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Steroid responsive meningitis-arteritis (SRMA) is a common disease of the dog with no specific ante-mortem diagnostic test and management is complicated by the requirement for prolonged treatment and the potential for relapse. The value of immunosuppressive prednisolone has been established but an optimal regime is not described. The lack of diagnostic and prognostic markers makes management frustrating. This study prospectively evaluates a protocol for the use of a prednisolone monotherapy in the management of SRMA. The utility of conventional and novel protein markers was evaluated by examining their expression at various milestones in the management of SRMA and by comparing this to their expression in other canine inflammatory and non-inflammatory central nervous system (CNS) diseases. This prospective study recruited twenty dogs with a clinical diagnosis of SRMA presenting to the University of Glasgow Small Animal Hospital between May 2006 and May 2008. These patients were enrolled on a strict prednisolone regimen with serum and cerebrospinal fluid samples taken at key points in the management of this disease. The protocol was successful at achieving resolution of clinical signs with no relapse in the follow up period in all 20 dogs. Clinical remission was achieved in all cases within 2 weeks of starting the protocol. When relapse occurred during the treatment schedule (4/20), restarting the treatment schedule led to resolution of the disease. The fact that dogs did not relapse post-treatment in this study is supportive of the value of this protocol in managing SRMA. Overall, the findings detailed in this thesis support the use of an immunosuppressive prednisolone monotherapy in the treatment of canine SRMA. Acute phase proteins are significantly elevated at initial presentation with the remission of clinical signs, induced by immunosuppressive therapy, reducing but not eliminating this increase in serum concentrations. APPs are of particular value in the identification of putative relapse. In contrast, serum and cerebrospinal fluid IgA provides valuable information at diagnosis but a persistent increase throughout the disease limits their value in the monitoring of therapy. This immunoglobulin was found to be also be elevated in the serum and cerebrospinal fluid of other inflammatory and non-inflammatory canine CNS diseases. A robust prognostic marker for SRMA remains elusive

Purpose Endocrine agents, such as letrozole, are established in the treatment of hormone-dependent breast cancer. However, response rates are only 50% to 70% in the neoadjuvant setting and lower in advanced disease. Thus there is a need to identify novel markers predicting for response and to understand molecular mechanisms of resistance. Patients and Methods Sequential tumor biopsies were taken before and after 10 to 14 days of neoadjuvant treatment with letrozole in patients with estrogen receptor–rich breast cancer. Expression profiles on high-density microarray chips were then related to clinical responses as assessed from tumor volume measurements after 3 months of treatment. Results Of 52 patients, 37 (71%) were classified as having a clinical response to letrozole and 15 being clinically resistant. Bioinformatic analysis identified 205 covariables (69 baseline expression, 45 day 14 expression, and 91 change in expression with treatment) which differentiated between clinical responders and nonresponders. Hierarchical clustering using the variables separated responders and nonresponders into two distinct groups. Ontological assessment indicated that discriminating genes were enriched toward cellular biosynthetic processes. In particular, functional gene assessment showed ribosomal protein probes to have higher baseline expression in tumors responsive to letrozole and increased expression with treatment in nonresponding cases. Conclusion To our knowledge, this is the first study to describe genetic covariables and molecular processes discriminating between tumors clinically responsive and resistant to an aromatase inhibitor. The understanding of such molecular phenotypes will be important in optimizing the clinical use of aromatase inhibitors, both in terms of identifying responsive breast cancers and developing new agents to target resistance pathways.

It is very important to examine the influence of inhibition of in situ estrogen production on the pathobiology of human sex steroid-dependent tumors in order to understand the clinical effects of aromatase inhibitors. We have examined the biological changes before and after aromatase inhibitor treatment in vitro (endometrial and ovarian cancer) and in vivo (breast cancer). First, we analyzed these changes using histoculture of 15 human endometrial cancers and 9 ovarian cancers. Five of the fifteen endometrial cancers and four of the nine ovarian cancers demonstrated decreased [3H]thymidine uptake or Ki67 labeling index after 14alpha-hydroxy-4-androstene-3,6,17-trione (NKS01) treatment. In ovarian cancer cases, the responsive cases tended to be associated with higher aromatase and estrogen receptor alpha (ER) expression compared with the other cases but this was not seen in the endometrial cancer cases. There were no changes in ER and aromatase expression before and after NKS01 treatment in either ovarian or endometrial cancer cases. We then studied the same primary human breast tumors before and after aminoglutethimide (AMG, n=3) and 4-hydroxyandrostenedione (4-OHA, n=3) treatment. Tumor aromatase activity increased in 3 cases and decreased or was unchanged in 3 cases but aromatase immunoreactivity in stroma and adipocytes was unaltered in 5 cases. There were no changes in the ER labeling index before or after treatment. Five of the six cases including the responsive cases tended to be associated with decreased cell proliferation or Ki67 expression and increased apoptosis when examined by the TUNEL method. These results indicate that aromatase inhibitors may exert their effects on human breast and other cancers through decreasing proliferation and increasing apoptosis, possibly without altering ER status.

We studied proliferative activity in the breast tissue from 40 healthy premenopausal women who underwent reduction mammoplasty. Twenty-four women had regular menstrual cycles; 16 were taking combined oral contraceptives. Lobuloalveolar tissue was examined by means of the Ki-67/MIB 1 antibody to identify proliferating cells. The number of positive-staining cells was related to the estimated number of cells to form an activity ratio (AR). We found a significantly higher AR in the secretory compared with the proliferative phase of the menstrual cycle, and a tendency for higher AR values in late compared with early oral contraceptive treatment cycles. In multivariate analyses, the secretory phase was associated with a significantly higher AR, and oral contraceptive use was associated with a higher AR than natural cycles. Our data suggest that progesterone/progestins augment proliferation in the normal breast epithelium and highlight the complexity of cell regulatory factors affected by exogenous steroids.

Both transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF) have been shown to affect cell proliferation in vitro. The hypothesis being tested was that the effects of the 2 cytokines would be modulated by the presence of serum in the medium. Gingival fibroblasts, obtained from periodontally healthy patients, were maintained in primary culture. Dose response experiments were performed for each growth factor in serum-free medium and in medium containing natural or heat-inactivated fetal bovine serum (10% FBS). Changes in cell numbers were quantified by crystal violet staining. The optimal concentrations of the individual factors (10 ng/ml TGF-beta1, 20 ng/ ml PDGF-BB) were then used when the 2 factors were tested in various sequences. In serum-free medium or in medium with 10% natural serum, the response to PDGF-BB was dose-dependent up to 40 ng/ml; however, with 10% heat-inactivated serum, the maximal response was seen at 20 ng/ml. The largest increase in cell numbers was produced by the simultaneous exposure to the two cytokines, rather than a sequential presentation. The findings suggest that the 48-h growth response of human gingival fibroblasts to 10 ng/ml TGF-beta1 or 20 ng/ ml PDGF-BB in serum-free medium was equivalent to growth obtained in medium containing heat-inactivated 10% FBS without added growth factors.

Based on preclinical studies demonstrating synergy between gallium and hydroxyurea, we evaluated the efficacy and toxicity of continuous intravenous gallium nitrate in combination with oral hydroxyurea in patients with refractory non-Hodgkin's lymphoma. Fourteen patients, median age 64 years (range 53-89), with stage III or IV low- or intermediate-grade lymphoma were treated with gallium nitrate and hydroxyurea in combination for 7 days at four different dose levels: (a) gallium nitrate, 200 mg/m2/day; hydroxyurea, 500 mg/day; (b) gallium nitrate, 250 mg/m2/day; hydroxyurea, 1,000 mg/day; (c) gallium nitrate, 300 mg/m2/day; hydroxyurea, 1,000 mg/day; and (d) gallium nitrate, 350 mg/m2/day, hydroxyurea, 1,000 mg/day. All patients had progressive disease and had been heavily pretreated. Six of 14 patients had objective tumor regression following treatment (one complete response, one near-complete response, and four partial responses) with a median duration of response of 7 weeks (range 3-38 weeks). An additional four patients had minor responses. Responses occurred at all dose levels and in both low- and intermediate-grade histologic subtypes. The predominant toxicities encountered were anemia and reversible nephrotoxicity. Combination gallium nitrate and hydroxyurea has significant activity in lymphoma and is well tolerated even by elderly patients. Because of the lack of cross-resistance to other drugs and the potential synergistic antineoplastic activity, gallium nitrate and hydroxyurea should be further evaluated in combination with other chemotherapeutic agents.

Current treatments for metastatic breast cancer are not associated with significant survival benefits despite response rates of over 50%. High-dose therapy with autologous bone marrow transplantation (ABMT) has been investigated, particularly in North America, and prolonged survival in up to 25% of women has been reported, but with a significant treatment-related mortality. However, in patients with haematological malignancies undergoing autologous transplantation, haematopoietic reconstruction is significantly quicker and mortality lower than with ABMT, when peripheral blood progenitor cells (PBPCs) are used. In 32 women with metastatic breast cancer, we investigated the feasibility of PBPC mobilisation with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) after 12 weeks' infusional induction chemotherapy and the subsequent efficacy of the haematopoietic reconstitution after conditioning with melphalan and either etoposide or thiotepa. PBPC mobilisation was successful in 28/32 (88%) patients, and there was a rapid post-transplantation haematopoietic recovery: median time to neutrophils > 0.5 x 10(9) l-1 was 14 days and to platelets > 20 x 10(9) l-1 was 10 days. There was no procedure-related mortality, and the major morbidity was mucositis (WHO grade 3-4) in 18/32 patients (56%). In a patient group of which the majority had very poor prognostic features, the median survival from start of induction chemotherapy was 15 months. Thus, PBPC mobilisation and support of high-dose chemotherapy is feasible after infusional induction chemotherapy for patients with metastatic breast cancer, although the optimum drug combination has not yet been determined.

Patterns of protein phosphorylation were examined in particulate fractions prepared from normal breast from 111 women. Material was obtained from a variety of physiological states including pregnancy (16 cases), lactation (4 cases), post-lactational involution (6 cases), prolonged involution (11 cases) and the ‘resting’ state (74 cases; 52 nulliparous and 22 parous). Total level of phosphorylation varied with the physiological state of the tissue, being higher in pregnancy, lactation and post-lactational involution than in the resting breast. The molecular weights of major bands phosphorylated were 180, 52, 48 and 44 kDa. Evidence from base hydrolysis in five cases, indicated that the 180 kDa band was phosphorylated primarily on tyrosine residues. Quantitation of this protein showed variability within sub-groups, but levels were highest in post-lactational involuting breast. Sub-division of the nulliparous group according to phase of the menstrual cycle, oral contraceptive use and breast epithelial proliferation, showed significantly lower phosphorylation in this band amongst oral contraceptive users. In contrast to the 180 kDa band, base hydrolysis of the protein at 44 kDa did not indicate phosphorylation on tyrosine residues. Levels of phosphorylation were highest in pregnancy and lactation and were significantly reduced in examples showing prolonged involution. In the nulliparous resting breast, phosphorylation of the 44 kDa band was not associated with phase of the menstrual cycle or oral contraceptive use. However, there was a strong positive association between the phosphorylation of 44 kDa band and level of proliferation.

Congenital central hypothyroidism was diagnosed in a one-year-old boxer dog. The dog was presented for investigation of lameness, lethargy and obesity. Survey skeletal radiographs revealed delayed bone maturation and epiphyseal dysgenesis. A diagnosis of hypothyroidism was confirmed on the basis of a low basal serum thyroxine (T4) concentration that failed to increase following bovine thyroid stimulating hormone (TSH) administration. However, repeated administration of TSH resulted in reactivation of the thyroid gland suggesting a central rather than a primary problem. Consistently low basal plasma Cortisol concentrations were suggestive of a concurrent secondary or tertiary hypoadrenocorticism. Surprisingly, plasma growth hormone concentrations were elevated before treatment but decreased once thyroid replacement therapy had commenced.

Eighty-eight patients presenting with operable breast cancer of 4 cm or greater in diameter (T2, T3, N0, N1, M0) have received primary systemic therapy. Response was assessed following 12 weeks of systemic therapy by linear regression analysis of changes in tumour volume. Definitive locoregional surgery (mastectomy n = 82, wide local excision n = 6) was performed on completion of systemic therapy (3-6 months). Response was observed in 24 (39%) of the 61 patients who received endocrine therapy; all 24 had tumours with an oestrogen receptor (ER) concentration of greater than or equal to 20 fmol mb-1 cytosol protein. Cytotoxic therapy was reserved for patients with tumours of ER concentration less than 20 fmol mg-1 cytosol protein (n = 27) or when endocrine therapy had failed (n = 20). Response was observed in 34 patients (72%). The overall survival rate at 3 years was 86%, with 81% remaining free from local relapse. We propose that the treatment policy outlined in this paper should now be tested against orthodox management by controlled randomised trial.

Twenty-four patients with advanced metastatic cancer were treated with continuous intravenous 5-fluorouracil infusion 200-300 mg/m2/day and alpha interferon 3 million units subcutaneously 3 times per week. The average duration of treatment was 87 days (range 22-204 days). 5-fluorouracil could be infused 66% of the planned time on treatment, and patients received an average of 60% of the planned interferon injections. Objective tumor responses were seen in 6 of 17 previously untreated patients (35%). Twenty-two of the 24 patients (92%) experienced toxicity (greater than or equal to ECOG grade II) that required treatment interruption and subsequent dose reduction predominantly for the following reasons: mucositis (67%), hand-foot syndrome (21%), and leukopenia (25%). The incidence of treatment limiting toxicity is higher than previously observed with 5-fluorouracil infusion alone. This suggests true augmentation of 5-fluorouracil effect by interferon. 5-Fluorouracil infusion and alpha interferon is a potentially useful combination that needs further evaluation in future phase II and phase III trials.

Aromatase activity has been measured in human breast cancers by incubating tumour minces with [7 alpha-3H]testosterone and characterizing purified oestradiol (E2) fractions by chemical derivative formation. Of 247 primary tumours, 178 showed evidence of oestrogen biosynthesis, levels varying between 0.5 and 12.5 fmol E2 produced/h/g tissue. These values were quantitatively small but at least comparable with those in other peripheral tissues. There was no correlation between presence or level of aromatase activity and the histopathology of the tumours although oestrogen biosynthesis was more likely to be present in more cellular tumours. Aromatase activity was also unrelated to age, menopausal status, lymph node status and T stage of the patient from which the tumour was derived. In a subgroup of patients presenting without clinical evidence of distant metastatic disease, no significant relation was detected between tumour aromatase and disease-free interval, but tumours without aromatase activity were associated with increased survival at 36 months after primary treatment. A statistically significant correlation was also detected between the presence of tumour aromatase and oestrogen receptors. Furthermore, in small subgroups of patients with "advanced" breast cancer tumour aromatase was related to response to aminoglutethimide but not tamoxifen therapy. Whilst these results do not conclusively define a role for local synthesis of oestrogen in the progression of breast cancer, this possibility still exists and further studies on tumour aromatase are warranted.

It has been suggested that the addition of weekly low-dose cisplatin (DDP) may potentiate the efficacy of continuous infusion 5-fluorouracil (5-FU) without adding significant toxicity. To investigate the extent of added toxicity, an analysis of toxicity was completed in 18 patients with advanced cancers treated with continuous ambulatory 5-FU infusion 300 mg/m2/day and weekly low-dose cisplatin (DDP) 20 mg/m2. Ten of the 18 patients (56%) developed multiple (four or more) toxicities during treatment. In addition, toxicity categorized as severe occurred in 10 patients (56%). Seventeen of the 18 patients (94%) required treatment interruption or dose attenuation due to toxicity and most patients experienced a decline in Eastern Cooperative Oncology Group performance status due to treatment-related toxicity. Compared with historical toxicity patterns when 5-FU infusion is administered alone, the addition of DDP has resulted in significant increases in nausea and vomiting, anorexia, diarrhea, stomatitis, and myelosuppression. The addition of low-dose weekly DDP adds significant toxicity and morbidity to the continuous 5-FU infusion regimen.

Selection for endocrine therapy requires the identification of markers that accurately predict response/resistance. In this report, the authors review their published work and abstract results from an unpublished study to illustrate the potential of RNA microarrays from sequential tumor biopsies from patients who were offered neoadjuvant endocrine therapy treatment to identify the molecular signatures associated with tumor sensitivity/resistance. Clinical response was assessed by serial ultrasound measurements in postmenopausal women with large, primary, estrogen receptor-rich breast cancers who received neoadjuvant treatment with letrozole for 3 months. Tumor RNA from biopsies that were taken before and after 14 days of treatment was hybridized on Affymetrix U133A chips to determine expression profiles. Classic estrogen-dependent genes and markers of proliferation were changed with treatment in most tumors but were poorly associated with clinical response (they frequently were changed in letrozole-resistant tumors). Differential expression patterns could be used to identify heterogeneity in clinically resistant tumors. The results indicated that molecular profiling of early changes with letrozole treatment offers the opportunity to distinguish between clinically responsive and nonresponsive tumors and provides important information about the heterogeneity of endocrine resistance.

A prospective study of 14225 patients has been undertaken to determine the inter-relationship between periductal mastitis and duct ectasia and to establish whether there is an association between smoking and either of these two conditions. Periductal mastitis affected women at a younger age than did duct ectasia. Of 139 patients with the clinical syndrome of periductal mastitis, 97 (70 per cent) had a past history of previous periductal mastitis, compared with only one (1 per cent) of 186 patients with the clinical syndrome of duct ectasia (P< 0·0001). There was a significant excess of smokers in patients with clinically (124 (89 per cent) of 139) and pathologically (71 (91 per cent) of 78) diagnosed periductal mastitis compared with age-matched controls (both P< 0·001), but there was no such excess in those with clinically (52 (28 per cent) of 186) or pathologically (15 (23 per cent) of 64) diagnosed duct ectasia. These data suggest that periductal mastitis and duct ectasia are separate conditions which affect different age groups, have different aetiologies, and should now be considered as separate entities.

Purpose: To determine the safety and efficacy of treatment with gamma interferon (IFNγ) in patients with metastatic carcinoid tumor. Patients and methods: 51 patients were enrolled on this Phase II Eastern Cooperative Oncology Group (ECOG) study. Seventy five percent of them had hormonally active tumors. Treatment consisted of IFNγ subcutaneously at a daily dose of 0.1 mg/m2. Patents were evaluated for toxicity weekly for the first month and monthly thereafter; response was determined radiologically every 8 weeks. Results: Patients received treatment with IFNγ for a median of 17.9 weeks (range 2–175). Toxicity was generally mild and expected: 61% experienced noninfected fever and 21% developed granulocytopenia. Three patients (6%) had a partial response; there were no complete responses. Median time to progression was 5.5 months (95% confidence interval 3.9–11.1). The 1-year progression free rate was 28% (13.4–43.4%). Median survival was 42 months, with a 1-year survival rate of 67% (53.3–80%). Discussion: This Phase II study demonstrated that therapy with IFNγ in patients with metastatic carcinoid tumor was well-tolerated, but did not produce significant antitumor effects. The overall results were somewhat comparable to those previously seen with alpha interferons as well as cytotoxic drugs.

Despite knowledge of oestrogen receptor status, it is not always possible to predict which breast cancers will respond to tamoxifen. We have previously reported that decreased expression of Bcl-2 and/or Ki-S1 were associated with tumour response to neo-adjuvant tamoxifen in 50 elderly women with oestrogen receptor (ER)-positive breast cancer. In this study, we confirm that the expression of Bcl-2 and Ki-S1 are surrogates for the frequency of apoptosis and mitosis respectively, within these untreated breast cancers, with an inverse relationship between Bcl-2 expression and the apoptotic index (P

Objective— To determine the pathological and biological characteristics of breast cancers diagnosed by screening and examined at the Edinburgh University pathology department. Methods— These cancers were classified by screening status: never screened (n=111), prevalence screen detected (n=105), and previously screened (n=74). The last category arose in women who had been regularly screened during the trial; the cancers were diagnosed as interval cases before the first invitation to service screening (n=33) or were incidence screen detected at that time (n=41). Results— Association (for operable invasive cancers, n=250) of cancer characteristics with screening status reflects influences of biology (aggressiveness) or chronology (time of diagnosis), or both. The prognostic indicators tumour grade, histological type, and oestrogen receptor status were found in a smaller percentage of the patients with poor prognosis among the prevalence screen detected cases (9%, 77%, 18%) than among those previously screened (29%, 84%, 35%). The chronological factors size and node status were found in a smaller percentage of patients with poor prognosis among women previously screened (31%, 24%) than among those never screened (62%, 39%)). Apart from these two, no other factors improved the diagnosis in the previously screened group compared with the never screened group. Conclusions— These results suggest that favourable characteristics of screen detected cases are often due to the effects of length bias on “biological factors” and fail to show that current local screening practice has succeeded in advancing the diagnosis of breast cancers to a less aggressive phase.

Background : Phase II studies of fluorouracil (5-FU) administered by protracted intravenous infusion have suggested an improved response rate and decreased toxicity profile when compared with 5-FU given by bolus injection in patients with metastatic colorectal cancer. Additional studies have suggested further enhancement of infusion 5-FU activity when it is combined with low-dose weekly cisplatin administration. Purpose : This phase III study in adults with metastatic colorectal cancer was planned as a comparison of objective response rates, toxicity, and survival in patients receiving bolus versus protracted-infusion 5-FU with or without cisplatin. Methods : Four hundred ninety-seven previously untreated patients with advanced, measurable metastatic colorectal cancer were randomly assigned to receive treatment A (bolus 5-FU at 500 mg/m 2 for 5 days followed in 2 weeks by weekly bolus 5-FU at 600 mg/m 2 ), treatment B (bolus 5-FU at 500 mg/m 2 for 5 days followed in 2 weeks by weekly bolus 5-FU at 600 mg/m 2 , plus weekly cisplatin at 20 mg/m 2 ), treatment C (5-FU at 300 mg/m 2 per day by continuous infusion), or treatment D (5-FU at 300 mg/m 2 per day by continuous infusion plus weekly cisplatin at 20 mg/m 2 ). All drugs were administered intravenously. Enrollment in the trial occurred from August 1987 through December 1990, and follow-up was through September 1995. The Kaplan-Meier method was used to estimate overall and disease-free survival, and Cox regression models were used to assess the effects of patient characteristics on survival. All P values resulted from two-sided tests. Results : Objective tumor response was observed in 28 (18%) of 153 patients receiving treatment A, in 45 (28%) of 159 patients receiving treatment C (C versus A ; P =.045), and in 47 (31%) of 153 patients receiving treatment D (D versus A ; P =.016). Because of excessive toxicity, treatment B was discontinued after only 12 patients had begun treatment. Median time to disease progression was 5.1 months for patients in arm A compared with 6.2 and 6.5 months for patients in arms C and D, respectively (C versus A, P = .007 ; D versus A, P =.017). Patterns of toxic effects differed substantially among the treatment arms. Forty-five percent of the patients receiving bolus 5-FU alone (A) experienced grade 3-4 leukopenia, with two sepsis-related deaths. Hand-foot syndrome and mucositis were the major treatment-limiting toxic effects for patients in the two treatment arms involving infusion. Despite the improvement in response rates and time to disease progression with infusion 5-FU with or without cisplatin (C and D, respectively) (P = .003), the overall survival for the three groups (A, C, and D) was similar (P = .307). This may have been due in part to a longer median survival time of 10.4 months for patients in arm A, compared with an anticipated survival of 7 months. Conclusion : 5-FU given as a continuous infusion produced a higher objective response rate, a modest prolongation in time to disease progression, and less life-threatening myelosuppression in patients than bolus 5-FU. Concomitant treatment with low-dose cisplatin caused added toxicity and complexity of treatment and did not provide a major clinical benefit. No statistically significant survival differences were observed among the three treatment groups.

Twenty-two patients, ages 16.6 to 43.9 years (median age, 30 years), with relapsed or refractory lymphoma were treated by allogeneic bone marrow transplantation after high-dose chemotherapy with or without total body irradiation (TBI). Seven patients had Hodgkin's disease, four had low-grade histology non-Hodgkin's lymphoma (NHL), seven had intermediate-grade NHL, and four had high-grade NHL. Of the 22 patients, 17 received T-cell (CD-3)-depleted marrow after intensive pretransplant chemoradiotherapy, and five received T-cell-replete grafts after chemotherapy-based preparative regimens. Five patients were transplanted from donors other than genotypically HLA-identical siblings: four from partially HLA-matched relatives, and one from a phenotypically HLA-identical unrelated donor. Acute graft-versus-host disease (GVHD) was less than or equal to grade II in all patients, and chronic GVHD was limited or absent in all but one patient. Of the 21 assessable patients, 17 (80.9%) achieved complete remissions. Death due to transplant-associated complications occurred in five patients, and five patients have relapsed. Thirteen patients are alive, and 12 are continuously relapse-free at a median follow-up of longer than 28 months (range, greater than 10 to greater than 58 months) from transplant. The cumulative probability of treatment failure from relapse or progression of lymphoma was 29% (95% confidence interval [CI], 12% to 51%), while the actuarial lymphoma-free (ie, event-free) survival plateau is 54.6% (95% CI, 34% to 76%). For young patients with advanced malignant lymphoma, allogeneic bone marrow transplantation appears superior to salvage chemotherapy for achievement of long-term, lymphoma-free survival and may be preferable to autologous bone marrow transplantation for selected patients.

We would like to thank Dr. Cady for his kind words of support for our work and commend him for his outstanding, thorough, and insightful review of the current axillary lymph node dissection controversy. Dr. Cady capsulizes the problems regarding axillary lymph node dissection that oncologists face on a daily basis and makes a strong case for limiting the type and number of patients who must undergo axillary lymph node dissection as part of their treatment for breast carcinoma. At Dr. Cady’s suggestion, we analyzed our data by dividing the patients into two groups: those diagnosed from 1979–1987 versus those diagnosed from 1988–1995. As predicted by Dr. Cady, these data (Table 1) revealed an improvement for some categories in the more contemporary group, e.g., a higher percentage of T1a and low nuclear grade lesions, a smaller percentage of T1c lesions, an increase in nonpalpable lesions, and a decrease in the percentage of patients with lymphovascular invasion. Paradoxically, nuclear Grade 3 (high grade) morphology increased and there was a slight increase in the percentage of patients with positive axillary lymph nodes. For those factors that improved, not all the differences were significant, nor were they as large as might be expected. One reason for the small magnitude of these changes lies with the fact that we have been aggressively screening since late 1982 with a single outstanding radiologist, a physician who has been extremely interested in finding early breast carcinoma. Hence, the second time period (1988–1995) does not reflect the impact that screening would have made had it been introduced to our group 5 or 6 years later than it was. Invited editorials with author responses are often point-counterpoint discussions, but in this instance, we find ourselves in near comSee editorial counterpoint on pages 1856–61 and referenced original article on pages 1918– plete agreement with Dr. Cady’s approach and reasoning. For a proce22, this issue. dure that provides little or no measurable benefit in terms of breast carcinoma specific survival, axillary lymph node dissection is perAddress for reprints: Melvin J. Silverstein, M.D., formed far too commonly. The Breast Center, 14624 Sherman Way, Van Our group championed the elimination of axillary lymph node Nuys, CA 91405. dissection for patients with ductal carcinoma in situ (DCIS) beginning in 1986, when we reported a zero rate of axillary lymph node metastaReceived January 3, 1997; accepted January 9, 1997. ses for the first 100 patients in our DCIS series to undergo axillary

9657 Background: Human chorionic gonadotropin (hCG) is not by itself sensitive or specific for malignancy. However, in multiple carcinomas multivariate analysis indicates that preoperative serum hC...

In the Edinburgh Breast Screening Project 210 cancers were detected from commencement in 1979 up to December, 1984. By this time the full initial cohort had completed at least 3 visits and a proportion had attended for up to 5 visits, so pathological characteristics for prevalent and incident cancers could be compared. The main differences are in distribution of histological type of cancer, detection of occult invasive disease, and lymph-node positivity among incident tumours. Only the first of these was statistically significant. This evaluation shows that cancer detection by screening in Edinburgh conforms with screening theory, in which detection of good prognosis tumours is favoured at the prevalence screens, and faster growing, aggressive tumours are found at the incidence screens. Qualitative histopathology may provide a better measure than standard quantitative judgments of size and lymph node status to compare the varieties of cancer detected by screening programmes and to understand the biology of the disease.

5-Fluorouracil (5FU) administered by prolonged intravenous infusion may more effectively treat advanced, slow-growing tumors with low growth fractions and long doubling times. Protracted infusion provides continual cancer cell exposure to 5FU; limitations due to cell cycle specificity and a short plasma half-life are theoretically circumvented. Advances in catheter composition and pump technology now make ambulatory infusion therapy widely available. Clinical trials suggest that prolonged infusion may improve the response rate in colorectal cancer. In addition, preliminary results suggest clinical activity against gastric, pancreatic and refractory breast cancers with minimal toxicity. Despite the potential logistic problems of infusion chemotherapy, many patients report improved quality of life. Increased costs incurred from infusion therapy are probably justifiable if survival is prolonged and quality of life maintained.

An approach to the management of patients with large (greater than 4 cm) operable breast cancers is described. The conventional sequence of mastectomy followed by systemic therapy is reversed, allowing accurate measurements of response to individual forms of endocrine therapy or chemotherapy. Such a method not only permits individual selection of appropriate systemic therapy, but also allows clinical response to be related to histological and biochemical tumour parameters. A response was observed in eleven of twenty-three patients to endocrine treatment and in twelve of thirteen to combination chemotherapy. In five of the latter the response was histologically complete.

Ocular lymphoma is an uncommon clinical entity with a propensity for intracranial extension. Palliation has been reported following radiotherapy, but the ultimate prognosis is poor, and significant treatment-related morbidity is common. Recent pharmacokinetic studies have suggested that sustained therapeutic drug concentrations are achievable in cerebrospinal fluid after systemic administration of high-dose cytosine arabinoside (Ara-C). These data led the authors to attempt treatment of a case of recurrent ocular lymphoma with high-dose Ara-C. Therapeutic drug levels were documented in intraocular fluids, and prolonged objective regression of tumor was seen. Systemic high-dose Ara-C deserves consideration for the treatment of ocular lymphoma.

An aorta-derived inhibitor of endothelial cell and tumor cell growth and medroxyprogesterone, which depresses collagenase expression in vivo, were tested alone and in combination against B16-F10 melanoma in C57BL/6 mice in such doses that either agent alone had little effect. Together, these agents retarded growth of subcutaneously transplanted tumor cells and reduced the number and size of pulmonary tumors after iv tumor cell injection. Of the treatments used, only the aortic factor administered alone prolonged life in mice with pulmonary tumors.

Thirteen patients with metastatic colorectal adenocarcinoma underwent treatment with continuous ambulatory 5-fluorouracil (5-FU) infusion 300 mg/m2/day and intermittent bolus methotrexate (MTX) (200 mg/m2) with calcium leucovorin (LCV) 10 mg/m2 orally every 6 h X four to eight doses given 24 h after MTX. Although MTX administration was planned every 14 days, the average time between treatments exceeded 19 days (range 14-42) because of excessive toxicity. All patients experienced toxicity at some time in their treatment course, requiring interruption of 5-FU infusion in 12 of 13 patients. Significant toxicities included stomatitis (13 of 13 patients), hand-foot syndrome (8 of 13 patients), and diarrhea (3 of 13 patients). Toxicity did not appear to be minimized by attenuation of MTX and/or 5-FU dosage or by increasing the dose and/or duration of LCV. At this dosage schedule the addition of MTX/LCV to 5-FU infusion results in excessive and unacceptable toxicity and does not appear to improve treatment results.

We studied renal function and serum electrolytes in 51 patients receiving cisplatin chemotherapy by retrospectively reviewing the charts of 44 patients and prospectively following seven patients. Hypomagnesemia developed in 23 of 44 evaluable patients who were receiving cisplatin. We documented inappropriate renal magnesium wasting in four patients. Two patients required hospitalization for symptomatic hypomagnesemia. We conclude that cisplatin can induce a renal tubular defect in magnesium conservation and serious clinical syndromes of magnesium deficiency.

Excerpt To the editor: A typographic error was made in the article entitled "Testicular Germ-Cell Neoplasms: Recent Advances in Diagnosis and Therapy" (1) in the March 1979 issue. The first sentenc...

The diagnosis and treatment of testicular neoplasms have been facilitated by identification of the tumor-associated proteins alpha-fetoprotein and human chorionic gonadotropin. These circulating tumor markers, present in 85% to 90% of patients with nonseminomatous testicular cancer, reflect tumor presence and reliably indicate response to therapy. Alpha-fetoprotein is produced by embryonal carcinoma and yolk-sac tumors; human chorionic gonadotropin is produced by syncytiotrophoblastic giant cells and the syncytiotrophoblastic component of choriocarcinoma. Refinements in staging techniques and definitions have improved prognostication. Effective therapy for seminoma (cure rate, greater than 90%), early-stage (stage I, stage IIN1-2) testicular carcinoma (cure rate, 65% to 87%), and advanced (stage IIN3-4, stage III) testicular carcinoma (complete remission rate, 50% to 74%) has been shown in clinical trials. Adjuvant chemotherapy/radiotherapy trials for limited stages of testicular carcinoma, and further experience with intensive chemotherapy-based trials for advanced stages may further improve the prognosis for all testicular germ-cell neoplasms.

Fourteen patients with advanced gastric adenocarcinoma were treated with continuous 5-fluorouracil (5-FU) infusion, 300 mg/m2/day, through an indwelling central venous catheter; 13 were evaluable for response. The results were as follows; Partial remission was seen in 4 of 13 patients (31%), stable disease in 5 of 13 patients (38%), and progressive disease in 4 of 13 patients (31%). The median duration of response was 19 weeks (range, 10-41), and the median survival for all patients from initiation of infusion was 27 weeks (range, 9-54). Treatment interruption and/or dosage attenuation for toxicity was necessary in 7 of 14 patients (50%); however, myelosuppression, alopecia, and nausea and vomiting were not observed. 5-FU infusion is well-tolerated, palliative therapy for patients with advanced gastric carcinoma and may warrant further investigation in combination with other chemotherapeutic drugs.

Burkitt lymphoma is a unique tumor because of its unusual growth characteristics and its potential for allowing patients long-term survival with the use of single-agent chemotherapy. Previous reports have identified unusual and serious metabolic abnormalities that are a consequence of the basic disease and its treatment, including hyperkalemia, 1 hyperuricemia, 2 and lactic acidosis. 3 In this report, we describe two patients with Burkitt lymphoma in whom we encountered two previously unrecognized, to our knowledge, serious metabolic complications of the treatment of this disease, hyperphosphatemia and hypocalcemia. Recognition and management of these complications during the initial phase of therapy may prove lifesaving for the patient. Patient Summaries Patient 1. —A white boy, 6 years 9 months old, was admitted to the National Cancer Institute in August 1967 for evaluation and therapy of Burkitt lymphoma. The patient had complained of intermittent nonspecific abdominal pain for several months and four weeks prior

A man with long-standing common variable hypogammaglobulinemia was treated with chemotherapy and local radiation for diffuse mixed lymphoma. He continues in complete remission 42 months after the completion of therapy. Vigorous therapy for lymphoma can be used in the face of preexistent immunodeficiency. Complete staging and appropriate combination chemotherapy or radiation therapy should be carried out for lymphomas that occur in certain immunodeficient patients. ( Arch Intern Med 1982;142:90-92)

• A three-year review of the medical records of 76 patients with apparent thalassemic syndromes (mean corpuscular volume, 5 × 10 6 /cu mm) was performed to assess overall physician response to this information at a midwestern teaching institution. Abnormal indices were recognized in only 50% of the cases; in only 32% of cases was a thalassemic syndrome considered in the differential diagnosis. Residents in internal medicine failed to recognize microcytic indices and to consider thalassemic syndromes 42% and 59% of the time, respectively. Even though hemoglobin electrophoresis was performed in 25 patients, in only 15 (56%) of the 25 cases was β-thalassemia proved or α-thalassemia presumptively diagnosed. In 17% of all cases, the patients were treated with iron without diagnostic findings on iron studies and/or in spite of data suggesting a thalassemic syndrome. The RBC indices are an underused portion of the complete blood cell count, and readily apparent thalassemic syndromes are often not considered. ( Arch Intern Med 1985;145:93-94)