Wendy Recant

Phase II Trial of ZD1839 in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

PURPOSE The epidermal growth factor receptor (EGFR) is a mediator of squamous cell carcinoma of the head and neck (SCCHN) development. ZD1839 is an orally active, selective EGFR tyrosine kinase inhibitor. This phase II study sought to explore the activity, toxicity, and pharmacodynamics of ZD1839 in SCCHN. PATIENTS AND METHODS Patients with recurrent or metastatic SCCHN were enrolled through the University of Chicago Phase II Consortium. Patients were allowed no more than one prior therapy for recurrent or metastatic disease and were treated with single-agent ZD1839 500 mg/d. Patient tumor biopsies were obtained and stained immunohistochemically for EGFR, extracellular signal-regulated kinase 1 (ERK1), and phosphorylated ERK1 (p-ERK). Study end points included response rate, time to progression, median survival, and inhibition of p-ERK. RESULTS Fifty-two patients were enrolled (40 male and 12 female) with a median age of 59 years (range, 34 to 84 years). Fourteen patients received ZD1839 through a feeding tube. Half the cohort received ZD1839 as second-line therapy. Forty-seven patients were assessable for response, with an observed response rate of 10.6% and a disease control rate of 53%. Median time to progression and survival were 3.4 and 8.1 months, respectively. The only grade 3 toxicity encountered was diarrhea in three patients. Performance status and development of skin toxicity were found to be strong predictors of response, progression, and survival. Ten biopsy samples were assessable and revealed no significant change in EGFR or p-ERK expression with ZD1839 therapy. CONCLUSION ZD1839 has single-agent activity and is well tolerated in refractory SCCHN. In contrast to other reports, development of skin toxicity was a statistically significant predictor of response and improved outcome.

Loss of heterozygosity from the short arm of chromosome 8 is associated with invasive behavior in breast cancer.

Loss of heterozygosity (LOH) from the short arm of chromosome 8 (8p) is frequent in many human cancers, including breast, colon, prostate, and bladder cancers. LOH occurs in two regions of 8p, 8p21 and 8p22, and suggests the presence of two separate tumor suppressor genes. In breast cancers, 8p LOH occurs in both early and late clinical stage tumors, while in colon, prostate, and bladder cancers, there is an association between 8p LOH and advanced clinical stage. We investigated this discrepancy by comparing 8p LOH in infiltrating ductal carcinomas (IDC) to breast cancers of earlier clinical stage, i.e., tumors with no invasion [ductal carcinoma in situ (DCIS)‐only tumors]. We used three markers which sample several reported loci of 8p LOH. We microdissected tumor from paraffin blocks of 39 IDC and 23 DCIS‐only breast cancers and amplified tumor/normal DNA pairs for the microsatellite markers D8S254 (8p22), D8S133 (8p21.3), and NEFL (8p21). All cases of IDC were informative with at least one marker, with a combined rate of LOH of 46%. The results for each marker were [no. LOH/no. informative (%)]: D8S254, 8/26 (31%); D8S133 12/31 (39%), and NEFL, 9/25 (36%). In the DCIS‐only group, all 23 were informative for at least one marker, but 8p LOH was absent. We conclude that 8p LOH from 8p21–22 is frequent in IDC of the breast, but absent in DCIS‐only cases, and may play a role in breast cancer progression by conferring invasive ability. Genes Chromosom Cancer 16:189–195 (1996).

Radiation-induced thyroid carcinoma. Clinical course and results of therapy in 296 patients.

Of 5379 patients who had received radiation treatment at our institution for benign conditions of the head and neck, 318 developed thyroid cancer 3 to 42 years later. We report follow-up observations (median interval from diagnosis to recurrence or last contact, 10 years; longest interval, 31) for 296 of these patients. Three patients died of thyroid cancer and 40 had recurrences. The rate of recurrence during the 10 years after the detection of thyroid cancer, determined by life-table analysis, was 1.1%/yr. Factors that correlated with the risk of recurrence were tumor size, histologic type, number of lobes involved, vessel invasion, and lymph node metastases. The time from radiation exposure to the discovery of thyroid cancer (latency) and the age at diagnosis both inversely correlated with recurrence. The administration of thyroid hormones reduced the number of recurrences in patients with combined papillary and follicular cancer, but no reductions could be associated with the extent of surgery done or the prophylactic use of radioactive iodine ablation. We conclude that the course of radiation-induced thyroid cancer is the same as that of thyroid cancer found in other settings. We advocate a conservative approach to the treatment of small tumors that have no associated risk for thyroid cancer other than that they developed many years after the patient had been exposed to radiation.

Neurilemomas and salivary gland tumors of the head and neck following childhood irradiation

In a program to contact and examine 4180 individuals with a history of childhood irradiation treatment for enlarged tonsils and adenoids, the authors have discovered 29 neurilemomas, two neurofibromas, and one ganglioneuroma in the 2311 subjects who have been found. Ten of these presented as acoustic neuromas, 21 presented as cervical mass lesions, and one was found in the superior posterior mediastinum. Because of their numbers and their strict localization to the area of treatment, it was concluded that they were radiation‐induced. Analysis of the latency of these tumors indicates that they continue to occur for at least 30 years after the radiation exposure. In the same group of individuals, there have been 54 confirmed salivary gland tumors, 40 benign and 14 malignant. These tumors are also continuing to occur many years after the radiation exposure.

Triad of Columnar Cell Alteration, Lobular Carcinoma in Situ, and Tubular Carcinoma of the Breast

Abstract:  Columnar cell alteration in the breast encompasses a spectrum of pathologic changes ranging from simple columnar cell change to more complex columnar cell hyperplasia with and without atypia to in situ carcinoma, often with a micropapillary architecture. For reasons that remain unclear, the columnar cell lesions are associated with tubular carcinomas and lobular carcinoma in situ. Therefore it is important to be familiar with the spectrum of changes and the associated lesions, especially in breast core biopsies for further management. 

Anterior mediastinal endodermal sinus (yolk sac) tumor in a female infant

The first known case of primary anterior mediastinal endodermal sinus (yolk sac) tumor in a female patient, occurring in a 20‐month‐old infant, is reported. The child presented with cough, fever, and listlessness. Chest x‐ray revealed a right anterior mediastinal mass. At thoracotomy a large anterior mediastinal tumor extending from the neck to the diaphragm was found, and was almost totally resected. Microscopically, the tumor displayed many of the histologic patterns observed in EST. Other neoplastic germ cell elements were not identified. The ultrastructural and immunohistochemical findings further confirmed the diagnosis. Serum alpha‐fetoprotein (AFP) level, determined during surgery, was elevated to 65,200 ng/ml, whereas serum beta‐human chorionic gonadotropin level was normal. Postoperatively, combination chemotherapy consisting of vinblastine, bleomycin, cisplatin, dactinomycin, cyclophosphamide, and doxorubicin was administered with a maintenance program. After 18 weeks on this regimen all the findings were normal, including serum AFP level. The child is well and diseasefree 25 months after diagnosis.

Staging and therapy of orbital lymphomas

Ten patients with non‐Hodgkins lymphoma primarily affecting the orbital region were evaluated at Michael Reese Hospital and Medical Center, Chicago, between 1976 and 1983. Diagnoses were based on the histopathologic classification systems of the Working Formulation of the Non‐Hodgkins Lymphomas and Rappoport. Sequential staging procedures performed at the time of diagnosis included liver‐spleen scans, Technecium‐99 bone scans, gallium 67 scans, computerized axial tomograms of the orbit and abdomen, bone marrow examination and cerebral spinal fluid analyses. Adverse prognostic factors included the following: orbital bone erosions, Stage IV disease, and large cell or mixed cell, diffuse histologic features. The type of histopathologic findings combined with the results of sequential staging procedures is useful in identifying those patients who would benefit most from systemic chemotherapy.

Defining negative margins in DCIS patients treated with breast conservation therapy: The University of Chicago experience

Abstract:  Management of ductal carcinoma in situ (DCIS) has been evolving and the majority of women are now being treated with breast‐conserving surgery and radiation therapy (i.e. breast conservation therapy [BCT]). Controversies still exist regarding the histologic features and margin status that are associated with local recurrence. The goal of this study was to review our institutions experience in patients diagnosed with DCIS and treated with BCT to determine pathologic features that can predict local recurrence, with particular emphasis on the final surgical margin status. We analyzed 103 consecutive patients with DCIS who were treated with BCT between 1986 and 2000. The slides were reviewed to determine the final margin status, type of DCIS, size of DCIS, nuclear grade, presence of necrosis and calcification, and volume of excised specimen. Margins were considered positive when DCIS touched or was transected at an inked margin. Negative margins were further categorized as close (less than 1 mm), 1–5 mm, and more than 5 mm. The size of the DCIS was determined based on either the maximal dimension on a slide or from the number of consecutive slides containing DCIS. Morphology and immunohistochemical profiles of the recurrent DCIS cases were compared with original DCIS. All patients were treated uniformly with external beam radiation therapy to the entire breast (median dose 46 Gy) with a boost to the tumor bed (median dose 14 Gy). The median follow‐up was 63 months (range 7–191 months). The actuarial 5‐year local control rate was 89%. The median time to local recurrence was 55 months. There were 13 local recurrences, of which 9 recurred as pure DCIS and 4 as invasive ductal carcinomas. Univariate analysis showed a significant association with local recurrence for positive margin (p = 0.008), high nuclear grade (p = 0.02), and young age at diagnosis (p = 0.03). If margins were negative, the 5‐year local control was 93%, as compared to 69% if margins were positive. A multivariate analysis showed that early age at diagnosis, positive margin status, and high nuclear grade were independently associated with local recurrence. The morphology and immunohistochemical stains of all nine recurrent DCIS were similar to those of the original DCIS. Breast conservation can be achieved with excellent local control by obtaining microscopically negative margins as strictly defined by DCIS not touching the inked surgical margins, and postoperative radiation that includes boost therapy to the tumor bed.

Breast conserving surgery and definitive irradiation for early stage breast cancer

Breast conserving surgery and postoperative breast radiotherapy were used to treat 219 cases of AJCC Stage I and II breast carcinoma at the Michael Reese and University of Chicago Hospitals. Most patients were treated with lumpectomy and axillary sampling followed by breast irradiation to a dose of 46 Gy followed by a boost dose of 14-16 Gy to the surgical bed. The 5-year actuarial local control is 92%. Follow-up is 1 to 10 years and the median follow-up is 36 months. Of the seven patients who recurred in the breast, three failed in the boost site and three failed adjacent to the boost site. The seventh patient recurred diffusely in the breast and skin. Four of the seven recurrences were in patients with positive surgical margins. The 5-year actuarial relapse-free survival is 80%. Factors which had an adverse affect on the cosmetic results were a scar length greater than 8 cm and a volume of resected breast tissue greater than 100 cm3. Treatment related complications were minor and infrequent. Breast conserving surgery followed by radiation therapy is effective in achieving local control with good to excellent cosmetic results.

Comparative ultrastructure of tubular carcinoma and sclerosing adenosis of the breast.

The innocuous histologic appearance of tubular carcinoma of the breast and its superficial histologic resemblance to sclerosing adenosis will occasionally present diagnostic problems. A comparative ultrastructural analysis of two tubular carcinomas and three cases of sclerosing adenosis was made that showed definite differences in the pattern of myoepithelial cell differentiation and basal lamina deposition in these two entities. Prominent myoepithelial cells and basal lamina reduplication were both conspicuous features of sclerosing adenosis that appeared to be absent in tubular carcinoma. Intracytoplasmic “pseudo‐cysts” were frequently found in sclerosing adenosis, but not in tubular carcinoma. Conversely, intracytoplasmic lumina and incomplete tubular structures were present in tubular carcinoma and seemingly absent in sclerosing adenosis. Such basic ultrastructural differences may help to differentiate these two mammary lesions when diagnostic problems occur at the conventional light microscopic level.