Genomic and clinical landscape of metastatic hormone receptors-positive breast cancers carrying ESR1 alterations.

BACKGROUND: Somatic genetic alterations of the estrogen receptor 1 gene (ESR1) are enriched in endocrine therapy-resistant, estrogen receptor-positive (ER+) metastatic breast cancer (mBC). Herein, we investigated and compared the clinical and genomic landscape of ESR1-mutant (ESR1MUT) and ESR1 wild type (ESR1WT) ER+/ human epidermal growth factor receptor 2 (HER2)- mBCs. METHODS: Clinical and genomic data were retrieved from cBioPortal using the publicly-available MSK MetTropism dataset. Metastatic, ER+/HER2- mBC samples were included in the analysis. Only oncogenic and likely oncogenic alterations according to OncoKB were included. Statistical analyses were carried out using alpha level of 0.05, with a false discovery rate threshold of 10% for multiple comparisons using the Benjamini-Hochberg method. RESULTS: Among 679 samples, 136 ESR1MUT among 131 tumors were found (19.2%). The frequency of ESR1MUT was higher in ductal versus lobular mBC (21.2% versus 13.8%, P = 0.052) and enriched in liver metastasis compared with other sites (22.5% versus 12.7%; q = 0.02). Compared with ESR1WT mBC, ESR1MUT tumors showed higher fraction of genome altered (FGA) {[0.28 interquartile range (IQR), 0.15-0.43] versus 0.22 (0.11-0.38); P = 0.04} and tumor mutational burden (TMB) [4.89 (IQR 3.46-6.85) versus 3.92 (2.59-6.05) mut/Mb; P = 0.001]. Tumors harboring p.E380X alterations showed higher TMB compared with those with H11-12 alterations [8.24 (IQR 5.06-15.3) versus 4.89 (IQR 3.46-6.75) mut/Mb; P = 0.01]. Genetic alterations of TP53 were enriched in ESR1WT tumors (36% versus 14%) [odds ratio (OR) 3.17, 95% confidence interval (CI) 1.88-5.64, q = 0.001]. Considering signaling pathways, ESR1MUT tumors showed a lower occurrence of TP53 (OR 0.48, 95% CI 0.30-0.74; q = 0.003) and MAPK (OR 0.29, 95% CI 0.11-0.65; q = 0.009) alterations. TP53 (q < 0.001), CDH1 (q < 0.001), and ERBB2 (q < 0.001) demonstrated mutual exclusivity with ESR1MUT. CONCLUSIONS: ER+/HER2- mBCs carrying ESR1MUT exhibit a divergent genomic background, characterized by a lower prevalence of TP53 and MAPK pathway alterations. Less common ESR1 alterations falling outside the H11-H12 region seem to occur in tumors with higher TMB, deserving further investigation to understand their potential actionability.

Axillary web syndrome in women after breast cancer surgery referred to an Oncological Rehabilitation Unit: which are the main risk factors? A retrospective case-control study.

OBJECTIVE: Axillary web syndrome (AWS) is a complication of surgical procedures in breast cancer (BC) patients. This condition with poorly understood incidence and etiology is characterized by the locoregional development of scar tissue, leading to subcutaneous cording, motion impairment and pain. The early identification of patients at risk for AWS would improve their clinical management. Here, we sought to characterize the prevalence of and the risk factors associated with AWS in BC women after surgery. PATIENTS AND METHODS: All patients with BC that underwent axillary surgery referred to an Outpatient Service for Oncological Rehabilitation were retrospectively collected. These women were assessed two weeks after the surgical procedure for their clinicopathologic features, type of therapeutic interventions, and AWS presence, laterality, pain, localization, cords type, and number of cords. RESULTS: Altogether, 177 patients (mean aged 60.65 ± 12.26 years) were included and divided into two groups: AWSPOS (n=52; 29.4%) and AWSNEG (n=125; 70.6%). Patients with tumor N ≥1 (OR=3.7; p<0.001), subjected to mastectomy, axillary lymph node dissection (ALND) and chemotherapy showed significant correlations with AWS onset (p<0.05). The range of shoulder motion limitation (OR=11.2; p<0.001) and the presence of breast cancer related lymphedema (OR=3.5; p=0.020) were associated with AWS. CONCLUSIONS: Mastectomy, ALND, chemotherapy, low staging tumors, shoulder range of motion limitations, and BCRL represent risk factors for AWS onset. Realizing new strategies for assessing the individual risk of AWS is a crucial clinical need to improve the health-related quality of life of BC survivors.

Three-dimensional laser scanning as a reliable and reproducible diagnostic tool in breast cancer related lymphedema rehabilitation: a proof-of-principle study.

OBJECTIVE: In this study, we aimed to assess the reproducibility and reliability of a three-dimensional laser scanner (3DLS) in measuring the upper limb volume of BRCL women undergoing a 2-week complete decongestive therapy (CDT). PATIENTS AND METHODS: 3DLS and CM were used to measure the upper limb volume in a cohort of BCRL women before (T0) and after (T1) a 2-week CDT. We evaluated: a) correlation between 3DLS and CM at both time points; b) level of agreement and the consistency of the different measurements at both time points; c) correlation between the inter-rater operator analysis in terms of total limb volume differences before and after rehabilitative treatment of both circumferential method and laser scanning 3D in breast cancer related lymphedema patients. RESULTS: Taken together, 43 BCRL women (age 51.1 ± 5.4 years) were included. Both 3DLS and CM showed a significant inter and intra-operator correlation in the arm volume measurement at both time-points (T0: r2=0.99, p<0.0001; T1: r2=0.99, p<0.0001). 3DLS showed a strong correlation with CM (r2=0.99, p<0.0001) in terms of volume measurement and provided greater intra-operator correlation (r2=0.92 vs. 0.62) in detecting volume variations after the treatment (T1-T0). CONCLUSIONS: 3DLS confirmed to be highly sensitive, cheap and easy-to-use in the evaluation of the upper limb volume in BCRL women before and after a rehabilitative treatment. These findings suggest that augmented reality technologies might be very useful in oncological rehabilitation.

Diagnostic imaging of hepatic tuberculosis: case series.

BACKGROUND: Hepatic tuberculosis (TB) shows non-specific symptoms, and liver imaging may provide diagnostic clues. Here we describe a series of patients with hepatic TB showing characteristic radiological findings. METHODS: Single-centre retrospective evaluation of patients with hepatic TB diagnosed over a period of 16 years who underwent ultrasound, computed tomography (CT) and/or magnetic resonance imaging (MRI). Hepatic lesions were classified as miliary, nodular, serohepatic or cholangitis. RESULTS: Of 14 patients with hepatic TB, five were co-infected with the human immunodeficiency virus. All patients had additional extrahepatic TB localisations. An interferon-gamma release assay was performed in 11/14 patients, ultrasound and CT were available for all patients and MRI for four. Observed patterns were miliary (n = 6) with multiple nodules < 2 cm; nodular (n = 5), characterised by a variable number of nodules (2-7 cm); and serohepatic (n = 3), with multiple nodular subcapsular lesions with a thin, smooth wall. Shared findings were hypoechoic lesions on ultrasound, hypodense lesions with ring enhancement on CT, while MRI lesions were hypointense on T1- and hyperintense on T2-weighted images. CONCLUSIONS: Ultrasound, CT and MRI can independently contribute to detection of hepatic TB. While a miliary pattern or calcifications are characteristic, no pattern is completely pathognomonic and the diagnosis depends on microbiological evidence. Particularly in risk groups, characteristic radiological findings may prompt targeted diagnostic work-up.

Effects of hypnosis on the relative parasympathetic tone assessed by ANI (Analgesia/Nociception Index) in healthy volunteers: a prospective observational study.

Hypnosis has shown an effect on the regulation of the autonomic nervous system by increasing parasympathetic activity. The Analgesia/Nociception Index (ANI) is derived from heart rate variability and represents the relative parasympathetic tone. We investigated the effects of hypnosis on ANI in healthy volunteers. Participants to the 2016 International Hypnosis congress, Saint Malo, France were recruited in this prospective observational study. After comfortable positioning of the subject in the sitting position (T0), the hypnotic trance was induced (T1) then conducted with suggestions of comfort (T2) before return to normal consciousness (T3). The ANI, heart rate (HR) and respiratory rate (RR) were recorded at the different time-points. Forty subjects were enrolled (31 women, 9 men). The mean ± SD ANI at T2 (84 ± 12) was significantly greater than at T0 (60 ± 10), T1 (62 ± 9) and T3 (59 ± 11). The median [25th-75th percentile] ANI values at T2 were significantly greater in women (90 [83-95]) than in men (74 [68-83]). There were no significant variations of HR during time. The median [25th-75th percentile] RR at T1 (16 [14-18] breaths/min) and T2 (14 [12-16] breaths/min) were significantly smaller than at T0 (18 [16-20] breaths/min) and T3 (18 [16-20] breaths/min). This study shows that hypnosis induces an increase in the relative parasympathetic tone assessed by ANI in healthy volunteers, with greater ANI values observed in women. These results suggest that ANI monitoring may provide an objective tool for the measurement of the intensity of the hypnotic process, although this should be confirmed by further studies.

Cofilin is a cAMP effector in mediating actin cytoskeleton reorganization and steroidogenesis in mouse and human adrenocortical tumor cells.

cAMP pathway plays a major role in the pathogenesis of cortisol-producing adrenocortical adenomas (CPA). cAMP-induced steroidogenesis is preceded by actin cytoskeleton reorganization, a process regulated by cofilin activity. In this study we investigated cofilin role in mediating cAMP effects on cell morphology and steroidogenesis in adrenocortical tumor cells. We demonstrated that forskolin induced cell rounding and strongly reduced phosphorylated (P)-cofilin/total cofilin ratio in Y1 (-52 ± 16%, p < 0.001) and human CPA cells (-53 ± 18%, p < 0.05). Cofilin silencing significantly reduced both forskolin-induced morphological changes and progesterone production (1.3-fold vs 1.8-fold in controls, p < 0.05), whereas transfection of wild-type or S3A (active), but not S3D (inactive) cofilin, potentiated forskolin effects on cell rounding and increased 3-fold progesterone synthesis with respect to control (p < 0.05). Furthermore, cofilin dephosphorylation by a ROCK inhibitor potentiated forskolin-induced cell rounding and steroidogenesis (2-fold increase vs forskolin alone). Finally, we found a reduced P-cofilin/total cofilin ratio and increased cofilin expression in CPA vs endocrine inactive adenomas by western blot and immunohistochemistry. Overall, these results identified cofilin as a mediator of cAMP effects on both morphological changes and steroidogenesis in mouse and human adrenocortical tumor cells.

Airways allergic inflammation and L. reuterii treatment in asthmatic children.

Recently, it has been hypothesized that the oral administration of specific live probiotic strains may have therapeutic potential in the treatment of allergic inflammation. The aim of this study was to evaluate the effect of the oral L. reuteri DSM 17938 administration (1X108CFU), in airways allergic inflammation in mild persistent asthmatic children. In this DBPC randomized study we selected 50 children (6-14 years old), affected by mild persistent asthma (GINA step 2) and allergic to HDM. At the run-in period (T-2), the children were submitted to medical examination, prick tests for the main respiratory allergens, spirometry and children asthma control test (C-ACT). We selected only the children with well controlled asthma (C-ACT >19 and FEV1> 80%). After two weeks (T0) the children were allocated into two groups, the FeNO was measured and the breath condensate was collected. Group A children were treated with the placebo (5 drops per day) and Group B children with L. reuteri (108CFU =5 drops per day) for 60 days. After the treatment period (T1), all patients were evaluated by medical examination, C-ACT, spirometry, FeNO measurement and exaled breath condensate analysis. The FeNO values showed a significant reduction (p=0,045) in L. reuteri group but not in the placebo group at the end of the treatment (T1). Furthermore, the cytokines exam showed an increase in IL-10 levels (p less than 0.05) and a significant reduction in IL-2 levels (p less than 0.05) only in L. reuteri group at T1. No significant differences in FEV1 values and C-ACT score were found in both groups. In conclusion, these data showed that L. reuteri (108 CFU) was effective in reducing bronchial inflammation in asthmatic children. No significant effect was found on FEV1 values and C-ACT score, probably because we selected children with well controlled asthma.

Additional energetic cost due to belt speed variations when walking on a treadmill.

BACKGROUND: Treadmill is commonly used in routine evaluation of walking capacities, especially when dealing with energetic cost, as it allows to measure this motion on a long enough period. However, even when using powerful treadmills, it is impossible to avoid belt speed variations. The objective of this paper was to demonstrate that this instantaneous treadmill speed has to be taken into account in mechanical work calculation during treadmill walking. METHODS: To do so, 11 healthy subjects participated in the study. They walked on treadmill at four different speeds: very slow (0.3 ms(-1)), slow (0.8 ms(-1)), normal (1.4 ms(-1)) and fast (1.9 ms(-1)). To compute P(Vi), the instantaneous mechanical work relatively to the instantaneous treadmill speed, we applied the work-energy theorem in a non-inertial reference frame induced by the treadmill speed variations. This value was then compared to P(V¯), i.e. the instantaneous mechanical work computed with the usual approximation of a constant treadmill speed. FINDINGS: The speed variations had an average value of 17% for the very slow speed and around 4.5% for the three other and more usual speeds. These variations have a strong influence on instantaneous mechanical work. Indeed, P(V¯) is nearly null when not considering speed variations whereas P(Vi) goes up to 113 mW kg(-1) at higher speeds. INTERPRETATION: To conclude, our work showed that the instantaneous treadmill speed has to be taken into account in mechanical work computation. This method may provide supplementary information in clinical assessments and analyses of gait. Indeed, when using the same methodology on formerly acquired data in a group of 13 hemiplegic patients, we found that if P(V¯) is not null in this impaired subjects group, P(Vi) is still 30% higher.

Role of PET/CT in the detection of liver metastases from colorectal cancer.

PURPOSE: The aim of this study was to compare the diagnostic accuracy of 2-[fluorine-18] fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) and computed tomography (CT) with PET/CT in the detection of liver metastases during tumour staging in patients suffering from colorectal carcinoma for the purposes of correct surgical planning and follow-up. MATERIALS AND METHODS: A total of 467 patients underwent a PET/CT scan using an iodinated contrast medium. We compared images obtained by the single PET scan, the single CT scan and by the fusion of the two procedures (PET/CT). The final diagnosis was obtained by histological examination and/or by the follow-up of all patients, including those who did not undergo surgery or biopsy. RESULTS: The PET scan had 94.05% sensitivity, 91.60% specificity and 93.36% accuracy; the CT scan had 91.07% sensitivity, 95.42% specificity and 92.29% accuracy. The combined procedures (PET/CT) had the following values: sensitivity 97.92%, specificity 97.71% and accuracy 97.86%. CONCLUSIONS: This study indicates that PET/CT is very useful in staging and restaging patients suffering from colorectal cancer. It was particularly useful when recurrences could not be visualised either clinically or by imaging despite increasing tumour markers, as it guaranteed an earlier diagnosis. PET/CT not only provides high diagnostic performance in terms of sensitivity and specificity, enabling modification of patient treatment, but it is also a unique, high-profile procedure that can produce cost savings.

Role of interventional radiology in pudendal neuralgia: a description of techniques and review of the literature.

PURPOSE: The authors sought to evaluate indications, technical feasibility and clinical efficacy of computed tomography (CT)-guided pudendal nerve infiltration in patients with chronic anoperineal pain by reviewing the role of the CT technique in their personal experience and in the recent interventional literature. MATERIALS AND METHODS: Twenty-eight women, mean age 50 years, and with a diagnosis of pudendal neuralgia on the basis of clinical and electromyographic criteria were enrolled in the study. CT-guided pudendal nerve injections were performed during three consecutive sessions held 2 weeks apart. In each session, patients received two percutaneous injections: one in the ischial spine, and the other in the pudendal (Alcock's) canal. RESULTS: One patient dropped out of the study after the first session. At clinical assessment, 24h h after treatment, 21/27 patients reported significant pain relief. At follow-up at 3, 6, 9 and 12 months, 24/27 patients reported a>or=20% improvement in the Quality of Life (QOL) index. CONCLUSIONS: In pudendal nerve entrapment, CT-guided perineural injection in the anatomical sites of nerve impingement is a safe and reproducible treatment with a clinical efficacy of 92% at 12 months.

Instantaneous treadmill speed determination using subject's kinematic data.

The treadmill is frequently used in research and clinical assessments for gait analysis. To evaluate mechanical energy and dynamics of walking, the fluctuations of the treadmill speed have to be taken into account. A new algorithm is presented in this study to determine instantaneous treadmill speed using solely the kinematic data of subjects. The algorithm uses an automatic detection of heel contact (HC) and toe off (TO) during treadmill walking. Kinematic data were collected from two groups (healthy adult, n=11; hemiplegic adult, n=9). The gait events determination is validated by comparison with two visual inspection methods. Our algorithm is able to determine instantaneous treadmill speed with accuracy. In fact, the root mean square error between the computed speed (CS) and the measure speed (MS) was weak with an average value of 0.04+/-0.021ms(-1). So, the computed speed reflects the variations of the belt speed and could be an important contribution to energetic and dynamic gait analysis on a treadmill.

Bennett movement of mandible: a comparison between traditional methods and a 64-slices CT scanner.

OBJECTIVE: compare the values of the Bennett angle measured by an average value articulator with the ones measured by a 64 slices Computed Tomography (CT). METHODS: we have studied a patient aged 72. Maxillary and mandibular impressions were obtained from the patient and placed on the average value articulator using wax-ups and a facial arch in order to perform the Bennett angle measurations by such device. CT measurements were carried out using templates in order to block the Patient in the correct mandibular position. RESULTS: our study has demonstrated that the measurements of the Bennett angle obtained with the average value articulator are consistent with the ones obtained with the 64 slices CT. CONCLUSIONS: CT scanning is a useful method, alternative to conventional procedures, as the average value articulator for Bennett angle measurements, and it could become an important diagnostic tool in the gnathological and rehabilitative area.

Role of diagnostic imaging to malignant sinus tumors in presurgical staging.

The aim of this study is to describe the current role of imaging in pre-surgical planning, reporting 25 cases of paranasal sinus tumors examined in our Institute. Between June 2006 and May 2008, we identified 25 patients with malignant tumors of the paranasal sinuses. All of the patients were evaluated with CT and/or MR exams. US were used to assess regional lymph node involvement. When necessary CT-PET scanning using FDG, was done. Diagnostic imaging is essential during the initial work-up of a patient suspected of having a paranasal sinus tumor. The role of imaging is to define the tumor extension, nodal involvement, metastases and recurrences in the postoperative patient. CT and MR imaging are the primary modalities employed; each have advantages and disadvantages but tend to be complementary. The involvement of fine bone structures is best evaluated with CT. In assessing the extent of the tumor, MR provides excellent soft tissue detail, allowing for delineation of neoplasm from surrounding inflammatory tissue and secretions. For evaluation of lymph node enlargement color-Doppler US, CT and MR provide morphologic data, while CT-PET provides metabolic data. CT-PET can be used to stage nodal and metastatic disease and for assessing the efficacy of therapy or recurrent disease.

[Clinical correlations between lumbar superficial veins and Batson's epidural plexus congestion in chronic low back pain: analysis of two case reports]. / Correlazioni cliniche tra reticolo venoso superficiale lombare e congestione venosa profonda del plesso epidurale di Batson nel paziente con lombalgia cronica: analisi di 2 case reports.

Batson's epidural venous plexus plays a crucial role for the generation of vascular back pain, in particular in those conditions characterized by venous congestion, such as heart failure or pregnancy. Except some rudimentary cuspids, the vertebral venous system is considered to be a valveless anastomotic system; as a result the blood is supposed to flow in either direction depending on changes of cardiovascular conditions during the day. Within the narrow boundaries of the neural canal, the epidural veins can therefore get congested, inducing low back pain. The aim of this case report was to highlight a correlation between lumbar superficial veins in patients with chronic low back pain and epidural deep venous plexus congestion. The patients selected underwent a morphologic examination of venous epidural plexus (included its connections with lumbar superficial blood vessels) through a 3D dynamic contrast-enhanced Magnetic Resonance Angiography. The Authors found two different radiological behaviours: total and partial congestion of the vertebral deep venous system. Clinical consequences were discussed and therapeutic strategies were suggested.

Liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a retrospective comparative study of single-agent dosages.

PURPOSE: The aim of this study was to evaluate the relative activity and tolerance of liposomal doxorubicin in recurrent ovarian, peritoneal, and tubal carcinoma at an initial dose of 40 or 50 mg/m(2) every 4 weeks. METHODS: A retrospective single-institution study was performed on patients who received liposomal doxorubicin from 1/97 to 12/00. Demographic data, liposomal doxorubicin dose, dose reductions, response, and progression-free and overall survival were recorded. RESULTS: Seventy-eight patients, 38 treated at 40 mg/m(2) and 40 treated at 50 mg/m(2), were identified. There was no difference with respect to patient age, performance status, percentage of patients who were platinum resistant or paclitaxel resistant, or tumor bulk. The response rate in this highly resistant population was 13.5 and 7.7% for liposomal doxorubicin at 40 and 50 mg/m(2) every 4 weeks, respectively. Stable disease was observed in 49 and 51% of patients treated with liposomal doxorubicin at a dose of 40 and 50 mg/m(2) every 4 weeks, respectively. The progression-free survival for patients with responding and stable disease was similar. Dose reductions were required in 27.5% of patients treated at 50 mg/m(2) versus no patients treated at 40 mg/m(2) (P < 0.001). Treatment delays due to toxicity were required in 32.5% of patients treated at 50 mg/m(2) versus 16% of patients treated at 40 mg/m(2) (P = 0.14). CONCLUSION: Liposomal doxorubicin at a dose of 40 mg/m(2) appears to be as active as liposomal doxorubicin at a dose of 50 mg/m(2) in ovarian, peritoneal, and tubal carcinoma and is better tolerated based on the frequency of dose reductions and treatment delays.

A phase II and pharmacokinetic study of weekly 72-h topotecan infusion in patients with platinum-resistant and paclitaxel-resistant ovarian carcinoma.

BACKGROUND: As suggested by preclinical trials, prolonged administration of topotecan, a reversible inhibitor of topoisomerase-I, may have a therapeutic advantage. Following a phase I trial of weekly 72-h topotecan infusion, we performed a phase II trial utilizing this schedule in ovarian carcinoma. METHODS: Eligibility included platinum-/paclitaxel-resistant ovarian carcinoma, measurable disease, and adequate hematologic, renal, and hepatic function. A dose of 2.0 mg/m(2) of topotecan was administered as a 72-h infusion weekly via an ambulatory pump. Plasma topotecan concentrations were determined prior to and at the completion of each weekly course. RESULTS: Twenty-four patients were entered and 23 patients were evaluable for toxicity and response. Two hundred eighteen weekly courses of therapy were administered (median 7 weeks, range 4-46 weeks). Toxicity was mild with grade 3 leukopenia, neutropenia, and anemia occurring in 13, 13, and 17% of patients, respectively. Two of 23 patients (9.1%) (CI 1-28%) had partial responses of 2 and 3 months' duration and 6 had stable disease. Steady state plasma topotecan lactone concentrations were a median of 1.2 ng/ml (range 0.4-8.00 ng/ml) following the first week of infusion. Steady state topotecan lactone concentrations after the first week of infusion were highest in 2 patients with partial responses. Mean steady state plasma topotecan lactone concentrations after the first week of infusion were 4.6, 2.0, and 1.3 ng/ml for partial response, stable disease, and progressive disease, respectively. An analysis of variance of steady state plasma topotecan concentrations after the first week of infusion over all administered cycles demonstrated a significant difference in steady state plasma topotecan lactone concentrations between patients with partial response and stable disease and between partial response and no response (significant at the 0.05 level after adjustment for multiple comparisons). Controlling for cycle number, steady state topotecan lactone concentrations are significantly greater for patients with responding or stable disease than those with progressive disease (P = 0.0003) and have a lower bound of > or = 1.9 ng/ml (95% confidence level). CONCLUSION: Steady state topotecan lactone concentrations are associated with responding or stable disease in platinum- and paclitaxel-resistant ovarian cancer. Steady state topotecan concentrations could potentially be utilized to modify tumor exposure and response.

Tolerance of twenty-four hour paclitaxel and carboplatin as first-line therapy in ovarian, peritoneal and fallopian tube carcinoma.

Rose PG, Fusco N, Fluellen L, Rodriguiz M. Tolerance of twenty-four hour paclitaxel and carboplatin as first-line therapy in ovarian, peritoneal and fallopian tube carcinoma. A combination of a platinum and taxane are accepted as standard first-line therapy for ovarian cancer. However, both 24-h paclitaxel and cisplatin and 3-h paclitaxel and carboplatin have significant neurotoxicity. The present study was undertaken to determine the toxicity of 24-h paclitaxel and carboplatin as first-line therapy. Ovarian, peritoneal, and fallopian tubal carcinoma patients treated with 24-h paclitaxel and carboplatin as first-line therapy were retrospectively reviewed. Paclitaxel was administered at a dose of 135 mg/m2 as a 24-h infusion followed by carboplatin at an AUC of 5 every 21 days. Toxicity was graded according to NCI Common Toxicity Scale. Fourteen patients with ovarian, peritoneal or tubal carcinoma were studied. Twelve were treated primarily with paclitaxel and carboplatin and two were originally treated with paclitaxel and cisplatin for two cycles but switched to paclitaxel and carboplatin for severe cisplatin-associated toxicities. A total of 86 courses were administered (median 6, range 1-9). Hematologic toxicity was the principal toxicity with neutropenic fever occurring in 8 patients (57%). The duration of neutropenia was brief and no septic deaths occurred. Following paclitaxel dose reduction to 110 mg/m2 neutropenic sepsis did not recur except in one patient with recurrent C. difficile colitis. The two patients who switched from paclitaxel/cisplatin to paclitaxel/carboplatin reported better tolerance of the chemotherapy regimen. Among the 13 patients with ovarian and peritoneal carcinoma 100% achieved a clinical complete response. Although associated with a high incidence of neutropenia, this regimen had rare severe or chronic toxicities in particular neurotoxicity and a high response rate.

Ninety-six-hour infusional paclitaxel as salvage therapy of ovarian cancer patients previously failing treatment with 3-hour or 24-hour paclitaxel infusion regimens.

PURPOSE: To test the hypothesis that prolonged infusion of paclitaxel (96 hours) might overcome resistance to shorter infusion schedules (3 or 24 hours) in ovarian cancer. PATIENTS AND METHODS: A total of 30 patients with advanced ovarian cancer (24 patients), primary carcinoma of the peritoneum (four patients), or fallopian tube cancer (two patients) who previously had received paclitaxel administered on either a 3-hour or 24-hour schedule were treated with the agent delivered as a 96-hour infusion (30 to 35 mg/m2/d x 4 days) on an every 3-week program. RESULTS: Although the regimen generally was well tolerated, no objective responses were observed. CONCLUSION: In patients with ovarian cancer who have shown resistance to shorter paclitaxel infusion schedules, ninety-six hour infusional paclitaxel is an inactive treatment strategy. This makes it less likely that protracted infusion of paclitaxel will improve outcome when used as part of primary therapy of ovarian cancer. An ongoing randomized study will answer that question.

Second-line therapy with paclitaxel and carboplatin for recurrent disease following first-line therapy with paclitaxel and platinum in ovarian or peritoneal carcinoma.

PURPOSE: The combination of paclitaxel and a platinum compound is the most active first-line regimen for advanced ovarian carcinoma. The current study was undertaken to evaluate this combination in the re-treatment of patients with ovarian or peritoneal carcinoma who had disease recurrence > or = 6 months following this combination. METHODS: Twenty-five patients with recurrent ovarian or peritoneal carcinoma > or = 6 months after a complete clinical response with first-line paclitaxel and platinum chemotherapy were studied. Recurrent disease was documented by computed tomography (CT), elevated CA 125 level, or surgical findings. Second-line chemotherapy consisted of paclitaxel 135 mg/m2 as a 24 hour infusion and carboplatin at an area under the concentration-time curve (AUC) of 5 to 6 every 21 days. Response to therapy was classified as measurable or assessable. RESULTS: The median time to recurrence after first-line therapy was 10 months (range, 6 to 30). Among 20 measurable and assessable patients, 14 (70%) demonstrated a complete clinical response and four (20%) a partial clinical response. The response rate with measurable disease was 91% and with assessable disease was 89%. The median progression-free interval for all patients was 9.0+ months (range, 2 to 15). The median progression-free interval for patients with measurable or assessable disease was 9.0+ months and for nonassessable disease was 7.0+ months. Fifteen patients (60%) have developed recurrence after secondary therapy at a median interval of 9.0 months (range, 2 to 15). Only two patients have died with a median survival after secondary therapy of 10.0+ months (range, 2.0 to 21.0+). CONCLUSION: The use of this combination, in this sensitive population, has a high response rate and long progression-free interval. In a chemotherapy-sensitive population, the activity of alternative second-line agents must be interpreted with this perspective.