Significance of tumor burden, vascular endothelial growth factor, lactate dehydrogenase and beta-2 microglobulin serum levels in advanced diffuse large B cell lymphoma.

PURPOSE: Lactate dehydrogenase (LDH) and beta-2 microglobulin (B2M) are incorporated in the so-called "serologic staging system", as independent parameters for predicting time to treatment failure (TTF) and overall survival (OS) for aggressive non-Hodgkin's lymphoma (NHL) patients. Elevated values of serum vascular endothelial growth factor (sVEGF) was associated with poor survival in the largest histological subgroup, the diffuse large B cell (DLBCL) and immunoblastic lymphomas. sVEGF has independent influence on survival in multivariate models when tested together with the components of the International Prognostic Index (IPI). The purpose of this study was to define possible correlations between LDH, B2M levels and the novel prognostic parameter sVEGF, with assessed tumor burden, as another parameter of aggressiveness for advanced-stage DLBCLs. METHODS: Serum samples were collected from 29 patients with DLBCL, Ann Arbor clinical stages III and IV, to measure pretreatment serum levels of LDH, B2M and sVEGF. Tumor burden was defined as low and high according to criteria's defined by Jagannath and colleagues. RESULTS: A trend toward significant correlation between high initial levels of sVEGF and high tumor burden was observed (p=0.077). High serum LDH level was strongly associated with high tumor burden (p=0.0091), but B2M correlation with either low or high tumor burden was not confirmed (p=0.249). Complete response (CR) rates (CR vs. non CR) and OS according to tumor burden (low vs. high) showed no statistically significant differences (p=0.245 and p=0.202). CONCLUSION: Our preliminary data confirmed association between serum LDH level and DLBCL burden with a satisfactory sensitivity-specificity relationship. The other two parameters, sVEGF and B2M, failed to demonstrate significant relationship with tumor burden.

Vinblastin-carboplatin for metastatic cutaneous melanoma as first-line chemotherapy and in dacarbazine failures: a single-center study.

First-line treatments of metastatic melanoma are usually decarbazine (DTIC) and/or alpha-interferon based, with response rates in the range of at most 20-30%. In this study, initiated, in fact, by a temporary DTIC shortage in the country, we have assessed the efficacy and toxicity of a vinblastine-carboplatin regimen for metastatic melanoma. The regimen was subsequently applied in two cohorts of patients: a chemotherapy-naive one and in DTIC failures (because the regimen was claimed non-cross-resistant). The regimen contained 6 mg/m2 vinblastine on d 1 and 450 mg/m2 carboplatin on d 1 for 3 wk. In the chemotherapy-naïve cohort, 50 patients were included, 29 males and 21 females, median age 54 yr (range: 33-68), performance status 0+1 for 26 patients and 2+3 for 24 patients. Forty-eight patients were evaluable for activity. The response was the following: complete response (CR), 1/48 (2%); partial response (PR), 13/48 (27%); stable disease (SD), 20/48 (42%); progressive disease (PD), 14/48 (29%). The overall response rate was 14/48 (29%). The median response duration was 7 mo (range: 3-14); the median time to progression was 4 mo (range: 2-14). Toxicity included granulocytopenia and thrombocytopenia grade IV in 3/50 patients and nausea grade II in 8/50 patients. In the DTIC-failures cohort, 58 patients were included, 38 males and 20 females, median age 51 yr (range: 20-65), performance status 0+1 for 25 patients and 2+3 for 33 patients. All 58 patients were evaluable for activity. The response was the following: CR 3/58 (5%), PR 4/58 (7%), SD 10/58 (17%), PD 41/58 (71%). The overall response rate was 7/58 (12%). The median response duration was 11 mo (range: 3-24); the median time to progression was 4 mo (range: 2-24). Toxicities included granulocytopenia grade IV in 4/58 patients and nausea grade II in 4/58 patients. Thus, despite the fact that the regimen achieved a response rate comparable to DTIC in a first-line setting, the lack of cross-resistance did not prevent it from being of limited activity in DTIC failures, although, even in this group, several long-lasting responses and stabilizations were noted.

[Transmeatal direct myringoplasty]. / Transmeatusna direktna miringoplastika.

A surgical method of transmeatal direct myringoplasty (TDM) was performed in 30 patients. Out of those, 21 patients were previously treated for chronic otitis media, 4 patients were with dry perforations of neomembrane following myringoplasty, and 5 patients were with blasttraumatic ruptures of the eardrum. Fascia of the temporal muscle was used in the defect reconstruction. Graft healing and closure of the eardrum defect were observed in all patients 3 months after the surgery. Postoperative improvement of hearing in an interval of 15-20 dB was found in 21 patients. Milder sensorineural hearing damage was found in 1 patient, while in the others the hearing was on the preoperative level. Simplicity of the method, minimal surgical procedure and favorable postoperative results were the reason why the authors recommended TDM as the method of choice in the reconstruction of the eardrum defects caused by an inflammation or blasttraumatic damages of the eardrum.

Non-Hodgkin's lymphomas with primary localization in large bowel and rectum.

From 1989, at the Department of Medical Oncology of the Institute for Oncology and Radiology in Belgrade, seven patients with primary NHL of large bowel and rectum have been observed and treated, 3 males and 4 females. In 3 patients an urgent laparotomy without previous diagnostic procedures was performed, while 4 patients had laparotomy only after radiographic and endoscopic diagnosis of a tumor. Six patients had radical surgery and 1 palliative only. Five patients had lymphoma localized in cecoascedental part of colon (2 centroblastic, 1 lymphoplasmocytic, 1 Burkitt and 1 Burkitt's like), 1 patient had it in the transversal part of colon (centroblastic), and one in the rectum (diffuse centrocytic). By further investigation, in 2 cases with localization within transversal part of colon and rectum no other sites of NHL were found. They are under regular controls with 45+ and 45+ months disease free survival. Out of 5 patients with localization within cecum or ascendent part of colon, in 2 cases with Burkitt/Burkitt-like histology retroperitoneal lymphadenopathy were found, one female had NHL central propagation, and the other one lymphoma generalization. Both patients had early death from lymphoma. The remaining three patients following chemotherapy with the ProMACE regimen (as they too had a post laparotomy stage II disease) achieved a complete response lasting for 36+, 41+ and 66+ months. Since the median survival in our group of patients is at the moment 41+ months and the median has not yet been reached, our experience does not confirm literature data claiming bad prognosis of primary NHL of the colon and rectum. A long disease free survival can be obtained in these patients either with surgery only or surgery + chemotherapy, depending on disease stage and possibly initial topographic localization.

High-dose anthracyclines in the treatment of advanced primitive neuroectodermal tumors in adults--a single institution experience.

Primitive neuroectodermal tumors (PNET) are rare malignancies of presumed neural crest origin, most often presenting as bone or soft tissue masses in the trunk or axial skeleton, in children and young adults. Treatment of advanced PNET in adults is not clearly defined in the literature. Data concerning dose-intensive chemotherapy regimens for poor-risk patients with those tumors are sparse, due to rarity of PNET in adults, their diverse presentation, the variable treatment procedures applied and the absence of direct comparisons. On the other hand, the role of anthracyclines in the treatment of advanced soft tissue sarcomas is well known and substantial. Six advanced PNET patients were treated at the Institute for Oncology and Radiology of Serbia, during last five years, with high-doses of doxorubicin or epidoxorubicin combined with cisplatin. The paper reviews each of our patients, discussing how does chemotherapy influence the outcome in these patients, in context of the feasibility of high-doses of anthracyclines in advanced settings. High dose anthracyclines (epidoxorubicin 150 mg/m2) in combination with cisplatin 120 mg/m2 induced a complete response lasting for 63+ months in a patient with desmoplastic medulloblastoma of the cerebellum metastatic to bones and bone marrow. The same treatment but with the epidoxorubicin dose of 180 mg/m2 induced a complete response in a patient with olfactory neuroblastoma. Administration of high dose Doxorubicin (75 mg/m2) seems feasible in association with irradiation treatment in patients with extraosseal Ewing sarcoma/PNET but the place of high dose chemotherapy within this setting remains to be determined.

Epirubicin 150 mg/m2-cisplatin versus epirubicin 180 mg/m2-cisplatin for advanced soft tissue sarcoma.

We have previously reported the superiority of the epirubicin 180 mg/m2-cisplatin combination over single drug epirubicin 180 mg/m2 for advanced soft tissue sarcoma both in terms of response (54% vs. 29%, p = 0.025) and survival (p = 0.001). The aim of the present study was to establish whether decreasing the dosage of epirubicin to 150 mg/m2 would result in the same activity but with less hematological toxicity. One hundred fifty-nine patients with advanced soft tissue sarcoma were randomized for either epirubicin 150 mg/m2-cisplatin 120 mg/m2 (group A) or epirubicin 180 mg/m2-cisplatin 120 mg/m2 (group B). The results were as follows: group A: 79 patients were evaluated. Overall response rate was 24/79 (30%) (95% CI 21-41%). Median survival was 11 months and probability of survival at 1 year was 0.46. Grade IV granulocytopenia was present in 111/274 cycles and febrile neutropenia in 22/274. Group B: 73 patients were evaluated. The overall response rate was 39/73 (53%), (95% CI 42-64%). Median survival was 14 months and probability of survival at 1 year was 0.58. Grade IV granulocytopenia was present in 136/295 cycles and febrile neutropenia in 30/295. The differences were as follows: for overall response rate p = 0.004; power (for p = 0.05) 85%; for survival p = 0.09; for grade IV granulocytopenia p = 0.3; and for febrile neutropenia p = 0.61. A survival advantage (p = 0.043) was evident for patients randomized to group B and with performance status 0 or 1 compared with similar patients from group A. A plateau-like formation on the probability level of 0.26 on the survival curve started from month 26 onwards. In conclusion, both regimens share the same toxicity but epirubicin 180 mg/m2-cisplatin seems more active in soft tissue sarcoma, possibly indicating a breakthrough for activity between an epirubicin dosage of 150 mg/m2 and 180 mg/m2 in combination with cisplatin. The superiority of the epirubicin 180 mg/m2-cisplatin regimen appears evident both in terms of response and survival.

Comparison of two non-anthracycline-containing regimens for elderly patients with diffuse large-cell non Hodgkin's lymphoma--possible pitfalls in results reporting and interpretation.

Age over 65 years is a risk factor per se for doxorubicin administration, and coexisting diseases pose additional problems. There is still controversy whether chemotherapy regimens for elderly patients with aggressive NHL should be full-dose doxorubicin containing or whether development of non-anthracycline containing regimens is warranted. In this prospective study, 47 patients aged over 65 years with diffuse large cell NHL clinical Stage I/IE bulky-IV and no other initial exclusion criteria were randomized to receive either BCNU 120 mg/m2 d. l, VP 16 60 mg/in2 d.2-4, procarbazine 85 mg/m2 d. 2-8 (arm A, 27 patients) or mitoxantrone 6 mg/m2 d. l. with VP16 and procarbazine in the same dosage and schedule (Arm B, 20 patients). Partial responders received additional irradiation treatment if feasible. Arms were well balanced according to age, sex, clinical stage and performance status. Ten patients from arm A and 13 from arm B had PS 2 or 3; 14 patients from arm A and 8 from arm B had clinically significant antecedent and/or concomitant disease (SACD: cardiac, vascular, cerebrovascular, neurological, renal or other). On the intent-to-treat basis, the results were the following. ARM A: median number of cycles 3 (range 1--6); early death 3 patients; 16/27 responses (59%), 7 complete (30%). ARM B: median number of cycles 3 (range 1-6); early death 4 patients; 12/20 responses (60%), 3 complete (15%). There was no difference either in response rate or survival between the two arms, and pooled results from the two arms displayed a plateau on the survival curve from the 20-th month onwards on the probability level of 0.40. Clinical stage of NHL, bulky disease, age and sex did not influence survival. Initial performance status did influence survival at the significance level of p = 0.045. Although presence of SACD did not influence initial performance status, it had a strong negative impact on survival p = 0.0004). The results point to the existence of two prognostic categories of elderly patients with large cell NHL, one with a poor survival, the other achieving a significant response rate and relapse free survival. Comorbidity (SACD) apparently accounts for the poor survival in a subpopulation of elderly patients. Clinical trials with elderly patients with NHL with PS 0 or 1 and no serious coexisting disease as inclusion criteria, analyzed on an evaluable patients basis, target only to a prognostically better subpopulation among these patients.

[Submandibular secretion of immunoglobulins IgA and IgG in peripheral paralysis of the facial nerve]. / Submandibularna sekrecija imunoglobulina IgA i IgG kod perifernih paraliza zivca lica.

INTRODUCTION: In all lesions of the facial nerve suprachoroidally localized, and due to disturbance of parasympathetic and sympathetic component, there comes to qualitative and quantitative disorders of the secretion of submandibular salivary gland. Glandular immunoglobulins IgA and IgG are the secretion of the specific plasma cells in the interstice of this gland. The mechanism of the secretion of immunoglobulins is not sufficiently clear, but it is certainly under the direct neurogenic control, since the disorders of the secretion emerge after the denervation of the submandibular salivary gland. The aim of the study was to prove the direct relation between the degree of submandibular immunoglobulin secretion IgA and IgG, and the degree of the lesion of the facial nerve U which is vitally important in the clinical estimation of the peripheral paralysis of this nerve. MATERIAL AND METHODS: In 35 patients with peripheral idiopathic facial nerve paralysis, the quantity of the secreted immunoglobulins IgA and IgG was examined by laser nephelometar BLN, Module 3. The quantity of the secreted immunoglobulins IgA and IgG (mg lit) in the saliva of the paralysed side was indirectly compared to the secreted immunoglobulins of the healthy, i.e. control side. The examination was performed three times: a) after the appearance of the disease, in the first 30 days; b) two to three months later; c) after six to twelve months. RESULTS: The quantity of the secreted immunoglobulins is significantly higher in the saliva samples taken from the paralysed side (9.50U204.77 mg lit), in comparison with the samples taken from the healthy side (9.50U70.36 mg lit). In the group of patients with favourable results and significantly higher secretion (p 0.01) normalization occurred in the final period of observation. In patients with unfavourable results the difference in secretion was continuously present (p 0.05) (table 1). DISCUSSION: In the lesions of the facial nerve suprachoroidally localized, there comes to disorder concerning the secretion of immunoglobulins IgA and IgG by submandibular salivary gland, which can be applied in the estimation of the degree of paralysis and the prognosis of the final result. CONCLUSION: The results of the research show that in the peripheral idiopathic facial nerve paralysis, there comes to increased secretion of immunoglobulins IgA and IgG in submandibular gland, at the paralysed side. In the patients who, during the paralysis, show quicker fall and normalization of the previously increased quantities of immunoglobulins, the recovery of the motor function of the facial nerve comes more successfully and more certainly. The degree of the secretion of immunoglobulins IgA and IgG can be used for the estimation of the severely of the pathological process in the suprachoroidal part of the nerve, and it can be used as a reliable parameter for the prognosis of the paralysis outcome.

Pilot study of daily ifosfamide 1 g/m2 until grade III granulocytopenia as second-line chemotherapy for anthracycline-pretreated advanced soft tissue sarcoma.

BACKGROUND AND AIMS: Second-line chemotherapy regimens for advanced soft tissue sarcomas after treatment failure or tumor relapse following anthracyclines are still investigational. The aim of the present study was to assess the activity of ifosfamide with a new schedule for patients with advanced soft tissue sarcoma failing to achieve remission or relapsing following anthracycline-containing regimens; it was attempted to individualize dosages and prevent excessive toxicity. STUDY DESIGN: A second-line chemotherapy regimen of ifosfamide 1 g/m2 daily, with drug withdrawal until the next cycle upon appearance of grade III granulocytopenia, was administered to 21 patients with advanced soft tissue sarcoma. All patients failed to achieve remission or relapsed following a first-line high-dose anthracycline regimen (epirubicin 180 mg/m2 or zorubicin 600 mg/m2 per cycle). The cycles were repeated every four weeks. RESULTS: The median number of cycles applied was three (range, 1-15). The ifosfamide dosage reached was 4-13 g/m2 per cycle, median 5 g/m2. A complete response was achieved in 1/21 patient (5%), no partial responses were observed, 4/21 patients (20%) had stable disease, and 16/21 (75%) had progressive disease. No difference in response and stable disease rates was observed between responders and non-responders to first-line chemotherapy. No difference in the ifosfamide dose reached was noted between patients receiving second-line chemotherapy directly following first-line therapy and those with a time interval between first- and second-line chemotherapy. The granulocytopenia grade III nadir lasted for a median of one day (range, 1-3) and other toxicities including hematological toxicity were mild and infrequent. CONCLUSIONS: In view of the swift regeneration from grade III granulocytopenia, continuation of the study with granulocytopenia grade IV as a limiting factor for ifosfamide dose escalation seems feasible, with the prospect of better efficacy without excessive toxicity.

View of a war from a pathology department: Croatian experience.

This report presents an analysis of autopsy records from the Department of Pathology and Forensic Medicine, Osijek General Hospital, in the period from 2 May 1991, when 12 Croatian policemen were killed in an ambush in Borovo Selo and the war against Croatia unofficially began, until 15 January 1992, when the last cease-fire agreement between Croatia and Serbia, sponsored by the United Nations, became effective. During that time, 651 war-related autopsies were performed, constituting 42 per cent of all the deaths recorded in eastern Slavonia for that period. This number presents an 11-fold increase in the number of violent deaths in comparison to the same period of the pre-war year 1989 to 90. Forty-four per cent of all deaths were civilian ones. Explosive wounds were the most frequent cause of death: they accounted for 60 per cent of the civilian and 49 per cent of all the deaths. This fact and the extensive destruction of the cities in eastern Slavonia, including their hospitals, indicate that a principal characteristic of this and many modern wars is sudden and unexpected ground and air attacks on civilian targets.

[Intravenous leiomyomatosis of the uterus. (A case report)]. / Intravenska leiomiomatoza maternice. (Prikaz bolesnice).

A case of the intravenous leiomyomatosis of the uterus in a 53-year-old woman is reported. The patient complained of abdominal enlargement, frequent urination, and a sensation of pressure on the rectum and urinary bladder. Her uterus contained 3 fibroids which ranged from 1.5 to 11 cm in diameter. The largest fibroid contained numerous areas of hydropic degeneration. In the vascular space of the myometrium a polypoid ramifying thrombus 4 x 1 cm was present, arising fom the capsular aspects of large fibroids. It is the smallest tumor reported so far. st could have been overlooked very easily. Only one similar case was found in the literature. The case presented is in agreement with the observation made by Harper i Scully that "intravenous leiomyomatosis may not always appear in obtrusive form" and "that a careful search should be made for it in cases of uterine leiomyoma". The authors analyse the relation between intravenous leiomyomatosis and metastasizing fibroleiomyoma of the uterus. The lesions reported so far suggest that they were well differentiated smooth muscle tumors with a different biologic potential and that they should not be taken as different stages of the same process. It is not suitable to use these terms as synonyms.