface, providing the first evidence of osseointegration in mice. In addition, an extensive surface of the implant interfaced directly with regenerated bone marrow, a condition that persisted for at least 18 weeks. Some bone marrow cells forming an incomplete layer in contact with the titanium interface had morphologic characteristics of macrophages and giant multinucleated cells. The results demonstrated a long-term integration between titanium implants and cellular elements of bone marrow and provide an experimental model to examine the possible implications of this interaction on the processes of lymphopoiesis and hemopoiesis.

Changes in the populations of null, NK1.1+, and Thy1lo lymphocytes in the bone marrow of tumor-bearing mice: effect of indomethacin treatment.

Mouse bone marrow produces many "null" lymphocytes which lack B and T lineage markers (B220-Thy1-). A subset of these cells expresses the natural killer (NK) cell marker, NK1.1. In addition, some rapidly renewed bone marrow lymphocytes express low intensities of Thy1 (Thy1lo). In view of their possible implication in tumor-host interactions these various cell populations have now been examined in mice injected with either the nonmetastatic Ehrlich ascites (EA) tumor or the Lewis lung carcinoma (LLc), a highly metastatic solid tumor. In each case, the number of null lymphocytes, as defined by a lack of radioautographic labeling of either B220 glycoprotein or Thy1, increased markedly in both the bone marrow and spleen. Treatment with the prostaglandin inhibitor, indomethacin, enhanced the increase in null cells in the bone marrow and spleen of LLc-bearing mice. The number of null small lymphocytes expressing NK1.1, as detected by combined radioautographic and immunoperoxidase techniques, increased almost 30-fold in LLc-bearing mice. The number of Thy1lo small lymphocytes increased in parallel with null cells during EA tumor growth. The findings accord with the hypothesis that the null lymphocyte population produced in mouse bone marrow includes newly formed NK lineage cells which sequentially express NK1.1 and Thy1lo. The present work demonstrates that the populations of null, NK1.1+, and Thy1lo lymphocytes in mouse bone marrow expand rapidly during the early growth of transplanted tumors, the initial increase in null lymphocytes apparently being curtailed by prostaglandin production. The results suggest that the production of null lymphocytes in mouse bone marrow is responsive to tumor development, possibly providing cells to be involved in tumor-host interactions.

Alternating chemo-radiotherapy with cisplatin and 5-fluorouracil plus bleomycin by continuous infusion for locally advanced undifferentiated carcinoma nasopharyngeal type.

UNLABELLED: More than 80% of undifferentiated carcinoma nasopharyngeal type patients with N3 disease (AJC-UICC 1987) will die with or from distant metastases within 3 years after the first symptom. From February 1986 to November 1987 30 consecutive patients with very advanced local disease were entered in a programme with chemotherapy-radiotherapy (CT-RT) alternation after a thorough work-up to eliminate the possibility of distant metastases. PROTOCOL: two cycles of cisplatin 100 mg/m2 day 1, bleomycin 15 mg intravenously day 1 and 16 mg/m2 per day by continuous infusion days 1-5; 5-fluorouracil (5-FU) 650 mg/m2 per day by continuous infusion days 1-5 4 weeks apart. This was followed by two series of high-energy radiotherapy, 35 Gy/3.5 weeks, with a third chemotherapy cycle in between. 27 men and 3 women were treated, the median age was 37 years (range 17-71) and the mean WHO performance status was 1 (range 0-3). TNM classification: 15 T4, 9 T3, 6 T2, 28 N3 and 2 N2c. 18 patients had nodes larger than 8 cm and 24 had bulky bilateral cervical nodes. Toxicity for this protocol was moderate, nausea and vomiting being the main side-effects. Results after two CT cycles were 3 complete responses (CR; 10%), 22 partial responses (PR; 73%), 2 disease stabilizations, 2 progressions, and 1 patient inevaluable. Of the 30 patients, 27 patients completed the CT-RT protocol, 2 patients died before radiotherapy and 1 refused treatment after 2 days on protocol. 25 patients were in CR 3 months after the end of radiotherapy. As of August 1991, with a median follow-up of 55 months (range 43-63), there are 17 patients alive, 2 of them with active disease and 15 are NED (2 after salvage therapy).

Population dynamics of "null" and Thy1lo lymphocytes in mouse bone marrow: genesis of cells with natural killer cell lineage characteristics.

The population dynamics of "null" small lymphocytes lacking B and T lineage markers in mouse bone marrow have been examined using a combination of immunolabeling and hydroxyurea (HU) deletion techniques. The binding of the B lineage-associated mAb, 14.8, and anti-Thy1.2 to bone marrow cells has been detected radioautographically. Null cells lacking 14.8 and Thy1.2 determinants (14.8- Thy1-) formed a substantial subset (12-14%) of bone marrow small lymphocytes, representing 0.5 x 10(6) cells per femur (2-3% of nucleated cells). HU treatment revealed an exceptionally rapid turnover of the null small lymphocyte population (T1/2, 7.5 hr) compared with 14.8+ cells (T1/2, 20.5 hr) and Thy1+ cells (T1/2, 53 hr). Small lymphocytes bearing low intensities of Thy1 (Thy1lo) were also rapidly renewed (T1/2, 28 hr) whereas those with high intensities of Thy1 (Thy1hi) were renewed only slowly (T1/2, 123 hr). During ontogeny, null small lymphocytes first appeared in the fetal liver by Day 11 and the fetal spleen by Day 16, but increased rapidly in the bone marrow in early postnatal life. Double immunolabeling techniques demonstrated that 10% of null small lymphocytes in the bone marrow expressed NK1.1 antigen, while larger proportions bound to tumor (YAC.1) cells in vitro and displayed Fc receptors. The NK1.1-bearing fraction of null small lymphocytes in bone marrow was depleted by HU treatment only after an initial delay. NK1.1 was also expressed on subsets of Thy1lo cells and Thy1hi cells. The results have revealed the continuous production in mouse bone marrow of null and Thy1lo small lymphocytes, totaling 1-3 x 10(7) cells/day and 1.2 x 10(6) cells/day, respectively. The findings suggest that the large-scale production of null lymphocytes in mouse bone marrow includes the genesis of NK lineage cells which express NK1.1 and Thy1lo during a period of terminal maturation.