Current status and future perspectives in HER2 positive advanced gastric cancer

Gastric cancer is one of the most common malignancy worldwide with a prognosis less than 1 year in unresectable or metastatic disease. HER2 expression is the main biomarker to lead the addition of trastuzumab to first line systemic chemotherapy improving the overall survival in advanced HER2-positivegastric adenocarcinoma. The inevitable development of resistance to trastuzumab remains a great problem inasmuch several treatment strategies that have proven effective in breast cancer failed to show clinical benefit in advanced gastric cancer. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance toHER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Further, we describe the prognostic value of new non-invasive screening techniques, the current development of novel agents such us HER2 antibody–drug conjugates and bispecific antibodies, and the strategies with antitumor activity on going.

Current status and future perspectives in HER2 positive advanced gastric cancer.

Gastric cancer is one of the most common malignancy worldwide with a prognosis less than 1 year in unresectable or metastatic disease. HER2 expression is the main biomarker to lead the addition of trastuzumab to first line systemic chemotherapy improving the overall survival in advanced HER2-positivegastric adenocarcinoma. The inevitable development of resistance to trastuzumab remains a great problem inasmuch several treatment strategies that have proven effective in breast cancer failed to show clinical benefit in advanced gastric cancer. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance toHER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Further, we describe the prognostic value of new non-invasive screening techniques, the current development of novel agents such us HER2 antibody-drug conjugates and bispecific antibodies, and the strategies with antitumor activity on going.

The diagnostic accuracy of increased late night salivary cortisol for Cushing's syndrome: a real-life prospective study.

INTRODUCTION AND AIM: A prompt diagnosis of Cushing's Syndrome (CS) in high-risk populations is mandatory: 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and urinary-free cortisol (UFC) are recommended, despite thresholds calculated in retrospective studies. Our aim was to study the diagnostic accuracy of LNSC measured with chemiluminescence assay in a prospective study, confirming discrepancies with mass spectrometry (MS). MATERIALS AND METHODS: We enrolled 117 controls and 164 suspected CS (CS = 47, non-CS = 117). In case of increased LNSC, high clinical suspicion of CS or adrenal incidentaloma, patients were hospitalized to exclude/confirm CS. RESULTS: LNSC levels were higher in patients with suspected CS, CS, and non-CS than controls. Considering 16 nmol/L as threshold for CS, overall LNSC revealed SE 97% and SP 84% in the whole group of subjects considered, achieving positive/negative likelihood ratio of 5.56/0.045, respectively. 35 out of 81 subjects with increased LNSC were non-CS (15 diabetic and 20 obese): considering only those patients with increased likelihood to have a CS (the non-CS patients) SP decreased to 70%, and further reduced to 60% if we discharged subjects with adrenal incidentaloma. MS analyses reduced partially the number of false-positive LNSC. CONCLUSIONS: LNSC measured in automated chemiluminescence is reliable in clinical practice: it present a high diagnostic accuracy to exclude hypercortisolism in patients with normal cortisol levels. MS could be used to reduce the number of false-positive results; nevertheless, some non-CS subjects with functional hypercortisolism could have a mild impairment of cortisol rhythm.

The efficacy and tolerability of a sunitinib 3-week administration schedule in metastatic renal cell carcinoma patients: report of three cases.

Sunitinib, an orally multitargeted tyrosine kinase inhibitor and standard first-line treatment for metastatic renal cell carcinoma, is usually administered on a 6-week schedule. Toxicities reported with this drug are usually of moderate grade, which results in good treatment tolerability and patients' compliance. However, in some cases high-grade or prolonged toxicities require temporary treatment interruption or dose adjustment, possibly resulting in reduced treatment efficacy. We describe three cases of metastatic renal cell carcinoma patients (a 53-year-old male, a 70-year-old woman, and a 65-year-old woman) who received a shortened 3-week sunitinib administration schedule, 2 weeks daily administration followed by 1 week of rest (2/1) due to toxicities developed on the classic 6-week schedule, which would have required a temporary treatment interruption or a dose reduction. Treatment was generally well tolerated with manageable toxicities. A 3-week administration schedule of sunitinib may represent a valid alternative for managing toxicity while maintaining the planned dose intensity over a 6-weeks period of time. Sunitinib may thus be administered using a flexible dosing schedule to meet individual patient needs, achieving better tolerability and maintaining significant response to treatment.

Juvenile papillomatosis of the breast in young male: a case report.

Juvenile papillomatosis of the breast ("Swiss cheese disease'') is a benign localized proliferative condition of the breast which occurs almost exclusively in young adult women. Patients with this lesion often have a family history of breast carcinoma, but rarely carcinoma may coexist with the lesion at the time of diagnosis. We present a case of a young male with juvenile papillomatosis of the breast. The pathology and clinical management of this rare lesion is discussed.

[Adjuvant therapy in gastric cancer]. / La terapia adiuvante nel carcinoma gastrico.

In Western countries gastric cancer represents the third cause of death even if in the last twenty years the epidemiology of disease has changed. Surgery remains the treatment of choice and overall survival is still 7-15%. Survival data after curative resection are higher in Japan than in Western countries due to a substantial different surgical approach and "early" diagnosis. In both countries adjuvant treatment has been developed to increase the survival rate and different schedules and polipharmacological schemes have been tested. In Japanese trials a statistical significance in survival was observed with chemoimmunotherapy using chemotherapy as control arm. In Western countries data are not conclusive: most trial used surgery as control arm and sample size was not sufficient to show a significant difference between the two arms. The meta-analysis performed up to now have shown a trend of advantage in survival with adjuvant chemotherapy and many objections can be raised concerning the methodology of the same. In fact there are different types of meta-analyses according to whether they are based on the literature (MAL) or individual patient data (MAP or IPD meta-analysis). With an IPD meta-analysis a search is not only done in the literature for all relevant published trials, but also in the scientific community unpublished trials. For all trials, whether published or not, individual patient data on the endpoint of interest are obtained from the investigators. No meta-analysis performed up to now has adopted this methodology. Recently, combined therapy (CT/RT) has shown interesting results with an increase in DFS and OS. At the moment trials results are not sufficient to consider adjuvant chemotherapy the standard treatment: other large trials are required and a combined approach such as RT, IP chemotherapy, neoadjuvant plus adjuvant chemotherapy may be a future research possibility.

[Observations about the treatment of Cytomegalovirus retinitis in patients with HIV infection using Ganciclovir and Foscarnet] / Osservazioni relative al trattamento con Ganciclovir e Foscarnet della retinite da Cytomegalovirus in pazienti con infezione da HIV.

Objective: The Authors report their experience of Cytomegalovirus (CMV) retinitis therapy in HIV patients, using Ganciclovir and Foscarnet in monotherapy. They also evaluate the reliability of the Polymerase Chain Reaction (PCR) through the qualitative technique as an index of active disease. Methods: 18 patients suffering from CMV retinitis were treated: Ganciclovir was administered at a dosage of 10 mg/kg b.w./day and Foscarnet at 180 mg/kg b.w./day, both of them for 21 days during the induction phase. During the mantainance phase the former was administered at 5 mg/kg b.w./day and the latter at 90 mg/kg b.w./day for 5 days a week. Results: Both the drugs induced the stabilization or regression of the lesions. There was however a relapse with both therapies. We did not observe a significant difference either in the entity and the duration of the stabilization or in the survival from diagnosis time. Finally the PCR method was not helpful in the diagnosis of CMV retinitis.

Hepatitis C virus infection and mixed cryoglobulinaemia: assessment of HCV RNA copy numbers in supernatant, cryoprecipitate and non-liver cells.

The aim of this study was to characterize hepatitis C virus (HCV) infection in patients with mixed cryoglobulinaemia (MC). The HCV RNA copy number was assayed in clinical specimens from 15 consecutive patients with MC and HCV infection. Absolute quantification of HCV RNA molecules was performed using a competitive reverse transcription-polymerase chain reaction (cRT-PCR). Specific HCV RNA sequences were detected and quantified in plasma samples from all patients (mean HCV RNA copy number 4.9 x 10(6) ml-1 plasma). A high concentration of HCV RNA molecules was detected in the cryoprecipitates of eight of the 15 patients, who had a cryoprecipitate/supernatant ratio higher than 3.0 (range 3.60 to 186.80): in the remaining seven patients this ratio was close to or lower than 1.0 (range 0.13 to 1.60). Quantitative analysis of HCV RNA molecules in cells other than hepatocytes (i.e. peripheral blood mononuclear cells (PBMCs) and bone marrow cells (BMCs), in which the HCV replicative intermediate was detected using strand specific RT-PCR, demonstrated that infection is detectable in nearly 60% of these extrahepatic cells. Quantitative analysis of HCV RNA in PBMCs and BMCs revealed low levels of viral nucleic acids.

Natural interferon-beta and tamoxifen in hormone-resistant patients with advanced breast cancer.

Tamoxifen (T) is the mainstay of hormonal treatment and is able to give high response rates in selected postmenopausal women with advanced breast cancer (ABC). Nevertheless, even in responders, invariably resistance to hormones is developed. In a previous paper we reported that in a subset of patients (pts) with metastatic breast cancer the resistance to the antiestrogen could be overcome by pretreatment with natural interferon-beta (nIFN-beta) followed by the association of nIFN-beta and T. In the present study we adopted a treatment schedule employing nIFN-beta (3 x 10(6) IU/day im three times a week) and T (60 mg/day) concurrently in 30 pts with ABC progressive to previous treatment with T (30 mg/day). We obtained a 13% response rate with a median duration of response of 8 months (range 4-16 m). All the responses occurred in pts whose disease progressed after an initial response to T. Stabilisation of disease was observed in 37%. Toxicity was mild. In our opinion the use of the combination T plus nIFN-beta in the treatment of breast cancer remains investigational and the optimal scheduling still undetermined.

Quantitation of hepatitis C virus genome molecules in plasma samples.

A competitive reverse transcription PCR (cRT-PCR)-based assay for the quantitative detection of hepatitis C virus (HCV) viremia was developed, optimized, and applied to the direct molecular analysis of clinical samples from nine patients with persistent HCV infection. As for other competitive PCR-based applications, this method consists of the reverse transcription and subsequent amplification of two RNA species in the same tube: the wild-type template (to be quantified) and a known amount of a modified synthetic template. These templates have identical primer recognition sites and very similar (but not identical) sizes, thus allowing direct detection of both template species after gel electrophoresis and ethidium bromide staining. The results obtained by this cRT-PCR application for testing clinical samples from HCV-infected patients mainly indicate that the competitive approach reaches the degree of sensitivity (fewer than 5 HCV RNA molecules per 100 microliters) necessary to evaluate viral load in all HCV-infected patients, independently of clinical conditions, and that this technique is flexible enough to quantify highly divergent levels of cell-free HCV genome copy numbers in biological samples. Interestingly, we observed a sample-to-sample variation in the loss of detectable HCV genome molecules in serum in comparison with that in plasma from the same patient, thus indicating that serum specimens, although widely used in the past few years for qualitative molecular investigation of HCV-infected patients, cannot be used to obtain reliable quantitative data on HCV viremia from these patients.

Chronic liver disease and active hepatitis C virus infection in patients with antibodies to this virus.

AIMS: To assess the association between active hepatitis C virus (HCV) infection and liver damage in randomly selected patients with antibodies to the virus. METHODS: Thirty three consecutive subjects with serologically confirmed positivity for antibodies to HCV were studied for the presence of liver and circulating viral sequences by using the reverse transcription polymerase chain reaction (RT-PCR) and specific primers for the 5'-untranslated region (5'-UTR) of the HCV genome. Parallel clinical, biochemical, and histological investigations were carried out in all cases. RESULTS: A comparative virological and histological investigation showed the presence of molecular signs of active viral replication and different degrees of liver damage in all cases. Baseline values of liver and plasma samples from all the patients showed (with one exception) the presence of detectable HCV RNA sequences, despite alanine amino transferase activities being within normal values or within 1.5 times the upper limit of normal in 13 of them. Examination of percutaneous liver biopsy specimens showed the presence of confirmed liver damage (ranging from chronic persistent hepatitis to cirrhosis) in all 33 patients. CONCLUSIONS: Circulating HCV RNA sequences (a direct sign of active HCV infection) are associated with liver damage, even in the absence of clinical or biochemical signs of overt liver disease. Parallel molecular, histological, and clinical follow up of these patients is needed to understand precisely the natural history of HCV infection and for correct clinical management.

Vaginal micropapillary lesions are not related to human papillomavirus infection: in situ hybridization and polymerase chain reaction detection techniques.

The objective of this study was to assess the human papillomavirus DNA presence in vaginal papillary lesions, with particular regard to micropapillomatosis to better define their clinical significance. Prospective study: the study population was composed of 62 women who were recruited consecutively from the Colposcopy Centre of the Ancona University, Department of Obstetrics and Gynecology, on the grounds of vaginal papillomatosis or/and typical acuminata warts. Biopsies for routine histology, and for human papillomavirus (HPV) DNA detection by means of in situ hybridization and polymerase chain reaction (PCR) were taken from the papillary lesions and from 24 healthy women, who were selected as controls. Macroscopically, vaginal micropapillomatosis was ascertained in 51 cases (82.3%), while in 11 cases (17.7%) the colposcopic diagnosis was condyloma acuminatum. During in situ hybridization, HPV DNA positivity was observed in 8 (9.4%) out of 85 samples of squamous papillae and in 11 (64.7%) out of 17 samples of condylomata; in control specimens, HPV DNA was detected in 2 (8.3%) out of 24 bioptic samples. The correspondence between in situ hybridization and PCR was 96.1%, with 17.4% more diagnosis obtained by PCR. Vaginal micropapillomatosis may be regarded as a variation in the normal anatomy of the lower genital tract without any significant relationship with HPV infection, and as a lesion easily distinguishable from condylomata acuminata by clinical examination alone.

Low-dose aminoglutethimide with and without hydrocortisone replacement as a first-line endocrine treatment in advanced breast cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research.

PURPOSE: A randomized study comparing low-dose aminoglutethimide (AG) with and without hydrocortisone (HC) was performed to investigate whether corticosteroid replacement contributes to the therapeutic effects of the drug administered as a front-line endocrine therapy in postmenopausal advanced breast cancer. PATIENTS AND METHODS: Postmenopausal patients who had not had prior endocrine therapy for advanced disease and with estrogen receptor (ER) or progesterone receptor (PgR) status positive or unknown were eligible. AG was administered at a dose of 250 mg twice a day orally (125 mg twice a day during the first month) with or without HC (20 mg twice a day orally). Seventy-nine and 74 patients were assessable for response on the AG plus HC arm and on the AG arm, respectively. The two treatment groups were well balanced and patients were largely untreated. Approximately 60% had not received any adjuvant treatment, and approximately 75% had not received any medical treatment after relapse. RESULTS: The overall responses (complete response [CR] plus partial response [PR]) were 44% and 41% for the AG plus HC and the AG arm, respectively, showing no significant difference. Time to progression (median, 8.1 and 6.3 months), duration of response (median, 15.8 and 13.7 months), and duration of survival (median, 34.2 and 36.3 months) were not significantly different between the two treatment arms. Side effects were infrequent and mild in both arms, with no significant differences. CONCLUSION: We conclude that half of the conventional daily dose of AG has optimal therapeutic activity as a front-line endocrine treatment of postmenopausal advanced breast cancer and that HC does not significantly contribute to the therapeutic effects.

Combination of beta-interferon and tamoxifen as a new way to overcome clinical resistance to tamoxifen in advanced breast cancer.

This paper shows that the response to tamoxifen (T) can be improved and the resistance to the antiestrogen can be overcome, in advanced breast cancer, by a pretreatment with natural beta-interferon (nIFN-beta) followed by the association of nIFN-beta with T. Forty-three patients with advanced breast cancer, both progressive (group A) and stable or partially responsive (group B) to previous treatment with T received nIFN-beta i.m. 3 x 10(6) IU/day for 14 days and, subsequently, T30 mg/day and nIFN-beta once a week. The overall objective response rate was 26% (95% Confidence Interval = 13-39) with 8 PR obtained in group A and 3 CR in group B. The median duration of response was 6 months (range 3-12+). Stabilization of disease was observed in 44% of cases. Toxicity was mild.

Thrombocytopenia following treatment with low doses of aminoglutethimide.

The authors report a case of severe thrombocytopenia during treatment with low doses of aminoglutethimide in a woman with advanced breast cancer. Hematologic toxicity secondary to aminoglutethimide did not seem to be dose-related, and an immunologic mechanism may be postulated. Although the incidence of the side effect is probably low, monitoring of blood counts during the first months of therapy is necessary.

Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial.

From February 1983 to January 1985, 497 patients with advanced breast cancer were randomly allocated to receive either epirubicin or doxorubicin in the following combination chemotherapy regimen: fluorouracil (5-FU) 500 mg/m2 intravenous (IV) on days 1 and 8; epirubicin or doxorubicin 50 mg/m2 IV on day 1; cyclophosphamide 500 mg/m2 IV on day 1 (FEC or FAC). Cycles were repeated every 21 days until progression or to cumulative doses of 700 mg/m2 for epirubicin and 550 mg/m2 for doxorubicin. Dose reductions were applied according to the standard criteria. Activity was evaluated in 443 patients (222 in the FEC arm and 221 in the FAC arm). The two experimental groups were comparable in age, performance status, menopausal status, histology, previous treatments, and site of the disease. The overall response rate (complete response and partial response [CR + PR]) was not significantly different: 53.6% for FEC and 56.5% for FAC. The median time to progression was 273 days for FEC and 314 days for FAC; the median survival time was 591 and 613 days, respectively. Leukopenia, anemia, nausea, and vomiting were significantly lower in patients treated with FEC. As for cardiotoxicity, four cases of congestive heart failure (CHF) were recorded among patients treated with FAC while only one was observed in the FEC group. These results indicate that epirubicin in a combination chemotherapy regimen is as active as doxorubicin and is significantly less toxic.

High-dose folinic acid and 5-fluorouracil in advanced colorectal cancer.

Twenty-three patients with advanced colorectal cancer were treated with folinic acid (200 mg/m2/day 1-5 IV bolus injection) and 5-fluorouracil (400 mg/m2/day 1-5 IV in 15 minutes) every 28 days. Only three patients were pretreated. Objective response was observed in 6 (30%) of 20 evaluable patients (three complete and three partial responses). The median duration of response was 9 months (range 5-15) and time to disease progression ranged from 2 to 12 months (median 6 months). Median survival was 21 months (range 12-23+) for responders. Another 6 (30%) patients had stabilization of disease. Toxicity was generally gastrointestinal (mucositis, diarrhea, nausea); moderate leukopenia was noted. The response rate found in this study indicates that folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly in colorectal cancer.

Cisplatin and low-dose cytosine arabinoside in advanced cancer.

Twenty-two patients with advanced malignancies were treated with low-dose cytosine arabinoside (ara-C) (45 mg/m2 sc every 12 h for 3 days) and cisplatin (DDP) (100 mg/m2 ev on day 2, 2 h after ara-C. Patients received 61 cycles of ara-C + DDP with a median number per patient of 2.7 cycles (range, 1-5). All patients were evaluable for toxicity and response. Overall, 6 of 22 patients (27%) obtained an objective response (2 CR + 4 PR) with a median response duration of 20 weeks. Hematologic and gastrointestinal toxicities were moderate. Our results show a low response rate with the ara-C and DDP combination compared to the interesting results obtained in vitro.

Comparative effects of alpha, beta and gamma human interferons on a HBsAg-producing human hepatoma cell line.

The effects of all the three types of human interferons (alpha, beta and gamma) on a human hepatoma cell line with hepatitis B virus (HBV)-DNA sequences integrated into the host DNA and producing hepatitis B surface antigen (HBsAg) in culture medium were assayed. The aim of the present research was to test human interferon preparations in an in vitro system for hepatitis B virus, and to compare the observed effects. The results evidenced both the antireplicative activity principally showed by preparations of beta and gamma human interferons and the inhibition of HBsAg production by high concentrations of gamma human interferon.

[Determination of circulating immune complexes and complement activation in patients with urticaria-angioedema syndrome]. / Rilevazione di immunocomplessi circolanti ed attivazione del complemento in pazienti con sindrome orticaria-angioedema.

In the present study, we examined 102 patients with chronic urticaria and angioedema. The incidence of immune complexes (CIC)-mediated chronic urticaria with complement activation (C3b+) was 11.7% (12/102 patients). The 12 patients with CIC and C3b was divided in three diagnostic groups: with drug adverse reactions; with systemic disorders; without apparent associated pathologies. On the basis of data obtained it is remarkable the necessity of a careful etiologic diagnosis in presence of CIC mediated-chronic urticaria particularly when it is associated with arthralgies and/or elevated erythrocyte sedimentation rate (ESR) because of a likely presence of a serious systemic pathology.