Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer.

BACKGROUND: Women who carry germ-line mutations in BRCA1/2 are at very high risk of developing breast and ovarian cancer. Breast conserving therapy is associated with a similar risk of ipsilateral cancer recurrence in BRCA carriers compared with non-carriers. However, the risk of subsequent contralateral breast cancer in carriers is markedly increased. Therefore, mastectomy of the diseased breast along with risk reducing mastectomy of the contralateral breast is often advocated for BRCA carriers who are treated for early breast cancer. Yet, many BRCA carriers forgo this option for fear of harmful effects and choose breast conserving treatment and observation instead. In Israel, BRCA-associated breast cancer is relatively common. Accordingly, a national protocol was devised for this enriched population. PATIENTS AND METHODS: In this Institutional Review Board-approved phase II trial, the option of prophylactic irradiation to the contralateral breast, in addition to standard loco-regional treatment, was offered to BRCA carrier patients treated for early breast cancer who declined contralateral mastectomy. The primary end point was contralateral breast cancer. RESULTS: Between May 2007 and October 2017, 162 patients were enrolled. Eighty-one patients opted for standard loco-regional treatment including surgery and radiation to the involved side (control arm) and 81 patients chose additional contralateral breast irradiation (intervention arm). At a median follow-up of 58 months, 10 patients developed contralateral breast cancer in the control arm at a median of 32 months, as compared with 2 patients in the intervention arm who developed contralateral breast cancer 80 and 105 months after bilateral breast irradiation (log-rank P = 0.011). CONCLUSIONS: Among BRCA carrier patients treated for early breast cancer, the addition of contralateral breast irradiation was associated with a significant reduction of subsequent contralateral breast cancers and a delay in their onset. CLINICAL TRIAL: Phase II, comparative two-arm trial (NCT00496288).

Adjuvant aromatase inhibitor therapy in patients with stage I breast cancer at a regional oncology center in Israel: implementation of a 'switching' policy in postmenopausal patients after initial tamoxifen.

OBJECTIVE: To analyze the implementation of a switching policy of adjuvant aromatase inhibitor (AI) therapy sequentially after tamoxifen in consecutively treated stage I (T1N0M0) hormone receptor (HR)-positive breast cancer (BC) patients. METHODS: The records of 279 consecutive HR-positive BC patients diagnosed between 2002 and 2006 and followed at the Soroka Medical Center were reviewed. RESULTS: Two-hundred-seventeen patients who initially received tamoxifen were suitable for switching and 28 received an AI as initial adjuvant treatment. The switch was accomplished in 82.5% of the 217 patients. Those who switched to an AI had a higher proportion of T1c stage than patients eligible who were not switched, but did not differ in age, histologic grade, or having received chemotherapy. Of the 179 patients who switched, 155 (86.6%) completed at least 4.5-5 years of adjuvant tamoxifen/AI therapy. Eighteen patients discontinued AI therapy prematurely because of toxicity. CONCLUSIONS: In this stage I BC population, despite the toxicities of AI therapy, >84% of eligible patients received an AI as adjuvant therapy. Measures to improve the management of AI toxicity, such as changing to a different AI, may reduce early stopping.

The impact of the 21-gene recurrence score assay on decision making about adjuvant chemotherapy in early-stage estrogen-receptor-positive breast cancer in an oncology practice with a unified treatment policy.

BACKGROUND: The 21-gene recurrence score (RS) assay has been validated in retrospective studies as prognostic of distant disease recurrence and predictive of the benefit of adjuvant chemotherapy in estrogen-receptor-positive breast cancer (BC). There is limited published data on the impact of the assay on clinical practice, particularly in the context of a single practice with a unified treatment policy. PATIENTS AND METHODS: Between 2006 and 2009, RS was obtained on 135 patients in a single practice with a uniform treatment policy. Treatment recommendations before and after RS result were analyzed retrospectively. Pre-RS treatment recommendations were based on clinicopathological features and Adjuvant! Online (AO) calculated survival advantage. RS and AO survival advantage for adding chemotherapy were compared for each patient. RESULTS: The distribution by risk group of RS was low- 49.6%, intermediate-37.8%, and high-12.6%. In 34 patients (25.2%, 95% confidence interval 17.9% to 32.5%), recommendation for chemotherapy was changed after obtaining assay result. Most changes (70.6%) were from chemotherapy to no chemotherapy. The RS correlated poorly with AO predictions. CONCLUSION: The 21-gene assay, when applied in a consistent manner in early-stage BC, changes treatment recommendations in one-quarter of patients tested.

Small cell carcinoma of the breast: case report.

BACKGROUND: Small cell neuroendocrine carcinoma of the breast is a rare tumor with fewer than 30 cases reported in the literature. The reported age of incidence of mammary small cell carcinoma is similar to that of breast carcinoma of the usual types. CASE: The clinicopathologic findings of a primary mammary small cell neuroendocrine carcinoma occurring in a 28-year-old female are presented with a review of pertinent literature. She was treated with lumpectomy and sentinel node biopsy as well as chemotherapy and radiotherapy. CONCLUSIONS: To the best of our knowledge, this is the youngest patient with primary small cell carcinoma of the breast reported in the English literature, indicating that these tumors occur in a wide age range.

Renal involvement in diffuse aggressive lymphomas: results of treatment with combination chemotherapy.

Nine (5.1%) of 175 patients with advanced disseminated diffuse aggressive non-Hodgkin's lymphoma presented with renal involvement and were initially treated with combination chemotherapy alone. These patients were classified as having renal involvement based on histologic and radiographic criteria. Five of the nine patients presented with a serum creatinine level greater than 2.5 mg/dL. Four patients achieved a complete remission of all systemic disease. Eight patients had complete resolution of renal involvement. Two patients later had recurrent renal disease associated with other sites of recurrence. All five patients who presented with an elevated serum creatinine level recovered normal renal function; in fact, four patients had normal renal function by the end of the first cycle of therapy. No patient required hemodialysis. Only one patient remains alive and free of disease at 55 months; five patients have died with disseminated disease; two patients have died without evidence of disease; and one patient was lost to follow-up while in remission. Initial local control of renal involvement including normalization of renal function in diffuse aggressive lymphoma can be rapidly achieved by combination chemotherapy alone.

Cutaneous photosensitivity induced by paclitaxel and trastuzumab therapy associated with aberrations in the biosynthesis of porphyrins.

BACKGROUND: Paclitaxel and trastuzumab are new treatments for patients with metastatic breast cancer. CASE REPORT: We describe here a 40-year-old female patient with metastatic breast cancer who developed a photosensitive rash 1 month after initiation of paclitaxel and trastuzumab therapy. The eruption appeared on the dorsal aspect of her hands, forearms, legs and face and consisted of erythema, edema and vesicles, and was associated with distal onycholysis. Aberrations in various parameters of the metabolism of porphyrins were observed in urine and erythrocytes. Sun avoidance and withdrawal of paclitaxel was followed by resolution of the rash and a return to the normal pattern of porphyrins biosynthesis. CONCLUSION: The combination of paclitaxel and trastuzumab treatment and sun exposure may induce a photosensitive reaction, associated with changes in various parameters of porphyrins biosynthesis.

Comparison of the bioavailability of uridine in mice after either oral or parenteral administration.

We compared the bioavailability of uridine (Urd) (350 and 3500 mg/kg) administered either as a single SC injection or by gavage, in male CD8F1 mice. Plasma samples were analyzed for Urd and uracil (Ura) using high-pressure liquid chromatography. After Urd (3500 mg/kg, SC), plasma Urd levels peaked at 4900 microM and then declined to pretreatment levels (less than 10 microM) within 6 h. Plasma Ura concentrations peaked at 1400 microM and then declined initially more slowly than Urd. After Urd (3500 mg/kg, PO) plasma levels of Urd were fairly constant (range 33-82 microM) for up to 8 h and had returned to pretreatment levels at 16 h. Plasma Ura concentrations paralleled Urd, but were approximately ten-fold higher. Areas under the concentration-time curve for Urd showed that the bioavailability of Urd after PO administration was 7% of that after SC administration. After Urd (350 mg/kg, SC) Urd levels peaked at 210 microM returning to pretreatment levels within 2 h. Plasma Ura levels reached a peak with 300 microM and then declined initially more slowly than those of Urd. After Urd (350 mg/kg, PO) plasma Urd levels were not perturbed, although Ura levels peaked at 50 microM after which they declined and could no longer be detected at 4 h. These data indicate that the bioavailability of Urd (350 or 3500 mg/kg) was lower when given PO than when it was administered by SC injection; and Urd (3500 mg/kg) PO resulted in prolonged and relatively constant plasma Urd levels compared with Urd (3500 mg/kg) SC. These results suggest that Urd PO should be compared with parenterally administered Urd in attempts to increase the therapeutic index of 5-fluorouracil and of antimetabolite inhibitors of de novo pyrimidine biosynthesis.

Primary malignant lymphoma of the prostate--a report of three cases.

We report the clinical, morphological and immunohistochemical findings in 3 cases of primary non-Hodgkins malignant lymphoma of the prostate. After treatment with doxorubicin-based chemotherapy, two patients achieved a complete remission, and 1 died of infective endocarditis three months after diagnosis. Until a consensus has been reached regarding the optimal treatment of prostatic lymphoma, therapy should be determined by the histologic type diagnosed and stage of the lymphoma.

Interleukin-1 and tumor necrosis factor-alpha in the Reed-Sternberg cells of Hodgkin's disease. Correlation with clinical and morphological "inflammatory" features.

We examined paraffin sections for the expression of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor-alpha, in 40 cases of Hodgkin's disease. Our purpose was to study the role of these cytokines in the "inflammatory" histological features and "B" symptoms in this disease. Immunohistochemistry with the avidin-biotin-peroxidase complex method was used. The findings were compared with those of 20 cases of non-Hodgkin's lymphomas and of 20 non-neoplastic lymphadenopathies. Evidence for EBV infection and myc and ras oncoproteins expression was also studied in these patients, but no correlation between any of these features and cytokine expression was found. We found a significant correlation between the expression of interleukin-1 beta and several "inflammatory" histological features, as well as between the expression of tumor necrosis factor-alpha and B symptoms and tumor bulk. The differential correlations between these major pro-inflammatory cytokines expression and the "inflammatory" manifestations in Hodgkin's disease are remarkable, considering the complexity of the cytokines composing the cytokine network involved in this disease.

Multimodal treatment of metastatic thymic carcinoma including high-dose chemotherapy with autologous stem cell transplantation: report of a case with more than 4-year disease-free survival.

Thymic carcinoma is a rare epithelial malignancy differentiated from thymoma by the presence of cytologically malignant cells. There are few reports of the treatment of locally advanced or metastatic thymic carcinoma. We describe a patient who sought treatment for thymic carcinoma metastatic to pleura, pericardium, retroperitoneum, and neck nodes. He was treated with neoadjuvant etoposide, ifosfamide, and cisplatin, and underwent resection. We then administered high-dose chemotherapy with autologous stem cell support, followed by radiation therapy. The patient remains in complete remission more than 4 years after diagnosis. To our knowledge, this is the first report of metastatic thymic carcinoma treated with neoadjuvant therapy and postoperative high-dose chemotherapy. Metastatic thymic carcinoma may be curable by aggressive combined therapies.

Metastatic angiosarcoma of the spleen after accidental radiation exposure: a case report.

Angiosarcoma is a rare malignant tumor arising from endothelial cells of blood vessels or lymphatic channels. Therapeutic irradiation, thoriumdioxide administration, pyothorax, and polyvinyl chloride exposure have been shown to be predisposing factors for developing angiosarcoma. Accidental radiation exposure has not been associated with angiosarcoma. We present an unusual case of angiosarcoma of the spleen, with metastases to bone, liver, breast, and bone marrow, in a woman who lived near the Chernobyl nuclear facility in the former Soviet Union at the time of the reactor accident in 1986. To the best of our knowledge, this is the first report of metastatic angiosarcoma after accidental radiation exposure.

Pulmonary lymphangioleiomyomatosis. Report of a case with associated multiple soft-tissue tumors.

We describe a 55-year-old woman with pulmonary lymphangioleiomyomatosis. The patient died of respiratory failure 9 years after diagnosis. An autopsy confirmed the diagnosis and disclosed multiple soft-tissue tumors, including a large solitary fibrous tumor of the lung, a huge cavernous hemangioma of the liver, a meningioma of the right pontocerebellar angle, and a focus of nodular stromal hyperplasia of the ovary. In addition, endocrine tumors, including a papillary carcinoma of the thyroid gland and a parathyroid adenoma, were also found. There was no evidence of tuberous sclerosis or angiomyolipoma of the kidney. The connection between pulmonary lymphangioleiomyomatosis and tuberous sclerosis is discussed.

Irinotecan combined with bolus 5-fluorouracil and folinic acid for metastatic colorectal cancer: is this really a dangerous treatment?

Rothenberg et al called for caution in the palliative use of irinotecan, 5-fluorouracil (5-FU) bolus and leucovorin (IFL schedule), because of early treatment related deaths in C89803 and N9741 studies. The objective of our multicenter phase II study was to evaluate the efficacy and safety of the combination of 5-FU bolus, folinic acid (FA) and irinotecan as first-line chemotherapy for metastatic colorectal cancer. From December 1999 to June 2002 138 patients (pts) were treated. The chemotherapy regimen was as follows: irinotecan 125 mg/m2 i.v. over 90 min and 5-FU 500 mg/m2 preceded by FA 20 mg/m2, both given by bolus, weekly, for 4 weeks every 6 weeks. Treatment continued until disease progression or unacceptable toxicity. Total number of administered cycles was 404. Average dose intensity was 75%. 47 out of 131 evaluable pts achieved a complete (n = 6) or partial (n = 41) response, leading to an overall response rate (RR) of 36% [95% confidence interval (CI) 24% to 48%], stable disease was registered in 50 (38%). The estimated median time to progression and survival were 6.5 months (95% CI 5.2-9.4) and 16.6 months (95% CI 15.1-19.3) respectively. Two-year survival was 35%. Toxicity was well manageable. In 18 (13.8%) pts the chemotherapy was stopped because of toxicity. Treatment related death was not observed. Close clinical monitoring, early recognition of toxicity, immediate therapeutic intervention are recommended for pts receiving IFL. In our experience this regimen has manageable toxicity and appropriate level of dose intensity and seems to be a good option for first-line therapy in metastatic colorectal cancer.

A worrying increase in the incidence of mesothelioma in Israel.

BACKGROUND: Exposure to asbestos is the main established cause of mesothelioma; the incidence of this tumor is thus often interpreted as an index of past exposure. Asbestos has been widely used in Israel in industry and building, exposing certain population groups to the risk of developing mesothelioma. OBJECTIVES: To analyze the incidence of mesothelioma in Israel during the years 1960-96, and to project its trend for the following years. METHODS: We conducted a population-based study of the incidence of mesothelioma reported to the Israel Cancer Registry during 1960-96. Time trends were analyzed from data on the annual import of asbestos to Israel, which may indicate the magnitude of past exposure. Based on these findings, trends in the incidence of mesothelioma in Israel were projected for the subsequent years. RESULTS: A total of 327 cases of mesothelioma were reported to the Israel Cancer Registry during the study period. The incidence in Jews was higher than in Arabs (age-standardized incidence rate 2.64 vs. 1.35 per million/year, respectively). Among the Jewish population, Israeli-born males and males born in Europe and America showed the highest incidence (ASR 4.23 and 4.15 per million/year, respectively). Israeli-born males were 20 years younger than Jewish males born elsewhere. The incidence was twice as high among males than females and increased sevenfold from its nadir (1.17 per million/year) in 1978-80 to its peak (8.5 per million/year) in 1993-96. During a similar period the incidence among females increased from 0.33 to 2.56 per million/year. The incidence in both sexes does not appear to level off. The large wave of immigration from the former Soviet Union that began in 1989 only partly accounts for the increased incidence in 1993-96. The time trend in the incidence of mesothelioma in both sexes parallels the use of asbestos in Israel, which peaked in the years 1976-78. CONCLUSIONS: The incidence of mesothelioma in Israel has increased sharply in recent years, unrelated to a wave of immigration from East Europe, and is predicted to continue to rise for another 10-15 years.

[Etoposide and cisplatin for non-small cell lung cancer: trial at the Soroka Medical Center 1986-1994].

Etoposide and cisplatin (EP) has been the standard therapy for non-small cell lung cancer (NSCLC) at many cancer centers for over a decade. We analyzed our experience with EP in NSCLC to provide a baseline for comparison with new drugs. From 1986 through 1994, 46 of our patients with NSCLC received EP as first-line chemotherapy. Radiation therapy was administered to 25 of them, including 20 who received it immediately before or concomitantly with chemotherapy. Toxicity was mild and included only 1 episode of neutropenic fever and 1 case of reversible renal failure. Overall response was 22%. In 3, response was complete (pathologically documented in 2 of them) and in 7 partial. Median survival in locally advanced (stage III) and metastatic disease (stage IV and recurrent) were 12 months and 7 months, respectively. 2 patients are alive and free of disease more than 6 years after diagnosis. Our results are consistent with other published studies of EP in NSCLC. EP provides modest benefit in locally advanced NSCLC, with minimal toxicity.

[Metastatic tumor of the jaw--diagnosis and management].

Metastatic tumors to the oral region are not common. The most common primary sources of metastatic tumors to the oral region are the breast, lung and kidney. The breast is the most common primary site for metastatic tumors to the jawbone, whereas the lung is the most common source for metastases to the oral soft tissues. In the jawbones, the most common location is the mandible, with the molar area being the most frequent involved site. In nearly 30% of the cases, the metastatic lesion in the oral region is the first indication of an unknown malignancy at a distant primary site. The diagnosis and management of a case with metastatic tumor to the mandible is described.