Antitumor efficacy of the combination of photodynamic therapy and chemotherapy in murine tumors.

Photodynamic therapy (PDT) is based on the administration of tumor-localizing photosensitizers followed by light exposure of the tumor mass. The photocytotoxic effects are mainly caused by the generation of singlet oxygen. Recently, PDT has been proposed for use in combination with anticancer chemotherapy with a view to exploiting any additive antitumor effect. We investigated the effect of PDT with photoactivated aluminum disulfonated phthalocyanine (AlS2Pc) combined with the antiblastic drugs Adriamycin (ADR) and cisplatinum (CDDP) on murine tumors. Mice bearing L1210 leukemia and P388 lymphoma were treated with ADR or CDDP and subsequently treated with PDT. Low chemotherapy doses were ineffective, but the combination of antiblastic drugs + PDT had a significantly additive antitumor effect. In conclusion, with this combined therapy we were able to greatly reduce the effective doses of antiblastic drugs, thus lowering their toxic effects on normal host tissues.

Laser conization assisted by crypt visualization for cervical intraepithelial neoplasia.

OBJECTIVE: To describe intraoperative visualization of crypts and its effects on specimen clearance, safety, and clinical results of excisional treatment of cervical intraepithelial neoplasia (CIN). METHODS: We treated 147 patients with high-grade CIN (II-III) and colposcopically-assessed endocervical extension, using a CO2 laser instrument in a day-hospital setting. Endocervical walls were stained preoperatively with a 2% methylene blue aqueous solution. Cervical conization was done by laser under colposcopic vision. Stromal incision and cone shape were directed laterally to the endocervical crypts by intraoperative visualization in transparency of the stain. RESULTS: We were able to make stromal incisions at minimal and uniform radial distances from the cervical canal, thus allowing individualized cone shape and optimal bleeding control. Median (range) base diameter and height of specimens were 18 (13-24) and 20 (15-26) mm, respectively. The final histologic diagnosis was CIN II in 35 patients, CIN III in 111, and microinvasive carcinoma in one. Endocervical disease extension was confirmed in 103 patients (70%); the median (range) length of CIN in the 99 evaluable cases was 15.6 (0.5-25.7) mm, and crypt involvement was found in 39 (26.5%). All lateral margins were free of dysplasia. Four specimens (2.7%) had positive apical margins. No significant complications occurred, and fertility did not seem to be impaired. With a median (range) follow-up period of 68 (60-92) months, only 1.4% of patients experienced recurrence; two patients, both with involved crypts, had recurrent dysplasia at 23 and 45 months, respectively. CONCLUSION: Laser microsurgical conization assisted by crypt visualization facilitates safe and complete removal of CIN extending into the endocervix.

Laser microsurgery for superficial T1-T2 basal cell carcinoma of the eyelid margins.

BACKGROUND: Basal cell carcinoma (BCC), the most common malignancy of the eyelid margins, poses therapeutic problems. Surgery, radiation therapy, and cryotherapy are the currently accepted methods for the treatment of this affliction. To verify the technical and clinical effectiveness of the surgical laser method, a specific approach was developed by performing laser-combined procedures under microscopic control. METHODS: A series of 26 patients underwent carbon dioxide (CO2) laser microsurgical excision of 27 primary superficial BCCs of the eyelid margins. Eighteen tumors were T1 and 9 were T2. The lesions were located at the lid margins in 18 and at the canthus in 9 cases. The eyelash line was involved in all cases, whereas intermarginal space was involved in 17 cases, without extension to the conjunctival border. Six lesions were in the lacrimal region. Median linear extent of the lesion was 5 mm (range, 4-10 mm). Treatment was performed with the patient under local anesthesia in a Day Hospital regimen. The authors used the microscope-mounted CO2 laser as a scalpel to excise the tumor mass, thus obtaining the specimen for histologic evaluation. The authors treated the deep and lateral resection margins with laser vaporization and left the wound bed to heal by secondary intention. RESULTS: No significant complications were observed. As full-thickness eyelid resections were avoided, the authors noted conservation of lid function and cosmetic aspect in all patients. With a median follow-up of 73 months (range, 18-118), only one patient had tumor recurrence after 22 months. This tumor, located at the outer canthus, had a second microsurgical laser excision, and the patient is disease free 51 months after the last treatment. CONCLUSIONS: Laser microsurgery appears to be a safe and effective treatment method for primary superficial T1 and T2 BCC of the eyelid margins without conjunctival extension.

Up-to-date management of carcinoma of the penis.

Squamous cell carcinoma is the most common tumour of the penis. It is a rare disease in Western countries, and it is often associated with phimosis, poor hygiene or human papilloma virus infection. It could be prevented or diagnosed early in most cases, but, due to cultural and educational reasons, it is often diagnosed late. Nodal metastases are relatively common, but distant dissemination is very rare. Radical surgery gives the best control of the primary tumour, but it is mutilating. Laser surgery for limited superficial lesions and sophisticated radiotherapy for relatively small infiltrating tumours have been successfully employed, alone or in combination with chemotherapy. The use of radical surgery can therefore be restricted to cases which are unsuitable for conservative treatment or to relapses. Survival mainly depends on nodal metastases, but management of regional lymph nodes is controversial. Radical inguinal or ileoinguinal lymphadenectomy can cure approximately 40-50% of patients with positive nodes, but nearly half of the patients with clinically enlarged nodes actually have no metastases. Invalidating oedema is a frequent complication of inguinal lymphadenectomy. The point is to restrict the operation to patients with positive nodes. Expectant policy can be dangerous because results of delayed lymphadenectomy are usually poor. Fine needle aspiration biopsy and imaging may be of help in diagnosing nodal metastases. Modified surgical procedures have been advocated in order to obtain a pathological staging of the inguinal nodes avoiding invalidating sequelae, but results are controversial. Depth of invasion, tumour grade and growth pattern are of help in identifying patients at a very high risk of harbouring nodal metastases. Squamous cell carcinoma of the penis is relatively responsive to chemotherapy. Limited experiences suggest that adjuvant chemotherapy can improve the long-term survival of patients with radically resected positive nodes, and primary chemotherapy can make resectable approximately 50% of cases with fixed inguinal metastases. However, chemotherapy alone is not curative for metastatic disease.

Psychological aspects of genital human papillomavirus infection: a preliminary report.

Genital human papillomavirus (HPV) infection can lead to self-inflicted blame and hypochondriac fears as well as to problems with sexuality. The aim of this study was to assess the psychological and psychodynamic aspects of patients with widespread genital HPV infection entering into a clinical trial in which they were randomly assigned to three treatment groups: CO2 laser ablation, intramuscular interferon-alpha, CO2 laser ablation plus intramuscular interferon-alpha. Fifty-one patients were studied. Patients were asked to take a series of questionnaires which included a self-rating questionnaire for gathering information on sexuality, emotional relationship with the partner and social life. A visual analog scale was used to rate intensity of pain during sexual intercourse. Each patient went also through an in-depth interview with a clinical psychologist and filled out two personality tests to measure depression (CDQ = IPAT depression test) and anxiety (ASQ = IPAT anxiety test). Results indicated a high percentage of sexual impairments after therapy (28 cases), presence of fear of cancer (14 cases) and worsenings in the emotional relationship with the partner. No difference was found among groups of treatment.

Laser surgery for small perianal neoplasms.

Excisional laser surgery was used to treat 62 patients suffering from perianal, perineal, and anal canal neoplasms. 48 patients had benign epithelial or pigmented tumours, 12 had carcinoma in situ and 2 had invasive squamous cell carcinoma. Laser surgery was performed under local anaesthesia, in association with the operating microscope on an outpatient basis. 59 out of 62 patients (95%) had clear margins of resection after primary laser surgery, and 3 patients required a second excision for uncleared margins. 3 patients of the group of carcinoma in situ recurred, and 2 had new disease in an untreated area. These patients underwent re-section with the same technique. No significant local complications were observed for single or multiple operations at the perianal and anal canal level. All patients are disease-free in a follow-up ranging from 4 to 113 months, with a median of 25 months. Laser excisional surgery appears to be a suitable method for treating superficial tumours.

Genital human papilloma virus infection in males. A clinico-pathologic study.

From March 1987 to December 1988, 402 male sexual partners of 317 women with human papilloma virus (HPV) infection of the lower genital tract and 85 with HPV-associated cervical and/or vulvar intraepithelial neoplasia (CIN and/or VIN) were submitted to clinical examination and peniscopy. The latter was performed at a 6-15 X magnification after a 3 min exposure to 5% acetic acid solution. Visible lesions were biopsied. Thirty-one patients had clinical evidence of HPV infection in the glans, penile shaft or urethra, and 222 had peniscopic evidence of subclinical aceto-white lesions. Of 31 patients with clinical lesions, 11 showed also aceto-white subclinical lesions. Of 253 peniscopically positive males, 237 were biopsied and 191 of these were histologically ascertained. Three patients had penile intraepithelial neoplasia, one with clinical appearance of a Buschke-Löwenstein tumor. The incidence of HPV infection in male sexual partners of women affected by HPV infection of the lower genital tract associated or not with intraepithelial neoplasia is lower than expected. However, clinically negative males should not be considered disease free; in fact, 12 patients, negative at the first examination, showed histological evidence of HPV infection at subsequent controls. Therefore, follow-up of at least 6 months should be allowed to identify HPV bearing males. The reported low frequency of HPV infection may be due to the fact that the males may harbour the virus in the urethra, prostate or seminal vesicles or penis without any clinical evidence of disease. Although research for HPV-DNA in intraurethral and penile scraping material might be useful for diagnosis, peniscopy with a 5% acetic acid application remains the clinical test for evaluating HPV infection in males. The importance of peniscopy should be viewed with respect to the prevention of infection or reinfection of the female sexual partners, in addition to the specific diagnostic purpose in male patients.

Photodynamic therapy by topical meso-tetraphenylporphinesulfonate tetrasodium salt administration in superficial basal cell carcinomas.

The efficacy of an originally developed photodynamic approach, using topical administration of tetraphenylporphinesulfonate as the photosensitizer, was evaluated in a series of 292 basal cell carcinoma lesions (less than 2-mm thick) in 50 treated patients. The lack of indication for conventional therapies was the main selection criterion. The photosensitizing agent (2% solution) was topically applied at 0.1 ml/cm2, followed by light irradiation with a dye laser emitting at 645 nm (120 or 150 J/cm2). After initial treatment, all lesions responded, with 273 (93.5%) complete responses. Recurrences were observed in 29 (10.6%). A second application of photoradiation was performed in 15 persistent lesions and 11 relapsed lesions, producing 19/26 complete responses. Our results suggest that this technique can be considered a promising alternative treatment modality in selected cases of superficial basal cell carcinomas.

Follow-up of oral leukoplakia after carbon dioxide laser surgery.

We evaluate the 3-year result of 145 oral leukoplakias operated on by outpatient carbon dioxide laser surgery at the Istituto Nazionale Tumori, Milan, Italy. The surgical technique that was used consisted of excision in 140 patients and vaporization in 5 patients. Cancer was found in 14 out of 140 patients who underwent excision (10%). In the analysis of the disease-free survival rate and of the unfavorable pattern of events, only 131 patients with benign postoperative histologic diagnosis were considered. Fifty-eight patients developed unfavorable events. The probabilities of remaining free of disease or of developing local relapses or new lesions at 3-year survival was 0.57, 0.27, and 0.19, respectively. Two patients had oral carcinomas after the operation. Forty patients modified their alcohol or tobacco habits or their teeth and/or prosthesis. Moreover, only two patients modified these factors before the unfavorable events occurred.

Kaposi's sarcoma: malignant tumor or proliferative disorder?

UNLABELLED: In order to provide information on the response to treatments and clinico-pathological pattern, the clinical course of 41 patients with classic Kaposi's sarcoma (KS) was reconsidered. Twenty-six cases presented a single nodular lesion, and 15 multiple, pluricentric lesions. Surgery was the first treatment for patients with single lesions, 14 of 26 (54%) patients had recurrences: the disease-free interval ranged from a few months to 11 years. Five cases had disseminated disease, three of these were preceded by local recurrence. Cases with multiple lesions were treated by a combination of surgery, chemo- and radiation therapy (RT). In three cases spontaneous regression of disease was observed and two of these are presently disease-free. After chemotherapy and RT, many patients had complete remission of disseminated disease for up to 40 months. The drugs of first choice were vinblastine and bleomycin. Over all, only one patient died of KS, 10 years after diagnosis, nevertheless the cure rate was very poor and the final overall disease-free rate was around 30%. Proper treatment for nodular or disseminated lesions provides a fair disease-free period. FINAL CONSIDERATIONS: mortality of disease is exceptional despite the 80% risk of recurrence or dissemination. Data from our series do not provide proof that adequate control of the primary single lesion could screen against recurrence: the interval between treatment of the first lesion and recurrence is sometimes exceptionally long, up to more than 10 years, and for that it is not easy to state when disease is really cured. These considerations and other analogies between KS and lymphoproliferative disorders in immunodepressed people strongly suggests the possibility of a non-malignant or even non-tumoral pattern to this disease, with implications for therapeutic strategies.

Localized mastalgia as presenting symptom in breast cancer.

The importance of breast pain as a presenting symptom of breast cancer was assessed in 200 women with localized mastalgia but negative physical examination and in 478 women with operable breast cancer. In the first group, mammography detected five cases of subclinical breast cancer at the site of pain. In the second group, 86 patients (18%) reported localized pain as presenting symptom, followed, at different intervals, by the detection of a breast lump. Localized pain can be considered a presenting symptom of breast cancer thus requiring a careful physical and mammographic examination, especially when risk factors are associated.

Total resection of glans penis surface by CO2 laser microsurgery.

Fifteen patients underwent resection of the whole glans surface with laser microsurgical technique from May 1983 to September 1987. The operations were performed in one stage in 11 cases and in two stages in 4. In 3 cases the resected lesions represented multiple dysplasia grade III or carcinoma in situ, in 1 case hyper/parakeratosis and penile horn, and in 11 cases superficial squamous cell carcinoma. In 8 cases primary superficial and flat tumors occupied more than half the circumference of the organ, and in the remaining 7 cases there were flat, superficial residues after systemic chemotherapy for exophytic, non-infiltrating carcinomas. The CO2 laser beam was used under constant microscopic visual control at a mean output power of 20W, CW or pulsed for the tissue excision from the meatus to the sulcus level. Maximum depth of resection was 2.6 mm. Postoperative external radiotherapy (60 Gy) was given in the first case of the series (microscopically invasive cancer). Satisfactory cosmetic and functional results were observed in all cases. During the follow-up period, ranging from 2 to 48 months, persistent cancer was found at the perimeatal area in 1 case 4 months after laser resection. The procedure can be considered for conservative treatment of wide or multiple superficial lesions of the glans penis.

Laser microsurgery for superficial lesions of the penis.

A carbon dioxide laser microsurgical technique for partial or complete resection of superficial lesions of the penis is described. This technique was used in 47 patients from January 1982 to May 1985. Of the 47 patients 32 (68 per cent) were treated on an outpatient basis. Histological study of the lesions showed microscopically invasive cancer in 8 patients, carcinoma in situ in 4, grades II and III dysplasia in 5, hyperkeratosis or parakeratosis in 10, pigmented lesions in 2, papilloma in 1 and no residual disease after systemic chemotherapy for exophytic carcinoma in 3. Laser surgery was performed in 1 stage under constant microscopic visual control. The depth of the resection ranged from 0.5 to 2.6 mm. (mean depth 1.5 mm.). Surgical specimens were fit for a correct pathological examination when they were thicker than 0.5 mm. (95.7 per cent of the cases). Microscopically, the margins of the resection resulted in healthy tissue in 41 of the 45 evaluable specimens (87.2 per cent). The mean distance between the lesion and incision borders was 0.6 mm. (range 0.4 to 1 mm.). Of the 4 patients with microscopic evidence of disease at the resected margins 3 underwent another laser microsurgical procedure and 1 received external beam radiation. Healing by secondary intention had an average duration of 6 weeks. Cosmetic results were satisfactory in every patient. Only 1 patient (2 per cent) suffered complications (arterial hemorrhage). In conclusion, the short-term results of this surgical technique for penile lesions are satisfactory. Further followup is needed to evaluate the curative potential of this method.

Diagnostic efficacy of the clinical-radiological-cytological triad in solid breast lumps: results of a second prospective study on 631 patients.

The clinical-radiological-cytological triad was used for diagnostic evaluation in 631 women over 30 years old with a solid breast lump, excluding clinically obvious cancers. All the lumps were subsequently removed surgically, except for 105 cases which spontaneously regressed within 2 months. 285 of the 526 nodules removed were cancers, and 162 of 285 (57%) did not exceed 20 mm in size. The sensitivity of the individual tests (physical examination, mammography and fine-needle aspiration cytology) of the malignant lumps was respectively 0.83, 0.73 and 0.60, and it increased to 0.95 when they were associated. Of the remaining 346 benign lumps the specificity of the three tests was respectively 0.60, 0.78 and 0.98. The predictive value of a positive response (certain or probable) to the three tests was 0.63, 0.74 and 0.94. The certain positive responses of cytology (131 of 285 cases) reached a predictive value of 1.00. The predictive value of a negative response for the three tests was respectively 0.81, 0.80 and 0.82; in the absence of positive responses, the predictive value for benignancy of the triad was 0.93 (177 of 190 cases). The systematic use of the diagnostic triad and the organizational platform allowed the clinicians to select malignant cases and plan inpatient/outpatient surgical treatment.

Topical administration of tetrasodium-meso-tetraphenylporphinesulfonate (TPPS) and red light irradiation for the treatment of superficial neoplastic lesions.

In photodynamic therapy, systemic administration of photosensitizing agents induces cutaneous photosensitization in patients. This side-effect can be avoided by topical administration of the agents when only surface lesions are involved. A hydroalcoholic solution of tetrasodium-meso-tetraphenylporphinesulfonate (TPPS) containing Azone, a percutaneous penetration enhancer, was investigated to evaluate its photosensitizing potential in the treatment of 33 primary and recurrent neoplastic lesions of the skin. A complete remission was obtained of lesions with clinical thickness of less than 2 mm. Treatment effectiveness depends on both light and drug penetration through skin. Further studies are in progress to optimize treatment parameters.

Preliminary clinical studies with PDT by topical TPPS administration in neoplastic skin lesions.

Cutaneous photosensitization by topical administration of a porphyrin derivative has been previously reported from experimental studies. Preliminary clinical trials performed at the National Cancer Institute of Milan in the last six months have confirmed the feasibility of treating skin lesions by topical application of photosensitizers. Fourteen cases of basal cell carcinoma were treated by local administration of tetraphenylporphinesulphonate (TPPS), vehicled by azone. Later, the tumor was exposed to a wavelength of 630 nm from a dye laser. We noted complete remission, as documented by biopsies, in all tumors, with clinical thickness less than 2 mm, whereas partial remission was obtained in tumors with clinical thickness more than 2 mm. Our experience suggests the possibility of a routine treatment by this method for flat basal cell carcinoma and pre-malignant lesions, with remarkable advantages to conventional therapies. Our results have to be confirmed by increasing the number of cases and length of follow up; our short follow up does not allow us to make definitive claims regarding this therapy.

Laser microsurgery in oncology: indications, techniques, and results of 5-year experience.

Multidisciplinary collaboration has enabled us to use the CO2 laser in many different surgical fields. The 5-year experience at the National Tumor Institute of Milan is reviewed for the evaluation of short- and medium-term results of 321 laser surgical operations of the lower genital tract, 475 cases of lesions of the larynx and oral cavity, and 246 cases of skin lesions. A unified approach was used as regards safety measures, preoperative evaluation, and rules of application of laser instruments. The reliability of the surgical procedures, the proper selection of the cases, and the low rate of postoperative complications allowed outpatient treatment in 76% of the cases, thus reducing the hospitalization costs. The use of the microscope for laser resections under magnification was recognized to be preferable in routine surgical oncology practice. Short- and medium-term clinical results with laser microsurgery were comparable to those with conventional surgery, especially when precise and conservative removal of periorificial lesions was required.

Growth rate of primary breast cancer and prognosis: observations on a 3- to 7-year follow-up in 180 breast cancers.

The disease-free probabilities after 3 to 7 years of follow-up of 180 breast cancers of known doubling times were studied to assess the prognostic significance and clinical implications of the growth characteristics of primary breast cancer. Fast-growing tumours, N+ greater than 3, showed a prognosis significantly worse (P less than 0.01) than that of slow-growing tumours of the same class; no significant differences were found among N- or N+ (1-3) fast-, intermediate- and slow-growing tumours. Highly significant differences were found among fast- and intermediate-growing tumours with different degrees of lymph node involvement (respectively P less than 0.0001 and P less than 0.001), with the worst prognosis for N+ greater than 3 tumours. In contrast, no significant differences were found among slow-growing tumours of the different N classes. When the Cox model was applied, the relationship between lymph node involvement and doubling time was significant, as was the interaction term. It is suggested that growth rate and metastatic potential are not the same in primary breast cancers, and their relation should be investigated.

Excision of oral leukoplakias by CO2 laser on an out-patient basis: a useful procedure for prevention and early detection of oral carcinomas.

Several epidemiologic studies have shown that oral cancer develops among individuals with a prior diagnosis of an oral premalignant lesion. Canceration chance in these patients is 17%, with the greatest rate occurring in the second year of observation. Based on this data, since 1981, 92 leukoplakias have been treated by out-patient laser surgery at the Istituto Nazionale Tumori of Milano. The therapeutic technique was laser excision to obtain a specimen for histology. Two groups were distinguished according to the diagnostic procedure. Thirty-three lesions (December 1981 to December 1982) were operated on without preliminary histologic examination, on the basis of a simple clinical diagnosis. Since January 1983 all leukoplakias have been biopsied in a systematic way and those negative for cancer treated with laser. Histology of the specimen showed 5 squamous cell carcinomas (15%) in the group of patients who did not undergo preoperative biopsy. Postoperative histology showed malignancy in 6 of 59 (10.2%) cases in spite of negative preoperative biopsies. Speckled and erosive leukoplakias had the highest canceration rate. Three of 11 patients with cancer were treated by knife excision or interstitial needle implantation because of margins in tumoral tissue or because they were not evaluable for injury by heat. Results have been satisfactory, only 2 of 54 followed leukoplakias and none of the cancers recurred during a 2 year follow-up.