A Retrospective Analysis of the Impact of HIV Infection on Outcomes of Locally Advanced Cervical Cancers Treated With Either Conventional or Hypofractionated Radiotherapy: The Uganda Experience.

PURPOSE: We annually treat more than 800 new patients with cervical cancer, where the majority (approximately 60%) have locally advanced disease and approximately 40% of them are infected with HIV. To optimally care for this large number of patients in low-income settings is difficult. From July 2011, we started using 45.0 Gy/15# hypofractionated radiotherapy (HFRT) as a substitute to 50.0 Gy/25# conventional fractionated radiotherapy (CFRT), for the treatment of locally advanced cervical cancer (LACC). This study aims at comparing the 5-year treatment outcomes between patients with LACC, known HIV serostatus, and treated with either CFRT or HFRT. METHODS: A retrospective study was conducted according to demographic/clinical data, radiotherapy fractionations, and outcomes. Factors considered were FIGO stages IIB-IIIB, known HIV serostatus, and had completed external-beam radiotherapy and intracavitary brachytherapy. The primary end point was overall survival; the secondary end points were toxicity and compliance. RESULTS: The study included 221 patients. Squamous cell carcinomas were 95.1% and adenocarcinomas 2.3%. The median age was 45.0 (interquartile range, 38.0-52.0) years. Stages IIB, IIIA, and IIIB were 38.9%, 6.3%, and 54.8%, respectively. HIV-positive and HIV-negative were 87 (39.4%) and 134 (60.6%), respectively. Chemoradiation was administered in 100 (45.2%), and 52 (52.0%) completed chemotherapy. CFRT/HFRT were 116 (52.5%)/105 (47.5%). At 24 months, the overall response was 54.1% for HIV-negative compared with 45.0% for HIV-positive (P value .262). There was no significant differences in acute/late toxicity grades ≥ 2 for HIV-negative/positive treated with HFRT/CFRT. At 60 months, the survival probabilities were 45.7% and 27.7% for HIV-negative and HIV-positive treated with CFRT (P value = .006), whereas it was 44.2% and 30.7% for HIV-negative and HIV-positive treated with HFRT (P value = .048), respectively. CONCLUSION: For the treatment of LACC with known HIV serology, there was no significant statistical difference in terms of response, toxicity, and compliance between CFRT and HFRT. However, the difference in overall survival between HIV-negative and HIV-positive was significant.

Chemoradiation versus radiation alone in stage IIIB cervical cancer patients with or without human immunodeficiency virus.

OBJECTIVE: Cervical cancer remains the most common cancer among women in sub-Saharan Africa and is also a leading cause of cancer related deaths among these women. The benefit of chemoradiation in comparison with radiation alone for patients with stage IIIB disease has not been evaluated prospectively in women living with human immunodeficiency virus (HIV). We assessed the survival of chemoradiation versus radiation alone among stage IIIB cervical cancer patients based on HIV status. METHODS: Between February 2013 and June 2018, patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IIIB cervical cancer with or without HIV and treated with chemoradiation or radiation alone, were prospectively enrolled in an observational cohort study. Overall survival was evaluated using the Kaplan-Meier method. Cox proportional hazards modeling was used to analyze associations with survival. RESULTS: Among 187 patients, 63% (n=118) of women had co-infection with HIV, and 48% (n=69) received chemoradiation. Regardless of HIV status, patients who received chemoradiation had improved 2 year overall survival compared with those receiving radiation alone (59% vs 41%, p<0.01), even among women living with HIV (60% vs 38%, p=0.02). On multivariable Cox regression analysis, including all patients regardless of HIV status, 2 year overall survival was associated with receipt of chemoradiation (hazard ratio (HR) 0.63, p=0.04) and total radiation dose ≥80 Gy (HR 0.57, p=0.02). Among patients who received an adequate radiation dose of ≥80 Gy, adjusted overall survival rates were similar between chemoradiation versus radiation alone groups (HR 1.07; p=0.90). However, patients who received an inadequate radiation dose of <80 Gy, adjusted survival was significantly higher in chemoradiation versus radiation alone group (HR 0.45, p=0.01). CONCLUSIONS: Addition of chemotherapy to standard radiation improved overall survival, regardless of HIV status, and is even more essential in women who cannot receive full doses of radiation.

Patterns of Care of Cancers and Radiotherapy in Ethiopia.

PURPOSE: Radiotherapy (RT) is an essential component of cancer treatment. There is a lack of RT services in sub-Saharan Africa as well as limited knowledge regarding clinical practices. The purpose of this study was to identify and describe the patterns for RT treatment in Ethiopia. METHODS AND MATERIALS: We performed a retrospective analysis of 1,823 patients treated with cobalt RT at a large referral hospital in Addis Ababa, Ethiopia, from May 2015 through January 2018. Paper charts were reviewed for patient and treatment characteristics. Descriptive statistics were computed using SPSS (IBM, Armonk, NY). RESULTS: Among patients treated for cancer, 98% (n = 1,784) were adults, 78% (n = 1,426) were female, 5% (n = 85) were HIV positive, 30% (n = 555) were from Addis Ababa, and the median age was 48 years (interquartile range [IQR], 38-58 years). Cervical cancer was the most frequent cancer treated (47%, n = 851), followed by breast cancer (15%, n = 274) and head and neck cancer (10%, n = 184). Seventy-three percent of patients (n = 1,339) presented at a late stage, and 62% (n = 1,138) received palliative RT. The wait times were the shortest for patients receiving palliative treatment (median, 0 days; IQR, 0-15 days; n = 1,138), whereas wait times were longer for patients receiving curative treatment (median, 150 days; IQR, 60-210 days; n = 685). Three percent of patients (n = 56) had documented grade 3 or 4 acute toxicity; of these, 59% (n = 33) were patients with head and neck cancer. CONCLUSION: Cervical cancer accounted for half of patients treated; thus, a majority of patients were adult females. Most patients had advanced-stage cancer, and goals of care were palliative. Wait times were long for patients with curative-intent cancer as a result of low capacity for RT services.

Radioimmunotherapy as a Novel Approach in HIV, Bacterial, and Fungal Infectious Diseases.

In the past several decades, many antimicrobial agents have been used in treating different fungal, bacterial, and viral infections. However, these agents have faced challenges such as pronounced side-effect profiles and pathogen resistance. In addition, a cure for many chronic infections such as human immunodeficiency virus (HIV) has not been achieved, and the incidence of opportunistic infections in immunocompromised patients has increased significantly in the past decades. Therefore, an alternative strategy for combating these infections is needed. Radioimmunotherapy (RIT) has been proposed to be a valuable tool in the management of such infections. The side-effects associated with RIT are minimal as the targeted antigens are only expressed on microbial or infected cells. RIT demonstrated impressive potency in eradicating pathogens in animal models and patient samples. Cryptococcus neoformans, HIV, and Bacillus anthracis are few examples of infections for which RIT has been an effective treatment using radionuclides such as bismuth-213 (213Bi) or rhenium-188 (188Re).

Potential of Radiation-Induced Cellular Stress for Reactivation of Latent HIV-1 and Killing of Infected Cells.

The use of highly active antiretroviral therapy against HIV-1 for last two decades has reduced mortality of patients through extension of nonsymptomatic phase of infection. However, HIV-1 can be preserved in long-lived resting CD4(+) T cells, which form a viral reservoir in infected individuals, and potentially in macrophages and astrocytes. Reactivation of viral replication is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus (shock and kill strategy). In this opinion piece, we consider potential application of therapeutic doses of irradiation, the well-known and effective stress signal that induces DNA damage and activates cellular stress response, to resolve two problems: activate HIV-1 replication and virion production in persistent reservoirs under cART and deplete infected cells through selective cell killing using DNA damage responses.

Factors affecting progression-free survival in non-HIV-related Kaposi sarcoma.

BACKGROUND: Non-HIV related Kaposi sarcoma (NHKS) is a rare indolent neoplasm which is more common around Mediterranean origin. Data concerning factors that influence progression-free survival (PFS) for NHKS are insufficient. The purpose of present retrospective analysis was to distinguish the factors affecting PFS in patients with NHKS. METHODS: A hundred and twenty-eight consecutive patients with NHKS who were treated or observed between 1997 and 2014 at Istanbul University Institute of Oncology were included into the study. Treatment response and progression definitions were determined according to different treatment modalities administered at first line. RESULTS: Majority of patients were male (n = 97, 75.8%). Median age of the whole group was 66 years (28-85). Of the patients, 15 patients were immunosuppressant, whereas 113 patients had no disease that caused immunosuppression. Patients were treated with local excision (n = 57, 44.5%), chemotherapy (n = 32, 25.0%) and/or radiotherapy (n = 13, 10.2%) or observed without treatment (n = 26, 20.3%). At a median follow-up of 28 months, 71 (55.5%) patients had progression, while 3 patients (2.3%) died of NHKS. On univariate analysis, patients who had hypertension (HT) had poorer PFS compared with others (19 ± 12 versus 41 ± 22 months; p = 0.03), whereas plaque formation was associated with better outcome (25 ± 9 versus 54 ± 12 months; p = 0.03). In addition, heavy smoking (≥40 pack-years) had a borderline significance regarding better PFS time (23 ± 24 versus 45 ± 38 months, p = 0.06). On multivariate analysis, none of factors evaluated had any impact on PFS. CONCLUSIONS: HT was correlated with poorer outcome among NHKS patients. Patients with plaque formation and ≥40 pack-years of smoking had better PFS than others.

Preclinical testing of radiopharmaceuticals for novel applications in HIV, bacterial and fungal infectious diseases.

Antibiotics, antifungal and antiviral medications have traditionally been used in the management of infections. Due to widespread emergence of resistance to antimicrobial medications, and their side effects, there is a growing need for alternative approaches for management of such conditions. Antibiotic resistant bacterial pathogens are on the rise. A cure has not been achieved for viral infections like AIDS, while fungal and parasitic infections are constant threats to the health of general public. The incidence of opportunistic infections in immunocompromised individuals like HIV patients, patients receiving high dose steroids, chemotherapy patients, and organ transplant recipients is on the rise. Radioimmunotherapy (RIT) has the potential to be a suitable and viable therapeutic modality in the arena of infection management. Provided the target-associated antigen is expressed by the target cells and minimally or not expressed by other tissues, selective targeting of radiation to target sites can be theoretically accomplished with relative sparing normal tissues from radiation exposure. In our laboratory we successfully demonstrated the effectiveness of RIT for treating infectious diseases. We targeted murine cryptococcosis with a mAb to the Cryptococcus neoformans capsular glucuronoxylomannan labeled with Bismuth-213 ((213)Bi) or Rhenium-188 ((188)Re). We subsequently extended the applicability of RIT for treating bacterial and viral infections. One of the advantages of using RIT to treat infections as opposed to cancer is that, in contrast to tumor cells, cells expressing microbial antigens are antigenically very different from host tissues and thus provide the potential for exquisite specificity and low cross-reactivity. Ever increasing incidence of infectious pathologies, exhaustion of antimicrobial possibilities and rising drug resistance calls for use of alternative and novel therapeutic options and we believe RIT is the need of the hour to combat these infections.

Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells.

The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4(+) T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4(+) T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4(+) T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the "Shock and Kill" strategy for latently HIV-1 infected cells.

The potential of radioimmunotherapy as a new hope for HIV patients.

HIV/AIDS remains an enormous public health burden. Advances in anti-retroviral therapy (ART) have greatly reduced mortality and morbidity but HIV remains incurable, with patients suffering numerous disease- and treatment-related side effects. Any curative strategy for HIV must selectively eliminate existing infected cells. Radioimmunotherapy (RIT) is an established clinical modality in cancer treatment and has been shown to be effective in multiple infectious diseases models. We have recently demonstrated that RIT using a gp41-targeting antibody was effective and safe in eliminating HIV-infected cells in vivo (in mice), in vitro, and ex vivo in cells from HIV patients treated with ART. In addition, there is strong evidence that this radiolabeled antibody can eliminate HIV infected cells across the blood brain barrier. We consider RIT to be the most promising backbone strategy for HIV eradication.

Acute toxicity of second generation HIV protease-inhibitors in combination with radiotherapy: a retrospective case series.

BACKGROUND: There is little data on the safety of combining radiation therapy and human immunodeficiency virus (HIV) protease inhibitors to treat cancers in HIV-positive patients. We describe acute toxicities observed in a series of HIV-positive patients receiving modern radiation treatments, and compare patients receiving HIV protease inhibitors (PI) with patients not receiving HIV PIs. METHODS: By reviewing the clinical records beginning January 1, 2009 from the radiation oncology department, we identified 29 HIV-positive patients who received radiation therapy to 34 body sites. Baseline information, treatment regimen, and toxicities were documented by review of medical records: patient age, histology and source of the primary tumor, HIV medication regimen, pre-radiation CD4 count, systemic chemotherapy, radiation therapy dose and fractionation, irradiated body region, toxicities, and duration of follow-up. Patients were grouped according to whether they received concurrent HIV PIs and compared using Pearson's chi-square test. RESULTS: At baseline, the patients in the two groups were similar with the exception of HIV medication regimens, CD4 count and presence of AIDS-defining malignancy. Patients taking concurrent PIs were more likely to be taking other HIV medications (p = 0.001) and have CD4 count >500 (p = 0.006). Patients taking PIs were borderline less likely to have an AIDS-defining malignancy (p = 0.06). After radiation treatment, 100 acute toxicities were observed and were equally common in both groups (64 [median 3 per patient, IQR 1-7] with PIs; 36 [median 3 per patient, IQR 2-3] without PIs). The observed toxicities were also equally severe in the two groups (Grades I, II, III respectively: 30, 30, 4 with PIs; 23, 13, 0 without PIs: p = 0.38). There were two cases that were stopped early, one in each group; these were not attributable to toxicity. CONCLUSIONS: In this study of recent radiotherapy in HIV-positive patients taking second generation PIs, no difference in toxicities was observed in patients taking PIs compared to patients not taking PIs during radiation therapy. This suggests that it is safe to use unmodified doses of PIs and radiation therapy in HIV cancer patients, and that it is feasible to use PIs as a radiosensitizer in cancer therapy, as has been suggested by pre-clinical results.

Sterilization of HIV with irradiation: relevance to infected bone allografts.

BACKGROUND: Bone allograft banks commonly sterilize frozen bone by irradiation. The dose-response relationship for HIV is calculated and the dose required to inactivate the bioburden of virus that may be present in allograft bone is determined. METHODS: A virus titre experiment is performed using irradiated frozen HIV. The virus is maintained on dry ice (approximately -70 degrees C) and is exposed to a cobalt 60 source with 0-40 kGy irradiation at 5 kGy intervals. Lymphocyte cell cultures are exposed to serial dilutions of the irradiated virus. The virus titre is quantified by cytological changes of HIV infection and p24 immunofluorescence. RESULTS: There is a linear relationship between the virus titre and the radiation dose delivered. The inactivation rate of irradiated virus was 0.1134 log10 tissue culture infective doses 50/mL per kGy (95% confidence intervals, 0.1248-0.1020). The irradiation dose required to inactivate the HIV bioburden in allograft bone is 35 kGy. The irradiation dose required to achieve a sterility assurance level of 10(-6) is 89 kGy. This dose exceeds current recommendations for sterilizing medical products and the current practice of many bone banks. CONCLUSIONS: It is concluded that gamma irradiation should be disregarded as a significant virus inactivation method for bone allografts.

Treatment of HIV infection with cytoreductive agents.

Advances in antiretroviral therapy have resulted in significant improvement in virological markers and clinical end points. However, studies have demonstrated that HIV can be recovered from patients in whom HIV RNA has been undetectable for prolonged periods of time, suggesting that the elimination half-life of latently infected cells may be longer than previously speculated. When used in the appropriate setting, cytoreductive agents may help expedite the elimination of the long-lived viral reservoir, and result in shorter administration of antiviral agents. In this article we discuss the potential use of cytoreductive agents as adjunctive therapy to antiretrovirals. In addition, we review those agents most likely to impact the viral reservoir and describe ongoing clinical trials designed to define the effect of cytoreductive therapy on those reservoirs. If a positive effect is demonstrated, these agents could ultimately be a powerful addition to the potent drugs currently being used to block HIV replication.

[Bullous skin reactions after soft roentgen radiotherapy of HIV-associated Kaposi sarcomas]. / Bullöse Hautreaktionen nach Röntgenweichstrahltherapie von HIV-assoziierten Kaposi-Sarkomen.

Fractionated irradiation with X-rays or megavoltage is an important therapeutic option in the palliative treatment of Kaposi's sarcoma. We report on three HIV patients demonstrating bullous cutaneous eruptions in the irradiation field. Three homosexual men (age 45-60 y) stage of disease CDC 3C, were treated with fractionated soft X-rays with the scheme conventionally used by us (total dose 30 Gy, single doses 3 Gy). Immediately to three days after completion of treatment large blisters appeared within the irradiation field, resolving after 2-4 weeks, leaving post-inflammatory hyperpigmentation. The cause of this rare reaction to soft X-ray therapy, potentially suggesting an individually altered radiation sensitivity, is so far unknown. Controlled prospective studies applying different fractionation schemes will be necessary to better elucidate this issue.

Analysis of the low-energy laser treatment of some cancers and infectious diseases.

In this article, the results of a 5-year investigation of low-energy laser therapy for the treatment of some oncological and infection diseases are presented. We used special infrared (IR) lasers with a wavelength of 890 nm in our investigations. All laser actions on organisms occurred through the skin only (a noninvasive method).

Splenic irradiation in HIV-related thrombocytopenia.

Splenic irradiation has been used in patients with HIV-related thrombocytopenia. This retrospective review deals with four patients treated with low dose splenic irradiation. All patients had an increase in platelet count and tolerated the treatment without side effects. However, the treatment response lasted for several months only.