Multimodality treatment for poorly differentiated neuroendocrine head and neck carcinomas--a single institution experience.

Poorly differentiated head and neck neuroendocrine neoplasms are very rare. Surgical resection alone is insufficient to control the disease because of the high incidence of metastases. However, due to the lack of randomised clinical trials, treatment recommendations for this cancer vary considerably and are based on a limited number of small retrospective studies. We performed a retrospective analysis of all patients treated at our institution between 2003 and 2011. We assessed the stage of disease, type of therapy, toxicity, treatment response, time to progression and overall survival for all cases. Ten patients received combined modality treatment with chemotherapy in addition to surgery or radiation or both. According to Response Evaluation Criteria In Solid Tumours (RECIST) criteria, six of nine evaluable patients achieved complete remission and three patients had a partial remission. The mean duration of response was 358 days, with a range from 141 to 1080 days. The overall 1-year survival rate was 88%; however, only approximately 50% of patients were alive after 2 years. Multimodality treatment concepts induce high initial remission rates in poorly differentiated neuroendocrine head and neck carcinomas. However, the time to relapse is usually short, and therefore long-term prognosis of this rare head and neck tumour remains poor.

Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients.

BACKGROUND: The presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations. PATIENTS AND METHODS: Patients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured. RESULTS: DTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated. CONCLUSIONS: Treatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit.

Therapeutic outcome and relation of acute and late side effects in the adjuvant radiotherapy of endometrial carcinoma stage I and II.

BACKGROUND AND PURPOSE: Adjuvant radiotherapy is the standard treatment for endometrial carcinoma. However, until now there has been no clear indication that radiotherapy in that setting improves survival. This calls for critical assessment of the relation between the expected benefit and the number and severity of postradiotherapeutic side effects. MATERIAL AND METHODS: In a retrospective study 159 consecutive patients with stage I and II endometrial carcinoma were treated with external radiotherapy and vaginal brachytherapy after hysterectomy and bilateral salpingoophorectomy (no surgical lymph node staging). Recurrence rates, survival and side effects were evaluated, in particular with regard to the relation of acute and late toxicity. RESULTS: Five percent of all patients developed a recurrence either in the abdomen or at distant locations. No pelvic relapses were diagnosed. Five-year relapse-free survival was 92% for stage IA + B, 84% for stage IC, and 79% for stage II disease. Acute toxicity was seen in 65.4% of patients, all grade 1 or 2, late toxicity grade 1 or 2 in 18.8%, grade 3 or 4 complications in 1.8%. The estimated 5-year freedom from late toxicity was 76.8%. Seventy-seven percent of all patients with treatment interruptions or premature end of therapy experienced late injury. In ten of 33 patients with late sequelae there was no free interval between early and late toxicity. No relation of radiation technique/fractionation and the rate of side effects was noticed. CONCLUSIONS: Adjuvant radiotherapy leads to excellent pelvic control, with few serious complications. Major acute toxicity shows significant correlation with the incidence of severe late injury, which we suggest to classify in part as consequential late effects.

[T2*-weighted MR images of gynecologic tumors with the FLASH sequence: the initial experiences at 1.5 T]. / T2*-betonte MR-Bilder gynäkologischer Tumoren mit der FLASH-Sequenz: Erste Erfahrungen bei 1,5 T.

To speed up the time taken for MR examinations, 20 patients with malignant gynaecological lesions (carcinoma of the cervix, uterus or ovary) and two operative specimen (carcinoma of the cervix) were examined by T2*-weighted flash sequences; the results were compared with T2-weighted spin echo sequences. In ten out of 20 in vivo examinations, the flash method produced a similar contrast range between tumour and normal tissues, cystic lesions being particularly well seen in gradient echo sequences. In the remaining patients, and in the surgical specimen, demarcation of the tumour was significantly poorer on the flash sequences. There was also loss of anatomic detail and an increased susceptibility to artifacts. The flash sequence as used here can therefore not be regarded as of the same diagnostic value as T2-weighted spin echo sequences in the diagnosis of gynaecological malignancies.

[The value of NMR tomography in the planning of HDR-afterloading brachytherapy in cervical carcinomas. The experiences with 41 patients]. / Wert der Kernspintomographie zur Planung der HDR-Afterloading-Brachytherapie bei Zervixkarzinomen. Erfahrungen bei 41 Patientinnen.

In 41 patients with inoperable cervical carcinomas, afterloading brachytherapy was used in combination with radiotherapy after planning with MRI (1.5 T spin echo multislice technique). In 27 women, phantoms neutral to MRI were introduced into the uterus to create a topographic situation comparable to that during brachytherapy; at the same time, the position of the applicators was marked. Under the circumstances, MRI demonstrated the position of the uterus and the tumour, the vagina, the bladder, the rectosigmoid and the applicator phantoms in every case. In 88% it was possible to demonstrate the margin of the tumour and normal myometrium. In 18% of the patients, the technique lead to a significant and, in a further 30%, to a marginal improvement in brachytherapy technique.

Histological findings in rabbit lymph nodes after endolymphatic injection of liposomes containing blue dye.

Liposomes produced from phosphatidylcholine and cholesterol and containing Patent Blue V have been injected endolymphatically in the rabbit. The lymph nodes stained dark blue and retained this colour until termination of the experiment after 28 days. No toxic effects were observed histologically. The liposomes were deposited within the macrophages in a fine granular pattern. Because endolymphatic injection of such liposomes produces excellent contrast between retroperitoneal lymph nodes and their surrounding fatty tissue, it can improve both the radicality and the selectivity of lymphonodectomy in oncological surgery.

Preoperative lymph-node staining with liposomes containing patent blue violet. A clinical case report.

A case study is reported using patent blue violet entrapped in liposomes to localize lymph nodes before surgery. Liposomes containing 44 mg patent blue violet were injected into foot lymphatics of a patient due to undergo retroperitoneal staging-lymphonodectomy. Lymph nodes were readily visualized and removed, and urine and serum was collected for assay of the dye. The maximum concentration of patent blue violet in serum was 2.7 micrograms mL-1, 1.5 h after the termination of the injection, almost no dye was detectable by the time of the operation 24 h later. In the first urine sample (2 h after the termination of the injection) the concentration of patent blue violet was 1.3 micrograms mL-1, and subsequently diminished, with the last urine sample to contain detectable dye being collected 20 h later. A total of 0.8 mg dye (2% of the injected amount) was excreted in the urine suggesting 10% of the circulating amount of dye was renally excreted. Endolymphatic injection of patent blue violet simplifies the often difficult process of finding the lymph nodes and additionally reduces side-effects. All surgery cases demanding a radical lymphonodectomy may profit, including testicular or bladder cancers and many gynaecological tumours.

Endolymphatic application of bleomycin oil suspension in dog model.

To explore the potential usefulness of a cytostatic agent deposited directly in lymph nodes, 4ml Bleomycin oil suspension (Oil-Bleo) was injected over one hour into hind leg lymphatics of seven dogs. Five of these dogs received a second, identical dose one week later into lymphatics of the contralateral hind leg. Peak serum concentration of Oil-Bleo after the first injection (7 dogs) was 12.3 micrograms/ml but after the second injection (5 dogs) was slightly lower (10.8 micrograms/ml). Maximum level of Oil-Bleo in blood was 12% of the endolymphatic dose and represented the "spillover" from lymph transport. In a control experiment, in which 60mg of aqueous Bleomycin was injected, the serum spillover was one-third higher. Large amounts of Oil-Bleo were stored in popliteal and retroperitoneal lymph nodes for several weeks. Twenty-four hours after injection the weight of "treated" lymph nodes was 73% greater than "untreated" nodes and one month later treated lymph nodes were still 37% heavier. After 24 hours, 4.7% of Oil-Bleo instilled was distributed within extracted lymph nodes, and one month later 0.12% was still detectable. By contrast, after aqueous Bleomycin infusion, only 0.05% was detected in these lymph nodes after only six hours. In general, lymph nodal architecture was preserved after Oil-Bleo. Together the findings suggest that Bleomycin oil suspension may be a useful agent for treatment of lymph nodal metastases by endolymphatic infusion.

Histologic changes in dog lymph nodes after endolymphatic application of bleomycin oil suspension.

Bleomycin oil suspension (Oil-Bleo) was injected endolymphatically in a dog experiment. The drug remained in lymph nodes over many weeks in detectable concentrations. The histologic changes in these lymph nodes were examined and compared with 3 controls (aqueous Bleomycin, Lipiodol, and no treatment). Granulomatous reaction, microabscesses, and small necrotic foci were observed. After a month, fibrosis was detectable in all lymph nodes. The damage to microscopic lymph node structures after Oil-Bleo was moderate. These findings suggest that Oil-Bleo may be useful in local treatment of lymph node metastases.

Pregnancies after endolymphatic therapy of residual retroperitoneal Hodgkin lymphoma.

Three young women with Hodgkin lymphoma (stage III and IV) had residual retroperitoneal lymphoma after 6 cycles of standard chemotherapy. To preserve fertility, chemotherapy was subsequently continued as a single endolymphatic injection of 60 mg Bleomycin in oily suspension (Oil Bleo). Except for slight, transient fever in one patient, no side effects occurred. Follow-up plain X-rays with lipoidal stained lymph nodes showed a marked reduction in size of the retroperitoneal lymphomatous lymph nodes in all 3 patients. Each woman became pregnant between 2 and 14 months after endolymphatic therapy and bore healthy infants. Two of the women remain free of disease. The third has had a recurrence in the neck and has been treated with second-line intravenous chemotherapy. Endolymphatic therapy of retroperitoneal lymphoma may achieve a satisfactory result in selected patients while preserving fertility.

Retroperitoneal lymph nodal visualization using 30% Guajazulen blue (chromolymphography).

Guajazulen, a dark blue lipid-soluble dye was used to stain retroperitoneal lymph nodes before lymphadenectomy. Initially, a 30% solution of Guajazulen (Merck, Darmstadt, FRG) in iodinated oil (Lipiodol, Byk-Gulden, Konstant, FRG) was injected endolymphatically in the hindlimbs of pigs (n = 10) and dogs (n = 8) to better visualize retroperitoneal lymph nodes. Because of encouraging results, 11 patients with testicular cancer undergoing staging or therapeutic laparotomy underwent endolymphatic injection of this dye solution preoperatively. The excellent staining of retroperitoneal lymph nodes facilitated nodal selectivity during lymphadenectomy.

Blue liposomes for identification of the sentinel lymph nodes in pigs.

Effective preoperative staining of regional lymph nodes improves their intraoperative identification and thus the selectivity of "sentinel node" lymphadenectomy. Unfortunately, aqueous Patent Blue V (PBV) often fails to provide the requisite intensity and duration of contrast (1,2). A comparative study of staining characteristics of PBV in aqueous solution with those of liposomally encapsulated PBV was carried out on 7 female pigs with an average weight of 40 kg. The liposomes, consisting of lecithin and cholesterol in a molar ratio of 3:1, were produced by an extrusion technique using membranes with thicknesses of 5 microm, 1.2 microm, 0.4 microm and 0.2 microm. In each instance, a 0.5-ml depot containing 25 +/- 0.4 mg of PBV/ml was injected into each of the four upper and lower mammary glands in aqueous solution on the left side and in a liposomal preparation on the right side. Stained lymph nodes of the groin, pelvis and neck were identified after 3, 6, 12 or 24 hours, then excised and photographed. Their PBV concentrations were measured by spectrophotometry. In all cases, the liposome preparations provided greater intensity and a longer duration than the aqueous solution. Liposomal PBV compared with aqueous PBV can therefore be recommended for better preoperative lymph node staining and identification of "sentinel" lymph nodes.

Patent blue V encapsulation in liposomes: potential applicability to endolympatic therapy and preoperative chromolymphography.

The water soluble dark blue stain Patent Blue V was incorporated into liposomes to increase its depot properties. Experiments with intraperitoneal and intramuscular application in rats and with intralymphatic injections in rabbits showed a substantial difference between the pharmacokinetics of aqueous and liposomal solutions. Independent of the route of administration, the dye-stain remained much longer in the tissues using liposomes. Most notably, retroperitoneal lymph nodes in rabbits remained dark blue up to 28 days after hindlimb endolymphatic instillation of liposomal patent blue. This vastly superior depot effect may be clinically adaptable for endolymphatic therapy with cytostatic drugs to enhance nodal drug retention and concentration or for preoperative chromolymphography to facilitate nodal visualization at laparotomy.

Liposomes for drug targeting in the lymphatic system.

Suspensions, emulsions, solutions, and liposomes were used as carriers to deliver drugs endolymphatically in animals. The purpose was to find which preparation was best tolerated by lymph tissue while slowly releasing the highly concentrated drugs out of nodal depots. Large unilamellar liposomes manufactured by detergent dialysis yielded the best results.

Drug depots in lymph nodes: which carrier is most appropriate?

Different drug carriers for endolymphatic use (suspensions, emulsions, solutions, liposomes) were investigated in animal experiments to find the preparation which is best tolerated by lymph tissue, and which allows low release of highly concentrated drugs from nodal depots. The large unilamellar liposomes produced with detergent dialysis technique were found to be most appropriate for this purpose since they fulfill all the above criteria.

[The value of gynecologic ultrasonography in comparison with gynecologic palpation]. / Uber den Stellenwert der gynäkologischen Sonographie im Vergleich zur gynäkologischen Tastuntersuchung.

210 patients were included in a prospective study comparing the respective advantages of pelvic sonography and bimanual gynaecological palpation. The diagnoses resulting from these two methods were confirmed in each case at the anatomic situs by laparotomy and also histologically. Each kind of examination was conducted independently by one of two different teams to exclude any mutual influence on the diagnosis. Under these conditions, 158 (75.2%) of the sonographic examinations and 144 (68.6%) of the gynaecological palpations resulted in a correct diagnosis. This difference was not significant. However, these data varied depending on pathological findings. In 165 patients, uterus pathology was diagnosed sonographically. This result was only slightly better than that of the gynaecological examinations. Sonography was significantly more accurate (p less than 0.01) only in determining the uterus length. However, sonography was clearly superior in the diagnosis of pelvic, in particular ovarian, tumours. In 45 patients with proven tumorous growth in this area, the sonographic diagnosis proved correct in 34 cases (75.6%), palpation however only in 22 cases (48.9%). This difference was highly significant (p less than 0.005). More precisely, significant differences were found in favor of sonography in: organ identification (p less than 0.001), organ demarcation (p less than 0.002), determination of internal structure (p less than 0.002), volume measurement (p less than 0.01), and--most important--indication of tumour type (p less than 0.01).

[2 years' experience with a monitoring and recording system for gynecological afterloading irradiation]. / Zwei Jahre Erfahrung mit einem Uberwachungs- und Protokollierungssystem für gynäkologische Afterloading-Bestrahlungen.

A computer program running on a simple desk calculator has been developed for monitoring and recording gynecological high-dose afterloading therapy. For treatment monitoring the multiple-probe AM6-system (PTW-Freiburg) is used which allows for dose measurements in the urinary bladder and the rectum. The probe signals are processed on line in order to indicate the actual dose at the measuring points. After completing the irradiation the treatment is documented. Performing fractionated treatment the measuring data are stored in the computer memory for calculating total accumulated dose. The above-described monitoring and recording [correction of protocolling] system has proven its usefulness during two years of clinical work.

[Primary radiotherapy of endometrial carcinoma]. / Primäre Strahlentherapie beim Korpuskarzinom.

From 1987 to 1993 21 patients with inoperable endometrial carcinoma of all stages received primary radiation therapy. Patients were treated either with combined external beam radiation (EBRT) and afterloading therapy (AL) or AL alone. AL was delivered in high dose rate (HDR) mode. According to tumor stage 3 to 6 times 7 or 10 Gy were applied to line A, one session per week. Due to changing dose prescriptions total doses for EBRT ranged from 45 to 50.4 Gy. 65% of patients died until the end of follow-up (range 6 to 66 months). 23% died due to progressing tumor or therapeutic sequelae (hemorrhagic colitis), 42% died from intercurrent disease. Only 6 patients are alive, one of them with tumor. After a complete course of radiation therapy there was no in-field relapse. One patient irradiated with curative intention developed paraaortal lymph node metastases. During the observation time of our study most patients died of no tumor related reasons. Primary radiation therapy does effectively control endometrial carcinoma. However, old age, reduced general condition and concomitant disease compromise survival rates after radiation therapy alone.