Daniele Bertoloni

The role of surgery in the multimodal treatment of primary gastric non‐Hodgkin's lymphomas a report of 76 cases and review of the literature

Seventy‐six patients with primary gastric non‐Hodgkins lymphomas (PGL) were diagnosed, and 75 were treated between 1975 and 1985. According to the Working Formulation 22 patients had low‐grade malignant histologic subtypes, 27 intermediate‐grade, and 27 high‐grade. Twenty‐four cases were diagnosed by endoscopic biopsies, 52 through laparotomy biopsies. Forty‐five underwent subtotal or total gastric resection; seven were considered unresectable at laparotomy; 23 did not undergo surgery because of the high operative risk, mainly due to advanced age and coexisting diseases; and one died of myocardial infarction a few days after admission, before starting therapy. All patients who did not undergo laparotomy were staged with bipedal lymphangiography or abdominal ultrasonography and/or computed tomography. Stage, evaluated according to the criteria of Musshoff, was I or II1 in 16 cases, II2 in five, and IV in the remaining 55. Treatment modalities included surgery (S), chemotherapy (CT), radiotherapy (RT), and combinations thereof in the following proportions: only S in ten cases, S + CT in 32 cases, S + RT in one case, S + CT + RT in two cases, CT only in 25 cases, CT + RT in five cases. No substantial differences in response to therapy and in survival were found in relation to the different treatments. Ten‐year survival was 43% in Stage I or II and 20% in Stage IV. Of the 45 resected patients, five postoperative deaths were recorded (11%). No bleeding or perforations were observed in the 30 unresected patients, and survival of such cases compared with that of the resected ones. These findings, together with data from the literature, suggest that some of the advantages claimed for surgery in PGL (debulking and abatement of the risk of perforation or hemorrhage during CT or RT) have been overestimated in relation to the intrinsic surgical risk and to the possibility of anticancer therapy. Gastric resection may still be unavoidable as a diagnostic procedure in a minority of cases and may represent the primary therapeutic procedure in clinically assessed early‐stage and low‐risk patients, but it cannot be considered mandatory whenever possible merely for debulking purposes or to obviate possible perforation or hemorrhage. The CT and/or RT can be effective in unresected and even bulky cases, providing minimal risk of severe hemorrhage or perforation.

Changing clinical presentation of multiple myeloma

We compared the presentation features of three series of patients with multiple myeloma diagnosed between 1960 and 1971 (Kyle R, Mayo Clin Proc, 1975, 50, 29, n = 869), 1972 and 1986 (Clinica Medica, University of Pavia, n = 345) and 1987 and 1990 (Cooperative Group for Study and Treatment of Multiple Myeloma, n = 341). In the most recently diagnosed patients, the percentage of those who had symptoms related to multiple myeloma (i.e. any of bone pain, systemic symptoms, disturbances related to hypercalcemia, neurological involvement and hyperviscosity) was reduced (90 vs. 86 vs. 66%) (P less than 0.001), while the percentage of asymptomatic patients diagnosed by chance was increased (not reported, and 14 vs. 34%). In the most recent series, a lower percentage of spontaneous bone pain (68 vs. 60 vs. 37%, P less than 0.001) paralleled a lower incidence of advanced bone disease (osteolyses and pathological fractures, 60 vs. 64 vs. 34%), and renal failure (serum creatinine greater than 1.2 mg/dl) was also less common (56 vs. 44 vs. 33%, P less than 0.01), at least partially due to a decreased incidence of both hypercalcemia (30 vs. 20 vs. 18%, P less than 0.001) and of hyperuricemia (serum uric acid greater than 7 mg/dl, 47 vs. 32 vs. 26%, P less than 0.01). Systemic symptoms (weakness, infections, fever or weight loss) were reported more seldom by recently diagnosed patients, due to a decreased frequency of anaemia (haemoglobin less than 12 g/dl), leukopenia and thrombocytopenia, as well as of the systemic effects of bone pain and of renal insufficiency. These data indicate that multiple myeloma is diagnosed earlier now than in the past, and this must be taken into account when comparing survival data in treated series.

HODGKIN'S DISEASE PROGNOSIS: A DIRECTLY PREDICTIVE EQUATION

586 patients with Hodgkins disease diagnosed between 1970 and 1979 were staged and treated in the same way. Multivariate analysis was used to delineate the prognostic roles of several clinical features at diagnosis. A multiple regression analysis was applied to an exponential model for survival-time distribution, which proved to fit the data accurately. Several clinical characteristics were studied and those that could singly discriminate survival significantly were chosen as predictive variables for the multiple regression. These were: sex, age, stage, histological subtype, presence of constitutional symptoms, mediastinal mass, and erythrocyte sedimentation rate (ESR), and haemoglobin and serum albumin concentrations. ESR, stage, histological subtype, and age proved to be the best prognostic factors, while sex and albumin had minor value. The presence of symptoms, mediastinal bulk, and haemoglobin were not so important. A linear equation for the six variables was derived to calculate the estimated median survival time for any given patient. This equation was validated on an external group of 179 similar patients.

Ploidy and proliferative activity measurement by flow cytometry in non-hodgkin's lymphomas. Do speculative aspects prevail over clinical ones?

Paraffin-embedded lymph node biopsies from 107 patients with newly diagnosed non-Hodgkins lymphomas were examined for cell DNA content and proliferative activity (as percentage of S-phase cells) by means of flow cytometry. Patients were diagnosed between 1975 and 1985 and were homogeneously treated according to the grade of histologic malignancy. Cytofluorimetric data were studied with regard to their correlation with histology (classified and reviewed according to both Kiel and Working Formulation criteria), clinical stage, presence of constitutional symptoms, presence of bulky disease, sex, age, and the following laboratory data measured at diagnosis: erythrocyte sedimentation rate, hemoglobin, serum lactic dehydrogenase and serum albumin concentration. Aneuploidy was more frequent in the high grade malignant subtypes and in the miscellaneous group but showed no correlations with the other clinical parameters studied. Proliferative activity demonstrated a wide variation of data but a trend was evident toward higher proliferative values in the more severe histologic subtypes. The survival discrimination allowed by high- and low-grade malignant histology is exactly reproduced when highly and slowly proliferating lymphomas are considered (greater than or less than or equal to 12% of S-phase cells). These results, analyzed with those in the literature, suggest that measurements of ploidy and proliferative activity add little independent information to what is already provided by current histologic classifications, mainly as far as clinical evaluation and prognosis are concerned. Cytokinetic-aided therapeutic choices can be usefully proposed in a restricted number of cases. Improvement of the available lymphoma classifications through a better integration of ploidy and cytokinetic data with immunologic, genetic and histologic findings is still an object to be pursued in cytometric studies.

Night sweats in Hodgkin's disease : a manifestation of preceding minor febrile pulses

The authors verified the hypothesis regarding an unawareness of possible febrile alterations during night sleep in patients with Hodgkins disease who complain of night sweats as their only symptom. In these patients, body temperature was monitored by means of a 0.01°C‐sensitive linear transducer coupled with a digital multimeter. The palm of the hand (after it was passively closed in a fist by a full bandage) was the body site where temperature measurement was found to be most comfortable for a sleeping patient and independent of movements during sleep. A good correlation was found between the hand temperature taken with this technique and oral temperature. Of six patients with sweating as their only symptom, sweating recurred during the night in four and during the afternoon in the other two. In all patients sweating was preceded by a critical 0.5 to 1.5°C increase in hand temperature, which took place no more than 30 minutes before sweating. Those with nocturnal sweats awakened during the subsequent sweating‐related, rapid temperature decrease. These results are consistent with the occurrence of slight unperceived febrile pulses that precede sweating. The only peculiarity of night sweats consists in the higher probability that a preceding slight temperature rise may not be perceived by a sleeping patient, who is more likely to be awakened by the discomfort of the subsequent sweating. This would also explain the small prognostic significance of these sweats, which is the same as that of the preceding fever. These results are discussed in light of the increasing clinical evidence that patients with Hodgkins disease are often affected by an instability of the thermoregulatory hypothalamic centers.

Increasing Interdependency of Prognosis- and Therapy-Related Factors in Hodgkin’s Disease

Two subsequent series of patients with Hodgkins disease (HD) treated according to different therapeutic plans were compared: the study made it possible to analyze the role played by therapy in influencing the individual importance of a group of well-known prognostic factors. Study 1 concerned 667 patients treated in the period 1971-1979 without special measures for mediastinal bulky disease and with four-drug chemotherapy regimens (MOPP, COPP, ABVD) for stage B or IV. Study 2 included 220 patients treated between 1980 and 1984 with combined sandwich chemoradiotherapy when mediastinal bulk was present, and with eight-drug alternating chemotherapy regimens for stages B or IV (MOPP/ABVD, CcVPP/ABVD). Distribution of epidemiologic and clinical characteristics as well as staging accuracy were comparable in the two series. Only sex, serum albumin at onset and success or failure in achieving complete remission showed the same ability to discriminate survival in both studies. Age, stage and histology retained a reduced role in Study 2, where it was found they could be handled as binary variables, i.e. more or less than 50 years of age, stage IV or other stages, lymphocyte depletion histotype or other types. The influence of B symptoms on survival was sharply decreased in patients treated with alternating chemotherapy regimens, whereas combined sandwich therapy showed a truly leveling effect on the role of mediastinal bulk, which has to be considered a very unfavorable factor with other treatments. In HD the evaluation of clinical findings with respect to their impact on prognosis is crucial for validating and graduating the staging process, and for matching the intensity of the therapy to the needs of the patient. The ongoing evolution in the roles of single prognostic factors due to therapy needs periodic reevaluation for proper adjustments of therapeutic strategies.

A plea to overcome the concept of "staging" and related inadequacy in multiple myeloma.

Abstract:  From a retrospective multivariate study on 107 multiple myeloma (MM) patients, serum β2‐microglobulin (β2M) proved to be the best prognostic discriminator, better than each of the currently used staging systems (Durie and Salmons [DS], Merlini, Waldenström and Jayakars [MWJ] and the British Medical Research Councils [BMRC]). The predictive ability of each staging system is better improved by combining consideration of β2M as a continuous rather than a binary variable (even at its best prognostic cut‐off). The combination of BMRC with β2M demonstrated the highest prognostic value, followed by those involving DS or MWJ. Ease and measurability of clinical parameters at diagnosis, parametric type of statistical model assumed for description of survival, and supply of direct estimate of expected survival are the characteristics of the MWJ system that suggest it is best able to integrate β2M correctly in a prognostic index. The basic concepts and the clinical use of the available staging systems for MM are criticized along the following lines: a) the need to include new and homogeneously weighted parameters in future prognostic systems ‐ b) the lack of direct correspondence between treatment requirements (according to stage) and available therapeutic resources ‐ c) evidence of the rough stratification of the actual survival expectancy, as permitted by the current staging systems. A direct, and as accurate as possible estimate of prognosis ‐ based on easy and measurable parameters evaluable at diagnosis ‐ should replace the current classification of patients according to stages. This estimate should mark the clinical evaluation at diagnosis, should flexibly indicate treatment even according to different protocols or centers, and should allow very accurate statistical corrections for different survival expectancy at diagnosis when evaluating different treatments in clinical trials.