G.J. Fleuren

Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients

Mitotane is considered to be the drug of choice for patients with inoperable, recurrent and metastatic adrenocortical carcinoma, although a favourable effect of this drug on survival has never been documented. We evaluated the efficacy of mitotane treatment of 96 patients with adrenocortical carcinoma followed up in our department between 1959 and 1992. Complete tumour resection was the goal of the initial treatment. Mitotane treatment was classified according to serum trough concentrations on maintenance therapy: low (< 14 mg l-1) or high (> or = 14 mg l-1). Total tumour resection was feasible in 47 patients (49%), and subtotal resection was performed in 37 patients (39%). Patients who underwent total tumour resection survived significantly longer than those who did not (P < 0.001). Adjuvant mitotane therapy (n = 11) did not influence survival after total resection. Sixty-two patients were given mitotane treatment at some time during their illness, only 30 of whom reached high maintenance serum levels. Mitotane treatment with high serum levels had an independently favourable influence on patient survival, using univariate (P < 0.01) and multivariate analysis (P = 0.01). Mitotane treatment resulting in low serum levels was tantamount to not giving mitotane at all. We conclude that mitotane treatment in adrenocortical carcinoma is effective only when high serum levels can be achieved.

Surgical/pathologic-stage migration confounds comparisons of gastric cancer survival rates between Japan and Western countries.

PURPOSEnPossible causes underlying the substantial differences in gastric cancer survival rates observed between Japan and the West were examined in a randomized trial comparing the Western R1 resection with limited lymphadenectomy and the Japanese R2 resection with extended lymphadenectomy.nnnPATIENTS AND METHODSnThe effect of four factors associated with lymphadenectomy on microscopic tumor-node-metastasis (TNM) staging, and on stage-specific survival rates was assessed in 473 curatively resected patients.nnnRESULTSnAfter application of extended lymphadenectomy, additional information on N status was available, only in R2 resections with up-staging to N2 status in 30% of patients. The calculated effect of this stage migration on known 5-year survival rates was as follows: an increase of 1% in TNM stage Ia, 2% in Ib, 7% in II, 15% in IIIa, and 15% in IIIb. A further increase in survival was observed by stage migration to N3 or N4 status, due to selective extension of lymphadenectomy to clinically overt metastases located outside the allocated level of clearance (contamination). Incomplete lymphadenectomy of N1- or N2-level stations indicated for dissection (noncompliance) demonstrates that more migration can occur when strictly adhering to the protocol. Examining more nodes per N level (diligence) induces even more migration, since the number of nodes that were histologically examined per N level correlated significantly with nodal status (lymph node-negative [N-] or lymph node-positive [N+]).nnnCONCLUSIONnThese factors explain, at least partially, superior stage-specific survival rates after R2 compared with R1 resections, without a real survival benefit in individual patients.

The Accuracy of Frozen Section Diagnosis of Ovarian Tumors

We compared all frozen section examinations of ovarian tumors during a 6-year period in our institute with the final diagnosis from paraffin sections. In this period, 946 ovarian tumor specimens were removed for histologic assessment; 176 (18.6%) had frozen section examination. Final histological diagnosis was divided into benign (55.1%), borderline malignant (10.3%), and malignant (34.6%). Sensitivity of the frozen section method for malignant or borderline disease was 83.5% and specificity for a benign lesion, 92.8%. Predictive values and 95% confidence intervals were computed: 100% (93-100%) for malignancy, 62% (32-86%) for borderline malignancy, and 92% (85-96%) for a benign disease. Diagnostic problems occurred in large borderline tumors of mucinous cell type. Analysis of the 12 false negative diagnoses revealed that a sampling error was involved in 11 cases. A judgment error was made in the only false positive and in 1 out of 12 false negative frozen section diagnoses. It is concluded that when surgeons and pathologists are aware of the limitations of frozen section diagnosis of ovarian tumors, peroperative histologic examination can be worthwhile and prevent under- and overtreatment of gynecologic patients.

Evaluation of the extent of lymphadenectomy in a randomized trial of Western- versus Japanese-type surgery in gastric cancer.

PURPOSEnIn the context of a prospective, randomized trial of gastric cancer treatment, comparing Western surgical resection with limited lymphadenectomy (R1) versus Japanese surgical resection with extended lymphadenectomy (R2), we analyzed adherence to the specified surgical-pathologic guidelines.nnnPATIENTS AND METHODSnFollowing evaluation of 389 patients, we quantified noncompliance (ie, performance of less dissection than specified) and contamination (ie, performance of more extensive dissection than specified). Of 389 patients, pathologic data permitted identification of 237 eligible patients treated with curative intent.nnnRESULTSnNoncompliance occurred in 84% of R1 and R2 cases, with magnitude significantly (P < .001) higher in R2 cases versus R1 cases. Contamination occurred in 48% of R1 cases and 52% of R2 cases, with the magnitude of contamination moderate and equally distributed between the two groups. The contamination in R1 resections and the noncompliance in R2 resections lead to a partial homogenization of the groups, undermining the likelihood of detecting any potential therapeutic advantage to R2 dissection.nnnCONCLUSIONnThe observed tendency to perform R1 resections combined with insufficient retrieval of lymph nodes underlines the need for increased surgical-pathologic standardization in this trial. Potential remedies are discussed. Proper conduct of clinical trials requires reliable means of standardizing performance of the surgical-pathologic team, an elusive but important goal.

Lymph node retrieval in a randomized trial on western-type versus Japanese-type surgery in gastric cancer

PURPOSEnIn the tumor-node-metastasis (TNM) staging system, no recommendations are provided on what lymph node retrieval technique is to be used to determine lymph node status, which leads to variability in nodal status assessment and TNM staging.nnnPATIENT AND METHODSnLymph node retrieval was quantitated using data from 237 curatively resected gastric cancer patients, from a prospective, randomized trial that compared the Western resection with limited (D1) and the Japanese resection with extended lymphadenectomy (D2), and compared data from the literature. Moreover, the efficacy of different lymph node retrieval techniques was determined.nnnRESULTSnThe mean yield of lymph nodes was 15 in D1 and 30 in D2, which is similar to results from German investigators, but substantially lower than results from Japanese investigators (60 in D2). Use of a fat-clearance technique significantly increased (P = .01) nodal yields compared with conventional retrieval. Significantly higher yields (P < .001) were obtained by a Japanese surgeon using conventional retrieval directly postoperatively. Experience of surgicopathologic teams with processing resection specimens did not influence nodal yields. Further analysis showed that reference values for nodal yields per anatomically defined station as reported in the literature were contradicted by our results and indicated the ambiguity of such standards.nnnCONCLUSIONnDespite some anatomical variability in the distribution of lymph nodes, advice on the number of nodes to examine per N level, feasible in all patients, should be incorporated into the TNM classification to standardize nodal status assessment. Based on our findings, we advocate retrieval of nodes immediately postoperatively by the surgeon.

Loss of heterozygosity for defined regions on chromosomes 3, 11 and 17 in carcinomas of the uterine cervix.

Loss of heterozygosity (LOH) frequently occurs in squamous cell carcinomas of the uterine cervix and indicates the probable sites of tumour-suppressor genes that play a role in the development of this tumour. To define the localization of these tumour-suppressor genes, we studied loss of heterozygosity in 64 invasive cervical carcinomas (stage IB and IIA) using the polymerase chain reaction with 24 primers for polymorphic repeats of known chromosomal localization. Chromosomes 3, 11, 13, 16 and 17, in particular, were studied. LOH was frequently found on chromosome 11, in particular at 11q22 (46%) and 11q23.3 (43%). LOH on chromosome 11p was not frequent. On chromosome 17p13.3, a marker (D17S513) distal to p53 showed 38% LOH, whereas p53 itself showed only 20% LOH. On the short arm of chromosome 3, LOH was frequently found (41%) at 3p21.1. The beta-catenin gene is located in this chromosomal region. Therefore, expression of beta-catenin protein was studied in 39 cases using immunohistochemistry. Staining of beta-catenin at the plasma membrane of tumour cells was present in 38 cases and completely absent in only one case. The tumour-suppressor gene on chromosome 3p21.1 may be beta-catenin in this one case, but (an)other tumour-suppressor gene(s) must also be present in this region. For the other chromosomes studied, 13q (BRCA-2) and 16q (E-cadherin), only sporadic losses (< 15% of cases) were found. Expression of E-cadherin was found in all of 37 cases but in six cases the staining was very weak. No correlation was found between clinical and histological parameters and losses on chromosome 3p, 11q and 17p. In addition to LOH, microsatellite instability was found in one tumour for almost all loci and in eight tumours for one to three loci. In conclusion, we have identified three loci with frequent LOH, which may harbour new tumour-suppressor genes, and found microsatellite instability in 14% of cervical carcinomas.

Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions: Lesion Clearance Is Related to the Strength of the T-Cell Response

Purpose: Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical nonresponders displayed weak CD8+ T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8+ T-cell reactivity, clinical efficacy, and safety of HPV16-SLP (ISA101). Experimental Design: A multicenter open-label, randomized controlled trial was conducted in patients with HPV16+ high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex vivo detectable HPV16-specific CD8+ T-cell response. The secondary objectives were clinical responses (lesion size, histology, and virology) and their relation with the strength of vaccination-induced immune responses. Results: Forty-three patients were assigned to either ISA101 with imiquimod (n = 21) or ISA101 only (n = 22). Imiquimod did not improve the outcomes of vaccination. However, vaccine-induced clinical responses were observed in 18 of 34 (53%; 95% CI, 35.1–70.2) patients at 3 months and in 15 of 29 (52%; 95% CI, 32.5–70.6) patients, 8 of whom displayed a complete histologic response, at 12 months after the last vaccination. All patients displayed vaccine-induced T-cell responses, which were significantly stronger in patients with complete responses. Importantly, viral clearance occurred in all but one of the patients with complete histologic clearance. Conclusions: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN. Clin Cancer Res; 22(10); 2342–50. ©2016 AACR. See related commentary by Karaki et al., p. 2317

Factors influencing noncompliance and contamination in a randomized trial of “Western” (r1) versus “Japanese” (r2) type surgery in gastric cancer

Background. A randomized trial was undertaken comparing the Western R1 resection with limited N1‐level lymphadenectomy and the Japanese R2 resection with extended lymphadenectomy, including the N2‐level for curative resection of gastric cancer patients. After 389 patients were entered in the trial, protocol deviations were observed that reduced the intended distinction between the two types of lymphadenectomy: noncompliance, i.e., no substantiation of lymphadenectomy by nodal yields at indicated stations, and contamination, i.e., extension of lymphadenectomy outside the allocated level of nodal clearance.

Prognosis and morbidity after total thyroidectomy for papillary, follicular and medullary thyroid cancer

The prognosis and the morbidity results after total thyroidectomy are reported for 148 patients with differentiated thyroid cancer. Ninety-two patients (62%) had papillary cancer, 27 (18%) had follicular cancer and 29 (20%) had medullary cancer. In the latter group, 16 patients had no clinical signs of a tumour and underwent total thyroidectomy after elevated calcitonin levels were found in a family screening programme. The mean follow-up period was 9.7 years in the present series. The 5- and 10-year overall survival in the patient group with papillary cancer was 97% and 95% respectively, in the group with follicular cancer it was 78% and 50% respectively and in the group with medullary cancer it was 91% and 82% respectively. Significantly associated with reduced disease-free survival were: extrathyroidal growth (P less than 0.0001), distant metastases at diagnosis (P less than 0.0001), follicular histology (P less than 0.0001), age over 40 (P less than 0.001) and male sex (P less than 0.05). In patients with papillary cancer, recurrences were in most cases located in the neck, while recurrences at distant sites were encountered more frequently in patients with follicular or medullary cancer. Accidental permanent unilateral recurrent laryngeal nerve palsy were registered in 1.4% of the nerves at risk; all on the side of the tumour. Permanent hypoparathyroidism was present in 4% of the patients.

Differentiated Thyroid Cancer: a Stage Adapted Approach to the Treatment of Regional Lymph Node Metastases

The controversy in the management of regional lymph nodes in patients with differentiated thyroid cancer is discussed on the basis of a review of the literature. Since no prospective studies have yet compared limited dissections (node picking) with more extensive dissections [(modified) radical neck dissection], a retrospective analysis was performed using two patient groups in which patients were managed differently with regard to the preoperative diagnosis and treatment of regional lymph node metastases. Only patients with proven lymph node metastases were included in the study. Because of selection methods necessary to create comparable patient groups, only 83 patients could be included in the analysis. There was no difference in survival or recurrence rate in either group, although recurrences occurred less frequently in the explored side of the neck after MRND (3.9% vs. 6.3%). More postoperative morbidity was found in the patients who had been subjected to a more extensive search for and treatment of lymph node metastases. Because of the relatively small number of patients only the difference in occurrence of accessory nerve palsies reached statistical significance (P = 0.05). It is advocated that only in the case of papillary carcinoma with limited lymph node involvement node picking is the procedure of choice. In all other cases a modified radical neck dissection should be standard treatment.